Search

Your search keyword '"Philippe Jonveaux"' showing total 168 results
Start Over Author "Philippe Jonveaux"
168 results on '"Philippe Jonveaux"'

1. Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study

Author

Jean-Marie Ravel, Mathilde Renaud, Jean Muller, Aurélie Becker, Émeline Renard, Thomas Remen, Geneviève Lefort, Mylène Dexheimer, Philippe Jonveaux, Bruno Leheup, Céline Bonnet, and Laëtitia Lambert

Subjects
Array-CGH, Copy-number variation, CNV, VUS reinterpretation, ACMG criteria, Medicine, Genetics, QH426-470
Abstract

Abstract Background Array-CGH is the first-tier genetic test both in pre- and postnatal developmental disorders worldwide. Variants of uncertain significance (VUS) represent around 10~15% of reported copy number variants (CNVs). Even though VUS reanalysis has become usual in practice, no long-term study regarding CNV reinterpretation has been reported. Methods This retrospective study examined 1641 CGH arrays performed over 8 years (2010–2017) to demonstrate the contribution of periodically re-analyzing CNVs of uncertain significance. CNVs were classified using AnnotSV on the one hand and manually curated on the other hand. The classification was based on the 2020 American College of Medical Genetics (ACMG) criteria. Results Of the 1641 array-CGH analyzed, 259 (15.7%) showed at least one CNV initially reported as of uncertain significance. After reinterpretation, 106 of the 259 patients (40.9%) changed categories, and 12 of 259 (4.6%) had a VUS reclassified to likely pathogenic or pathogenic. Six were predisposing factors for neurodevelopmental disorder/autism spectrum disorder (ASD). CNV type (gain or loss) does not seem to impact the reclassification rate, unlike the length of the CNV: 75% of CNVs downgraded to benign or likely benign are less than 500 kb in size. Conclusions This study’s high rate of reinterpretation suggests that CNV interpretation has rapidly evolved since 2010, thanks to the continuous enrichment of available databases. The reinterpreted CNV explained the phenotype for ten patients, leading to optimal genetic counseling. These findings suggest that CNVs should be reinterpreted at least every 2 years.

Published
2023
Full Text
View/download PDF

2. Higher risk of pre-eclampsia and other vascular disorders with artificial cycle for frozen-thawed embryo transfer compared to ovulatory cycle or to fresh embryo transfer following in vitro fertilization

Author

Sylvie Epelboin, Julie Labrosse, Jacques De Mouzon, Aviva Devaux, Marie-José Gervoise-Boyer, Laetitia Hesters, Philippe Jonveaux, Rachel Levy, Nathalie Sermondade, Patricia Fauque, and Fabienne Pessione

Subjects
pre-eclampsia, artificial cycle, ovulatory cycle, frozen embryo transfer, fresh embryo transfer, endometrial preparation, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

BackgroundRisks of maternal morbidity are known to be reduced in pregnancies resulting from frozen embryo transfer (FET) compared to fresh-embryo transfer (fresh-ET), except for the risk of pre-eclampsia, reported to be higher in FET pregnancies compared to fresh-ET or natural conception. Few studies have compared the risk of maternal vascular morbidities according to endometrial preparation for FET, either with ovulatory cycle (OC-FET) or artificial cycle (AC-FET). Furthermore, maternal pre-eclampsia could be associated with subsequent vascular disorders in the offspring.MethodsA 2013-2018 French nationwide cohort study comparing maternal vascular morbidities in 3 groups of single pregnancies was conducted: FET with either OC or AC preparation, and fresh-ET. Data were extracted from the French National Health System database. Results were adjusted for maternal characteristics and infertility (age, parity, smoking, obesity, history of diabetes or hypertension, endometriosis, polycystic ovary syndrome and premature ovarian insufficiency).ResultsA total of 68025 single deliveries were included: fresh-ET (n=48152), OC-FET (n=9500), AC-FET (n=10373). The risk of pre-eclampsia was higher in AC-FET compared to OC-FET and fresh-ET groups in univariate analysis (5.3% vs. 2.3% and 2.4%, respectively, P

Published
2023
Full Text
View/download PDF

3. Obstetrical outcomes and maternal morbidities associated with COVID-19 in pregnant women in France: A national retrospective cohort study.

Author

Sylvie Epelboin, Julie Labrosse, Jacques De Mouzon, Patricia Fauque, Marie-José Gervoise-Boyer, Rachel Levy, Nathalie Sermondade, Laetitia Hesters, Marianne Bergère, Claire Devienne, Philippe Jonveaux, Jade Ghosn, and Fabienne Pessione

Subjects
Medicine
Abstract

BackgroundTo the best of our knowledge, no study has exhaustively evaluated the association between maternal morbidities and Coronavirus Disease 2019 (COVID-19) during the first wave of the pandemic in pregnant women. We investigated, in natural conceptions and assisted reproductive technique (ART) pregnancies, whether maternal morbidities were more frequent in pregnant women with COVID-19 diagnosis compared to pregnant women without COVID-19 diagnosis during the first wave of the COVID-19 pandemic.Methods and findingsWe conducted a retrospective analysis of prospectively collected data in a national cohort of all hospitalizations for births ≥22 weeks of gestation in France from January to June 2020 using the French national hospitalization database (PMSI). Pregnant women with COVID-19 were identified if they had been recorded in the database using the ICD-10 (International Classification of Disease) code for presence of a hospitalization for COVID-19. A total of 244,645 births were included, of which 874 (0.36%) in the COVID-19 group. Maternal morbidities and adverse obstetrical outcomes among those with or without COVID-19 were analyzed with a multivariable logistic regression model adjusted on patient characteristics. Among pregnant women, older age (31.1 (±5.9) years old versus 30.5 (±5.4) years old, respectively, p < 0.001), obesity (0.7% versus 0.3%, respectively, p < 0.001), multiple pregnancy (0.7% versus 0.4%, respectively, p < 0.001), and history of hypertension (0.9% versus 0.3%, respectively, p < 0.001) were more frequent with COVID-19 diagnosis. Active smoking (0.2% versus 0.4%, respectively, p < 0.001) and primiparity (0.3% versus 0.4%, respectively, p < 0.03) were less frequent with COVID-19 diagnosis. Frequency of ART conception was not different between those with and without COVID-19 diagnosis (p = 0.28). When compared to the non-COVID-19 group, women in the COVID-19 group had a higher frequency of admission to ICU (5.9% versus 0.1%, p < 0.001), mortality (0.2% versus 0.005%, p < 0.001), preeclampsia/eclampsia (4.8% versus 2.2%, p < 0.001), gestational hypertension (2.3% versus 1.3%, p < 0.03), postpartum hemorrhage (10.0% versus 5.7%, p < 0.001), preterm birth at ConclusionsWe observed an increased frequency of pregnant women with maternal morbidities and diagnosis of COVID-19 compared to pregnant women without COVID-19. It appears essential to be aware of this, notably in populations at known risk of developing a more severe form of infection or obstetrical morbidities and in order for obstetrical units to better inform pregnant women and provide the best care. Although causality cannot be determined from these associations, these results may be in line with recent recommendations in favor of vaccination for pregnant women.

Published
2021
Full Text
View/download PDF

6. The 'extreme phenotype approach' applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles

Author

Martin Chevarin, Diana Alcantara, Juliette Albuisson, Marie-Agnès Collonge-Rame, Céline Populaire, Zohair Selmani, Amandine Baurand, Caroline Sawka, Geoffrey Bertolone, Patrick Callier, Yannis Duffourd, Philippe Jonveaux, Yves-Jean Bignon, Isabelle Coupier, François Cornelis, Christophe Cordier, Monique Mozelle-Nivoix, Jean-Baptiste Rivière, Paul Kuentz, Christel Thauvin, Romain Boidot, François Ghiringhelli, Marc O'Driscoll, Laurence Faivre, and Sophie Nambot

Subjects
Oncology
Published
2023

7. Putative founder effect of Arg338* <scp> AP4M1 </scp> ( <scp>SPG50</scp> ) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families

Author

Aurélie Becker, Charlotte Felici, Laëtitia Lambert, Anne de Saint Martin, Marie‐Thérèse Abi‐Warde, Elise Schaefer, Christian Zix, Mina Zamani, Saeid Sadeghian, Jawaher Zeighami, Tahereh Seifi, Reza Azizimalamiri, Gholamreza Shariati, Hamid Galehdari, Mareike Selig, Can Ding, Sarah Duerinckx, Isabelle Pirson, Marc Abramowicz, Guillemette Clément, Bruno Leheup, Philippe Jonveaux, Geneviève Lefort, Myriam Bronner, Mathilde Renaud, and Céline Bonnet

Subjects
Genetics, Genetics (clinical)
Abstract

Bi-allelic variants affecting one of the four genes encoding the AP4 subunits are responsible for the "AP4 deficiency syndrome." Core features include hypotonia that progresses to hypertonia and spastic paraplegia, intellectual disability, postnatal microcephaly, epilepsy, and neuroimaging features. Namely, AP4M1 (SPG50) is involved in autosomal recessive spastic paraplegia 50 (MIM#612936). We report on three patients with core features from three unrelated consanguineous families originating from the Middle East. Exome sequencing identified the same homozygous nonsense variant: NM_004722.4(AP4M1):c.1012CT p.Arg338* (rs146262009). So far, four patients from three other families carrying this homozygous variant have been reported worldwide. We describe their phenotype and compare it to the phenotype of patients with other variants in AP4M1. We construct a shared single-nucleotide polymorphism (SNP) haplotype around AP4M1 in four families and suggest a probable founder effect of Arg338* AP4M1 variant with a common ancestor most likely of Turkish origin.

Published
2022

11. Endometriosis and assisted reproductive techniques independently related to mother–child morbidities: a French longitudinal national study

Author

Marie-José Gervoise-Boyer, Marianne Bergere, A. Devaux, Julie Labrosse, Claire de Vienne, Philippe Jonveaux, Sylvie Epelboin, Patricia Fauque, Jacques de Mouzon, Fabienne Pessione, and Rachel Levy

Subjects
Adult, 0301 basic medicine, Infertility, medicine.medical_specialty, Reproductive Techniques, Assisted, medicine.medical_treatment, Endometriosis, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Prevalence, Humans, Medicine, Longitudinal Studies, Risk factor, Fetus, 030219 obstetrics & reproductive medicine, Assisted reproductive technology, business.industry, Obstetrics, Infant, Newborn, Obstetrics and Gynecology, medicine.disease, Pregnancy Complications, 030104 developmental biology, Reproductive Medicine, Premature birth, Infant, Small for Gestational Age, National study, Female, France, business, Developmental Biology, Cohort study
Abstract

Does endometriosis increase obstetric and neonatal complications, and does assisted reproductive technology (ART) cause additional risk of maternal or fetal morbidity?A nationwide cohort study (2013-2018) comparing maternal and perinatal morbidities in three groups of single pregnancies: spontaneous pregnancies without endometriosis; spontaneous pregnancies with endometriosis; and ART pregnancies in women with endometriosis.Mean maternal ages were 30.0 (SD = 5.3), 31.7 (SD = 4.8) and 33.1 years (SD = 4.0), for spontaneous conceptions, spontaneous conceptions with endometriosis and ART pregnancies with endometriosis groups, respectively (P0.0001). Comparison of spontaneous conceptions with endometriosis and spontaneous conceptions: endometriosis independently increased the risk of venous thrombosis (adjusted OR [aOR] 1.51, P0.001), pre-eclampsia (aOR 1.29, P0.001), placenta previa (aOR 2.62, P0.001), placental abruption (aOR 1.54, P0.001), premature birth (aOR 1.37, P0.001), small for gestational age (aOR 1.05, P0.001) and malformations (aOR 1.06, P = 0.049). Comparison of ART pregnancies with endometriosis and spontaneous conceptions with endometriosis: ART increased the risk of placenta previa (aOR 2.43, 95% CI 2.10 to 2.82, P0.001), premature birth (aOR 1.42, 95% CI 1.29 to 1.55, P0.001) and small for gestational age (aOR 1.18, 95% CI 1.10 to 1.27, P0.001), independently from the effect of endometriosis. Risk of pre-eclampsia, placental abruption or congenital malformations was not increased with ART.Endometriosis is an independent risk factor for mother and child morbidities. Maternal morbidity and perinatal morbidity were significantly increased by ART in addition to endometriosis; however, some perinatal and maternal morbidity risks were increasingly linked to pathologies related to infertility.

Published
2021

12. Doin vitrofertilization, intrauterine insemination or female infertility impact the risk of congenital anomalies in singletons? A longitudinal national French study

Author

G. Viot, Jacques de Mouzon, Marie-José Gervoise-Boyer, Sylvie Epelboin, Fabienne Pessione, A. Devaux, Philippe Jonveaux, Patricia Fauque, Marianne Bergere, Morgane Valentin, Rachel Levy, and Claire de Vienne

Subjects
Male, Infertility, medicine.medical_specialty, Cleft Lip, Endometriosis, Fertilization in Vitro, Insemination, Male infertility, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, 030212 general & internal medicine, Child, Retrospective Studies, 030219 obstetrics & reproductive medicine, business.industry, Obstetrics, Rehabilitation, Female infertility, Infant, Newborn, Infant, Obstetrics and Gynecology, Odds ratio, medicine.disease, Polycystic ovary, Cleft Palate, Reproductive Medicine, Child, Preschool, Cohort, Female, France, business, Risk assessment, Infertility, Female
Abstract

STUDY QUESTIONDo IVF, IUI or female infertility (i.e. endometriosis, polycystic ovary syndrome [PCOS] and primary ovarian insufficiency [POI]) lead to an increased risk of congenital anomalies in singletons?SUMMARY ANSWERAfter multivariable adjustments, the increased risks of congenital defects associated with IUI were no longer significant, but the underlying maternal infertility presented a potential emental risk, in addition to the risk associated with IVF.WHAT IS KNOWN ALREADYMost epidemiological studies suggest that singletons born from ART have a higher risk of birth defects, specifically musculoskeletal, cardiovascular and urogenital disorders. However, most of these studies were established on data obtained at birth or in the neonatal period and from relatively small populations or several registries. Moreover, to our knowledge, female infertility, which is a potential confounder, has never been included in the risk assessment.STUDY DESIGN, SIZE, DURATIONUsing data from the French National Health System database, we conducted a comparative analysis of all singleton births (deliveries ≥22 weeks of gestation and/or >500 g of birthweight) in France over a 5-year period (2013–2017) resulting from fresh embryo or frozen embryo transfer (fresh-ET or FET from IVF/ICSI cycles), IUI and natural conception (NC). Data were available for this cohort of children at least up to early childhood (2.5 years old).PARTICIPANTS/MATERIALS, SETTING, METHODSA total of 3 501 495 singleton births were included (3 417 089 from NC, 20 218 from IUI, 45 303 from fresh-ET and 18 885 from FET). Data were extracted from national health databases and used to identify major birth defects. Malformations were classified according to the 10th revision of the International Classification of Disease. To analyse the effect of mode of conception, multivariable analyses were performed with multiple logistic regression models adjusted for maternal age, primiparity, obesity, smoking, history of high blood pressure or diabetes and female infertility.MAIN RESULTS AND THE ROLE OF CHANCEIn our cohort of children, the overall prevalence of congenital malformations was 3.78% after NC, 4.53% after fresh-ET, 4.39% after FET and 3.91% after IUI (132 646 children with major malformations). Compared with infants conceived naturally, children born after fresh-ET and after FET had a significantly higher prevalence of malformations, with an adjusted odds ratio (aOR) of 1.15 [95% CI 1.10–1.20, P LIMITATIONS, REASONS FOR CAUTIONMale infertility, the in vitro fertilization method (i.e. in vitro fertilization without or with sperm injection: conventional IVF vs ICSI) and embryo stage at transfer could not be taken into account. Furthermore, residual confounding cannot be excluded as well as uncertainties regarding the diagnostic criteria used for the three female infertilities. Findings for specific malformations should be interpreted with caution because the number of cases was small in some sub-groups (potentially due to the Type I error or multiple testing).WIDER IMPLICATIONS OF THE FINDINGSIn this large study, after multivariable maternal adjustments, a moderately increased risk of defects subsisted after IVF, while those associated with IUI were no longer significant. In addition, our results showed that underlying maternal infertility could contribute to the increased risk of defects associated with IVF. These novel findings highlight the importance of taking into account the ART treatment methods and the type of infertility.STUDY FUNDING/COMPETING INTEREST(s)This work was supported by the National Agency of Biomedicine. The authors have no competing interests to disclose.TRIAL REGISTRATION NUMBERNA.

Published
2020

14. Risques de morbidité maternelle et périnatale en fécondation in vitro : une étude nationale de cohorte française

Author

Morgane Valentin, Marie-José Gervoise-Boyer, Fabienne Pessione, Philippe Jonveaux, G. Viot, Rachel Levy, Sylvie Epelboin, Marianne Bergere, A. Deveaux, J. De Mouzon, C. Jimenez, and F. Merlet

Subjects
Gynecology, medicine.medical_specialty, Reproductive Medicine, business.industry, Obstetrics and Gynecology, Medicine, business
Abstract

Resume Objectifs L’objectif de cette etude etait de quantifier les risques de morbidite maternelle et perinatale en fecondation in vitro (FIV) par rapport aux grossesses non issues de FIV sur une cohorte nationale francaise recente. Methode Les donnees etaient issues du systeme d’information des donnees d’hospitalisation incluant toutes les grossesses ayant conduit a un accouchement et les naissances de 2013 a 2016. Les risques d’accouchement premature, de morbidite maternelle (thrombose veineuse et arterielle, diabete gestationnel, troubles vasculaires, placenta praevia, hematome retroplacentaire), d’hypotrophie et de malformation congenitale ont ete compares entre les deux groupes en analyse univariee et multivariee apres ajustement sur les caracteristiques des femmes (l’âge, la primiparite, l’obesite, la dependance au tabac, les antecedents de diabete ou d’hypertension arterielle), les accouchements multiples et le sexe des enfants. Resultats Au total, 2 875 662 grossesses ayant conduit a un accouchement et 2 922 712 naissances ont ete analysees, dont 49 224 (1,7 %) issues de FIV avec transfert d’embryons frais. En analyse multivariee, tous les risques de morbidite etaient significativement plus eleves en FIV : les accouchements prematures (ORajuste = 1,28 ; IC95 % = 1,24–1,32), la morbidite maternelle (ORajuste = 1,24 ; IC95 % = 1,21–2,28) (principalement pour les thromboses veineuses dans les accouchements multiples, le placenta praevia et les hematomes retroplacentaires). Les risques d’hypotrophie (ORajuste = 1,13 ; IC95 % = 1,10–1,16) et de malformations congenitales (ORajuste = 1,11 ; IC95 % = 1,05–1,17) etaient faiblement augmentes. Conclusion Les resultats de cette premiere etude portant sur un large effectif de naissances recentes en France confirment qu’il existait une augmentation des risques de morbidite maternelle et perinatale en FIV. Ces risques etaient comparables a ceux publies dans la litterature internationale. Cette etude constitue le point de depart d’une surveillance de la morbidite maternelle et perinatale en FIV.

Published
2020

15. O-182 Higher risk of preeclampsia and pregnancy-induced hypertension with artificial cycle for Frozen-thawed Embryo Transfer compared to ovulatory cycle or fresh transfer following In Vitro Fertilization

Author

J. de Mouzon, Marianne Bergere, Rachel Levy, Fabienne Pessione, Philippe Jonveaux, Morgane Valentin, Sylvie Epelboin, Patricia Fauque, Julie Labrosse, L Hester, C. De Vienne, M Boyer, A. Devaux, and Nathalie Sermondade

Subjects
Pregnancy, In vitro fertilisation, Eclampsia, medicine.medical_treatment, Rehabilitation, Obstetrics and Gynecology, Embryo, Luteal phase, Biology, medicine.disease, Embryo transfer, Preeclampsia, Andrology, Human fertilization, Reproductive Medicine, medicine
Abstract

Study question Is there an increased risk of preeclampsia after Frozen-thawed Embryo Transfer(FET) compared to In Vitro Fertilization-fresh transfer(IVF-fresh-ET) according to endometrial type of preparation for FET? Summary answer The frequency of preeclampsia and hypertension were significantly higher in the group of artificial cycle (AC-FET) compared to ovulatory cycle (OC-FET) and fresh-ET (P What is known already Risks of maternal morbidity are known to be reduced in pregnancies resulting from FET compared to fresh-ET except for the risk of preeclampsia, that was reported to be significantly higher in pregnancies resulting from FET compared to fresh-ET or spontaneous conception. Most recent studies demonstrate an equal live birth rate with either OC-FET or AC-FET preparation. Few studies compared the maternal vascular morbidities with the two hormonal environments that preside over the early stages of embryonic development: OC (major role of the corpus luteum) and AC (prolonged hormone replacement with high doses of estrogen and progesterone). Study design, size, duration We conducted a 2013-2018 French nationwide cohort study comparing maternal vascular morbidities in 3 groups of single pregnancies> 22 weeks of gestation (WG): FET with AC or OC preparation, and IVF (conventional or ICSI)-fresh-ET.Data were extracted from the French National Health System database (>99% of national deliveries) in which all hospitalizations are registered, containing information on patient characteristics, diagnoses and treatments. Records were merged anonymously. Access to the database was legally approved. Participants/materials, setting, methods 68 025 deliveries were included: fresh-ET(n = 48 152), OC-FET(n = 9 500), AC-FET(n = 10 373). In OC-FET, a luteal phase support with progesterone was administered for maximum 6 WG if pregnancy. In AC-FET, progesterone was co-administered with estrogen until 12 WG. Embryos were transferred at cleavage or blastocyst stage. Vascular disorders were recorded if hospitalization for preeclampsia/eclampsia or hypertension (history of hypertension excluded). Maternal characteristics were included in multivariate analysis. Adjusted odds ratios(aOR) and 95% confidence intervals(CI) were estimated. Main results and the role of chance Maternal characteristics: In multivariate analysis, patients in the FET groups were older (33.4 years (std=4.3) vs. 33.2 years (std=4.4) for fresh-ET, respectively, P In FET groups, 52.2% were AC-FET. There was no difference for maternal age, parity, obesity, smoking, history of diabetes between AC and OC-FET. Endometriosis (aOR=1.26[1.16-1.38]), PCOS (aOR=1.79[1.50-2.15]) and POI (aOR=2.0[1.48-2.72]) were more frequent in AC-FET. Risks of vascular disorders The rate of preeclampsia (5.3% vs. 2.3% vs. 2.4%, respectively, P In multivariate analysis, the risk of preeclampsia increased with age, primiparity, obesity, diabetes and POI. The risk was higher in AC-FET versus OC-FET (aOR=2.42 [2.06-2.85]) and fresh-ET (aOR=2.43[2.2-2.7]), P 40, primiparity, smoking, obesity and diabetes and was higher in AC-FET versus OC-FET (aOR=1.50[1.29-1.74], P Limitations, reasons for caution While the strength of this study relies in the number and exhaustiveness of subjects analysed, its limitations are its retrospective and register-based nature that did not enable to refine the risk according to details of techniques and treatments in each group. Wider implications of the findings This large nationwide cohort study highlights 2 important information for physicians : i) the possible deleterious role of high supra-physiological and prolonged doses of estrogen-progesterone supplementation on vascular pathologies ii) the protective role of the corpus luteum present in stimulated or spontaneous OC for their prevention. Trial registration number Not applicable

Published
2021

16. Reproductive technologies, female infertility, and the risk of imprinting-related disorders

Author

Marie-José Gervoise-Boyer, Morgane Valentin, Sylvie Epelboin, Claire de Vienne, Patricia Fauque, Philippe Jonveaux, G. Viot, A. Devaux, Jacques de Mouzon, Fabienne Pessione, Rachel Levy, and Arianne Bergère

Subjects
0301 basic medicine, Epigenomics, Male, medicine.medical_treatment, Endometriosis, Reproductive technology, Infant, Newborn, Diseases, Cohort Studies, 0302 clinical medicine, Neonatal diabetes mellitus, Pregnancy, Risk Factors, Female infertility, Prospective Studies, Epigenetic diseases, Child, Children, Genetics (clinical), 030219 obstetrics & reproductive medicine, Obstetrics, Middle Aged, Embryo transfer, Female, France, Assisted reproductive technologies, Infertility, Female, Adult, medicine.medical_specialty, Reproductive Techniques, Assisted, Fertilization in Vitro, 03 medical and health sciences, Genomic Imprinting, Genetics, medicine, Humans, Advanced maternal age, Molecular Biology, Singletons, In vitro fertilisation, business.industry, Research, Infant, Newborn, DNA Methylation, medicine.disease, Embryo Transfer, 030104 developmental biology, Case-Control Studies, Genomic imprinting, business, Developmental Biology
Abstract

Background Epidemiological studies suggest that singletons born from assisted reproductive technologies (ART) have a high risk of adverse perinatal outcomes, specifically for imprinting disorders. Because ART processes take place at times when epigenetic reprogramming/imprinting are occurring, there is concern that ART can affect genomic imprints. However, little is currently known about the risk of imprinting defects according to the type of ART or the type of underlying female infertility. From the French national health database, a cohort of 3,501,495 singletons born over a 5-year period (2013–2017) following fresh embryo or frozen embryo transfers (fresh-ET or FET from in vitro fertilization), intrauterine insemination, or natural conception was followed up to early childhood. Based on clinical features, several syndromes/diseases involving imprinted genes were monitored. The effects of ART conception and the underlying cause of female infertility were assessed. Results Compared with infants conceived naturally, children born after fresh-ET had a higher prevalence of imprinting-related diseases, with an aOR of 1.43 [95% CI 1.13–1.81, p = 0.003]. Namely, we observed an increased risk of neonatal diabetes mellitus (1.96 aOR [95% CI 1.43–2.70], p p = 0.02). Young and advanced maternal age, primiparity, obesity, smoking, and history of high blood pressure or diabetes were also associated with high global risk. Conclusions This prospective epidemiological study showed that the risk of clinically diagnosed imprinting-related diseases is increased in children conceived after fresh embryo transfers or from mothers with endometriosis. The increased perturbations in genomic imprinting could be caused by controlled ovarian hyperstimulation and potentially endometriosis through the impairment of endometrial receptivity and placentation, leading to epigenetic feto-placental changes. Further studies are now needed to improve understanding of the underlying molecular mechanisms (i.e. genetic or epigenetic causes).

Published
2020

17. Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations

Author

Tania Attié-Bitach, Philippe Jonveaux, Alice Goldenberg, Antonio Vitobello, Nicole Laurent, Marjolaine Willems, Valérie Kremer, Dominique Gaillard, Chloé Quélin, Sebastien Moutton, Marion Aubert-Lenoir, Yannis Duffourd, Anne-Sophie Lebre, Anne-Claire Brehin, James Lespinasse, Yline Capri, Nolwenn Jean-Marçais, Maria Cristina Antal, Frédéric Tran Mau-Them, Nathalie Marle, Daphné Lehalle, Nicolas Bourgon, Sophie Blesson, Bernard Foliguet, Laetita Lambert, Nicole Bigi, Mélanie Fradin, Emilie Tisserant, Christel Thauvin-Robinet, Ange-Line Bruel, Elisabeth Alanio, Marie-Hélène Saint-Frison, Christine Francannet, Anne-Marie Guerrot, Paul Kuentz, Elise Schaefer, Anne-Marie Beaufrere, Sylvie Odent, Francine Arbez-Gindre, Laurence Faivre, Christophe Philippe, Julien Thevenon, Sophie Patrier-Sallebert, Nada Houcinat, Celine Poirisier, Sophie Nambot, Mathilde Lefebvre, Mirna Assoum, Françoise Girard-Lemaitre, Sophie Collardeau-Frachon, Marie-José Perez, Jean-Louis Mandel, Jean-Pierre Mazutti, Renaud Touraine, Philippe Loget, Salima El Chehadeh, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CHU Strasbourg, Hôpital de Hautepierre [Strasbourg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), European Organization for Nuclear Research (CERN), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Anatomie pathologique [CHRU Besançon], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pontchaillou [Rennes], Hôpital Lapeyronie [Montpellier] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Biomécanique Humaine Georges Charpak (IBHGC), Université Sorbonne Paris Nord-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, CHU Rouen, Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Métropole Savoie [Chambéry], CHU Saint-Etienne, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Robert Debré, Plateau technique de Biologie [CHU de Dijon], Centre Hospitalier Universitaire [Grenoble] (CHU), CarMeN, laboratoire, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 14-013 FOETEX, Interregional French PHRC, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Candidate gene, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], Biology, Congenital Abnormalities, Cohort Studies, complex traits, 03 medical and health sciences, Fetus, Molecular genetics, medicine, Humans, Abnormalities, Multiple, Exome, Clinical significance, genetics, Gene, Genetic Association Studies, Genetics (clinical), Exome sequencing, 030304 developmental biology, Genetics, 0303 health sciences, 030305 genetics & heredity, Sequence Analysis, DNA, Phenotype, [SDV] Life Sciences [q-bio], molecular genetics, reproductive medicine
Abstract

PurposeMolecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.MethodsWe performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.ResultssES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).ConclusionsThis method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.

Published
2020

18. Assessment of chimerism and immunomodulation to prevent post-transplantation relapse in childhood acute myeloblastic leukemia: is it the right approach?

Author

Catherine Paillard, Cécile Pochon, Gilbert Semana, Virginie Gandemer, Regis Peffault de la Tour, Séverine Drunat, Yves Bertrand, Philippe Jonveaux, Pierre Bordigoni, Claire Galambrun, Pauline Simon, Pascale Schneider, Claire Freycon, Elie Cousin, Jean-François Eliaou, Emmanuel Oger, Pierre Rohrlich, Bénédicte Bruno, Sophie Pertuisel, Jean-Hugues Dalle, and Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)

Subjects
Oncology, Male, medicine.medical_specialty, Acute myeloblastic leukemia, medicine.medical_treatment, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Recurrence, hemic and lymphatic diseases, Internal medicine, Medicine, Humans, Prospective Studies, Child, neoplasms, ComputingMilieux_MISCELLANEOUS, Transplantation Chimera, business.industry, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Childhood Acute Myeloblastic Leukemia, Immunotherapy, medicine.disease, Allografts, Post transplant, Tissue Donors, 3. Good health, Transplantation, Haematopoiesis, Leukemia, Myeloid, Acute, surgical procedures, operative, 030220 oncology & carcinogenesis, Lymphocyte Transfusion, Pediatrics, Perinatology and Child Health, Cyclosporine, Female, business, Complication, 030215 immunology
Abstract

Relapse of acute myeloblastic leukemia (AML) after first allogenic hematopoietic stem-cell transplantation (allo-HSCT) is a fatal complication. Sixty-five children transplanted for AML were included in a prospective national study from June 2005 to July 2008 to explore the feasibility of preemptive immune modulation based on the monitoring of blood chimerism. Relapse occurred in 23 patients (35%). The median time between the last complete chimerism and relapse was 13.5 days (2-138). Prompt discontinuation of cyclosporin and the administration of donor lymphocyte infusions (DLIs) based on chimerism monitoring failed as a preemptive tool, either for detecting relapse or certifying long-term remission.

Published
2020

19. Obstetrical outcomes and maternal morbidities associated with COVID-19 in pregnant women in France: A national retrospective cohort study

Author

Philippe Jonveaux, Marianne Bergere, Julie Labrosse, Jade Ghosn, Patricia Fauque, Laetitia Hesters, Claire Devienne, Marie-José Gervoise-Boyer, Sylvie Epelboin, Fabienne Pessione, Rachel Levy, Nathalie Sermondade, Jacques de Mouzon, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unilabs Private Laboratory Group, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Joseph [Marseille], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Agence de la biomédecine [Saint-Denis la Plaine], Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, and HAL-SU, Gestionnaire

Subjects
Gestational hypertension, Viral Diseases, Epidemiology, Maternal Health, Blood Pressure, Vascular Medicine, Assisted Reproductive Technology, Fetal Distress, Medical Conditions, 0302 clinical medicine, Pre-Eclampsia, Pregnancy, Medicine and Health Sciences, Fetal distress, Hypertensive disorders in pregnancy, 030212 general & internal medicine, Gestational diabetes, 2. Zero hunger, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Obstetrics, Pregnancy Outcome, Obstetrics and Gynecology, General Medicine, 3. Good health, Intensive Care Units, Infectious Diseases, Maternal Mortality, Hypertension, Premature Birth, Medicine, Gestation, Female, France, COVID 19, Research Article, Adult, medicine.medical_specialty, Preeclampsia, 03 medical and health sciences, medicine, Humans, Obesity, Pandemics, Retrospective Studies, 030304 developmental biology, Eclampsia, Cesarean Section, SARS-CoV-2, business.industry, Postpartum Hemorrhage, Infant, Newborn, COVID-19, Preterm birth, Retrospective cohort study, Hypertension, Pregnancy-Induced, medicine.disease, Pregnancy Complications, Health Care, Diabetes, Gestational, Medical risk factors, Logistic Models, Birth, Women's Health, Pregnant Women, Health Statistics, Morbidity, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background To the best of our knowledge, no study has exhaustively evaluated the association between maternal morbidities and Coronavirus Disease 2019 (COVID-19) during the first wave of the pandemic in pregnant women. We investigated, in natural conceptions and assisted reproductive technique (ART) pregnancies, whether maternal morbidities were more frequent in pregnant women with COVID-19 diagnosis compared to pregnant women without COVID-19 diagnosis during the first wave of the COVID-19 pandemic. Methods and findings We conducted a retrospective analysis of prospectively collected data in a national cohort of all hospitalizations for births ≥22 weeks of gestation in France from January to June 2020 using the French national hospitalization database (PMSI). Pregnant women with COVID-19 were identified if they had been recorded in the database using the ICD-10 (International Classification of Disease) code for presence of a hospitalization for COVID-19. A total of 244,645 births were included, of which 874 (0.36%) in the COVID-19 group. Maternal morbidities and adverse obstetrical outcomes among those with or without COVID-19 were analyzed with a multivariable logistic regression model adjusted on patient characteristics. Among pregnant women, older age (31.1 (±5.9) years old versus 30.5 (±5.4) years old, respectively, p < 0.001), obesity (0.7% versus 0.3%, respectively, p < 0.001), multiple pregnancy (0.7% versus 0.4%, respectively, p < 0.001), and history of hypertension (0.9% versus 0.3%, respectively, p < 0.001) were more frequent with COVID-19 diagnosis. Active smoking (0.2% versus 0.4%, respectively, p < 0.001) and primiparity (0.3% versus 0.4%, respectively, p < 0.03) were less frequent with COVID-19 diagnosis. Frequency of ART conception was not different between those with and without COVID-19 diagnosis (p = 0.28). When compared to the non-COVID-19 group, women in the COVID-19 group had a higher frequency of admission to ICU (5.9% versus 0.1%, p < 0.001), mortality (0.2% versus 0.005%, p < 0.001), preeclampsia/eclampsia (4.8% versus 2.2%, p < 0.001), gestational hypertension (2.3% versus 1.3%, p < 0.03), postpartum hemorrhage (10.0% versus 5.7%, p < 0.001), preterm birth at, In a national retrospective study, Sylvie Epelboin and colleagues investigate obstetrical outcomes and maternal morbidities among pregnant women with a COVID-19 diagnosis in France., Author summary Why was this study done? In early 2020, as infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spread worldwide, it was not known whether pregnant women with Coronavirus Disease 2019 (COVID-19) were at greater risk for maternal morbidities and adverse obstetric outcomes. We sought to evaluate in what extent the risk of maternal morbidities and obstetrical adverse outcomes and COVID-19 diagnosis in pregnant women could be associated. The possibility of having access to obstetric data of all pregnant women hospitalized in France around childbirth during the first wave of COVID-19, from January to June 2020, through access to data from the National Health Data System, allowed us to obtain results on a large representative national cohort. What did the researchers do and find? We conducted a retrospective analysis of a national cohort of all hospitalizations for birth ≥22 weeks of gestation occurring in France from January to June 2020, using the French national hospitalization database (PMSI). Maternal morbidities and adverse obstetrical outcomes with or without COVID-19 were analyzed with a model adjusted on patient characteristics that could be risk factors: maternal age, body mass index, active smoking, parity, history of diabetes or hypertension, multiple pregnancy, and assisted reproductive technique (ART) conception. Pregnant women with COVID-19 diagnosis were more likely to be older, have obesity, a multiple pregnancy, and history of hypertension, compared to those without COVID-19. Active smoking and primiparity were less frequent among those with COVID-19 and rates of conception using ART were similar between the 2 groups. When compared to the non-COVID-19 group, women in the COVID-19 group had a higher frequency of admission to intensive care unit, mortality, preeclampsia/eclampsia, gestational hypertension, peripartum and postpartum hemorrhage, preterm and very preterm spontaneous and induced birth, and cesarean section. Rates of pregnancy terminations, stillbirths, gestational diabetes, placenta praevia, placenta abruption, and venous thromboembolic events were not increased. What do these findings mean? These findings suggest that pregnant women with COVID-19 disease may have an increased risk of obstetrical morbidities when compared to non-COVID-19 pregnant controls. Results of this study may inform prevention and treatment policies for pregnant women with COVID-19. In clinical practice, it appears essential to be aware of these complications, notably in populations at known risk of developing a more severe form of infection or obstetrical morbidities and in order for obstetrical units to better inform pregnant women and provide the best care. Although causality cannot be established from our study, these findings raise the possibility that vaccination, which can be offered to pregnant women starting from the second trimester according to recommendations of several health authorities, may be useful to protect women from obstetrical excess risk, in particular in high-risk populations.

Published
2021

20. Familial pancreatic adenocarcinoma: A retrospective analysis of germline genetic testing in a French multicentre cohort

Author

Marie Muller, Pascal Hammel, Florence Coulet, William Greenhalf, Angelique Riffault, Sandra Granier, Chrystelle Colas, Olivier Ingster, Meriem Benfoda, Philippe Jonveaux, Melissa Parrin, Vinciane Rebours, Philippe Lévy, Mathias Schwartz, Mickael Mary, Louis de Mestier, Clément Korenbaum, Jérôme Cros, and Nadem Soufir

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, endocrine system diseases, 030105 genetics & heredity, medicine.disease_cause, Germline, Cohort Studies, 03 medical and health sciences, Young Adult, CDKN2A, Internal medicine, Genetics, medicine, Genetic predisposition, Humans, Genetic Testing, Genetics (clinical), Genetic testing, Aged, BAP1, medicine.diagnostic_test, business.industry, Carcinoma, Middle Aged, medicine.disease, digestive system diseases, FANCA, Neoplasm Proteins, Pancreatic Neoplasms, 030104 developmental biology, Germ Cells, Adenocarcinoma, Female, Carcinogenesis, business
Abstract

The rate of genetic diagnosis of French patients with familial pancreatic ductal adenocarcinoma (PDAC) is not known. We report germline genetic testing data from 133 index cases meeting criteria for familial pancreatic cancer (FPC) as well as 87 'FPC-like' index cases who did not fulfilled strict FPC definition but were evocative for a PDAC predisposition. The overall rate of genetic diagnosis (in BRCA1, BRCA2, CDKN2A, and ATM genes) was 8.3% in FPC patients and 4.6% in FPC-like patients, consistent with the literature in other populations. Genetic variants were also identified in FANCA and BAP1 genes, as well as in the CDKN2A p12 transcript. This pancreas-specific transcript is a known key player in driving pancreatic oncogenesis. This might be the first described case of a PDAC genetic predisposition due to a variant in this specific transcript.

Published
2019

21. Duplication of 10q24 locus: broadening the clinical and radiological spectrum

Author

Joris Andrieux, Anna Sowińska-Seidler, Joo Wook Ahn, Elena Pollina, Clarisse Baumann, Chantal Farra, Florence Petit, Sébastien Jacquemont, Muriel Holder-Espinasse, Philippe Jonveaux, Jane A. Hurst, Sylvie Manouvrier-Hanu, Magdalena Socha, Neeti Ghali, Sahar Mansour, Albert David, Anne-Sylvie Valat, Michèle Mathieu-Dramard, Anne Moncla, Annick Toutain, Alain Verloes, Anna Jakubiuk-Tomaszuk, Nayana Lahiri, Estelle Colin, Annick Rossi, David Zhang, Philippe Bourgeot, Aleksander Jamsheer, Fabienne Escande, Marion Gérard, Aurélie Mezel, Valérie Cormier-Daire, Ghislaine Plessis, Christine Patch, Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), biology and pathological laboratory, Institut de Génétique Médicale [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Jeanne de Flandre [Lille], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Agricultural University of Krakow, Université de Lorraine (UL), Service de génétique médicale, CHU Amiens-Picardie, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, MLab, Dauphine Recherches en Management (DRM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Inst MitoVasc, Equipe MitoLab, Université d'Angers (UA), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Wessex Clinical Genetics Service, Wessex clinical genetics service, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Laboratoire de Génétique Chromosomique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Department of Clinical Genetics/EMGO Institute for Health and Care research, Biometrics Research Center, The Hong Kong Polytechnic University [Hong Kong] (POLYU), Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)

Subjects
Adult, Male, Proteasome Endopeptidase Complex, BTRC, Limb Deformities, Congenital, Locus (genetics), Review Article, Biology, Young Adult, 03 medical and health sciences, Exon, Segmental Duplications, Genomic, Proto-Oncogene Proteins, Gene duplication, Genetics, Humans, Genetic Predisposition to Disease, Genetics (clinical), Segmental duplication, Gene Rearrangement, Regulation of gene expression, Comparative Genomic Hybridization, 0303 health sciences, Chromosomes, Human, Pair 10, F-Box Proteins, 030305 genetics & heredity, Infant, Penetrance, Pedigree, Radiography, Wnt Proteins, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Female, Hand Deformities, Congenital, Limb morphogenesis
Abstract

International audience; Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.

Published
2019

22. Risk estimation of uniparental disomy of chromosome 14 or 15 in a fetus with a parent carrying a non‐homologous Robertsonian translocation. Should we still perform prenatal diagnosis?

Author

Sébastien Schmitt, Philippe Vago, Marie-Laure Maurin, Gregory Egea, Denise Molina Gomes, Emmanuelle Haquet, Marine Lebrun, Jacques Puechberty, François Vialard, Olivier Pichon, Perrine Malzac, Philippe Jonveaux, Martine Doco-Fenzy, Paul Kuentz, Sandra Chantot-Bastaraud, Kamran Moradkhani, Jean-Paul Bonnefont, Caroline Janel, Jean-Michel Dupont, Pierre Boisseau, Jean-Pierre Siffroi, Cédric Le Caignec, Anne-Laure Fauret-Amsellem, Damien Sanlaville, Chantal Missirian, Carole Goumy, Agnès Guichet, Marie-Christine Manca-Pellissier, Renaud Touraine, Laurence Cuisset, Pascale Saugier-Veber, Nicolas Gruchy, Houda Hamdi-Rozé, Bénédicte Duban-Bedu, Bruno Delobel, N. Joye, Isabelle Creveaux, Ines Harzallah, Frédéric Bilan, Philippe Gosset, Marie-Pierre Audrézet, Laboratoire de cytogénétique [CHU Nantes] (Service de génétique médicale), Centre hospitalier universitaire de Nantes (CHU Nantes), Depatment Biochemical Genetics, Université Paris Descartes - Paris 5 (UPD5), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Gatonero SA, Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Pontchaillou [Rennes], Service d'histologie, embryologie et cytogénétique [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de cytogénétique prénatale [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Assistance Publique - Hôpitaux de Marseille (APHM), Espace éthique méditerranéen, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Génétique, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire de Biochimie, Université d'Auvergne - Clermont-Ferrand I (UdA), CHU Clermont-Ferrand, Histologie Embryologie Cytogénétique, Université d'Auvergne - Clermont-Ferrand I (UdA)-Faculté de Médecine, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Les Hôpitaux Universitaires de Strasbourg (HUS), Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Centre de Génétique Chromosomique, Génétique Médicale, CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Département de biologie de la reproduction et de gynécologie [CHIPS, Poissy], Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], CHI Poissy-Saint-Germain, Gamètes, implantation, gestation (GIG), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Saint-Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), GHICL-Hôpital Saint Vincent de Paul, Hôpital Saint Vincent de Paul-GHICL, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biologie de la Reproduction, and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Robertsonian translocation, Chromosomal translocation, Prenatal diagnosis, 030105 genetics & heredity, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, medicine.disease_cause, Risk Assessment, Translocation, Genetic, Miscarriage, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Prenatal Diagnosis, medicine, Humans, Genetics (clinical), Retrospective Studies, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 15, Fetus, 030219 obstetrics & reproductive medicine, Obstetrics, business.industry, Obstetrics and Gynecology, Chromosome, Uniparental Disomy, medicine.disease, Uniparental disomy, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Female, business
Abstract

International audience; Objective: Uniparental disomy (UPD) testing is currently recommended during pregnancy in fetuses carrying a balanced Robertsonian translocation (ROB) involving chromosome 14 or 15, both chromosomes containing imprinted genes. The overall risk that such a fetus presents a UPD has been previously estimated to be around ~0.6‐0.8%. However, because UPD are rare events and this estimate has been calculated from a number of studies of limited size, we have reevaluated the risk of UPD in fetuses for whom one of the parents was known to carry a nonhomologous ROB (NHROB).Method: We focused our multicentric study on NHROB involving chromosome 14 and/or 15. A total of 1747 UPD testing were performed in fetuses during pregnancy for the presence of UPD(14) and/or UPD(15).Result: All fetuses were negative except one with a UPD(14) associated with a maternally inherited rob(13;14).Conclusion: Considering these data, the risk of UPD following prenatal diagnosis of an inherited ROB involving chromosome 14 and/or 15 could be estimated to be around 0.06%, far less than the previous estimation. Importantly, the risk of miscarriage following an invasive prenatal sampling is higher than the risk of UPD. Therefore, we do not recommend prenatal testing for UPD for these pregnancies and parents should be reassured.

Published
2019

23. Rett‐like phenotypes: expanding the genetic heterogeneity to the <scp>KCNA2</scp> gene and first familial case of <scp>CDKL5</scp> ‐related disease

Author

V. Roth, L. Allou, Daniel Amsallem, Philippe Jonveaux, Aline Saunier, P. Bouquet, Christophe Philippe, S. El Chehadeh, Sophie Julia, Julien Thevenon, A. Moustaïne, S. Pere, Laetitia Lambert, L. Ruaud, and Yannis Duffourd

Subjects
0301 basic medicine, Genetics, congenital, hereditary, and neonatal diseases and abnormalities, Candidate gene, Genetic heterogeneity, CDKL5, Rett syndrome, Biology, medicine.disease, 3. Good health, MECP2, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine, Missense mutation, Exome, 030217 neurology & neurosurgery, Genetics (clinical), Exome sequencing
Abstract

Several genes have been implicated in Rett syndrome (RTT) in its typical and variant forms. We applied next-generation sequencing (NGS) to evaluate for mutations in known or new candidate genes in patients with variant forms of Rett or Rett-like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett-like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile-onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT-like phenotypes. Moreover, we report the first familial case of CDKL5-related disease.

Published
2016

24. Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation

Author

Rosine Guimbaud, Odile Cabaret, Julie Leclerc, Thierry Frebourg, Lucie Delattre, Tonio Lovecchio, Gilles Morin, Sophie Lejeune, Nelly Burnichon, Myriam Bronner, Emilie Ait Yahya, Pierre Laurent-Puig, Marie-Pierre Buisine, Nicole Porchet, Stéphanie Baert-Desurmont, Philippe Jonveaux, Jacques Mauillon, and Cathy Flament

Subjects
0301 basic medicine, Adult, Male, Heterozygote, Alu element, Biology, MLH1, Polymorphism, Single Nucleotide, Epigenesis, Genetic, 03 medical and health sciences, symbols.namesake, Alu Elements, Gene duplication, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, Promoter Regions, Genetic, Gene, Genetics (clinical), Alleles, Genetics, Intron, High-Throughput Nucleotide Sequencing, DNA Methylation, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Lynch syndrome, Introns, Pedigree, 030104 developmental biology, Haplotypes, Mutation, Mendelian inheritance, symbols, Female, MutL Protein Homolog 1
Abstract

Constitutional epimutations are an alternative to genetic mutations in the etiology of genetic diseases. Some of these epimutations, termed secondary, correspond to the epigenetic effects of cis-acting genetic defects transmitted to the offspring following a Mendelian inheritance pattern. In Lynch syndrome, a few families with such apparently heritable MLH1 epimutations have been reported so far. We designed a long-range polymerase chain reaction next-generation sequencing strategy to screen MLH1 entire gene and applied it to 4 French families with heritable epimutations and 10 additional patients with no proven transmission of their epimutations. This strategy successfully detected the insertion of an Alu element in MLH1 coding sequence in one family. Two previously unreported MLH1 variants were also identified in other epimutation carriers: a nucleotide substitution within intron 1 and a single-nucleotide deletion in the 5′-UTR. Detection of a partial MLH1 duplication in another family required multiplex ligation-dependent probe amplification technology. We demonstrated the segregation of these variants with MLH1 methylation and studied the functional consequences of these defects on transcription. This is the largest cohort of patients with MLH1 secondary epimutations associated with a broad spectrum of genetic defects. This study provides further insight into the complexity of molecular mechanisms leading to secondary epimutations.

Published
2017

25. Pyrimidine 5’-nucleotidase deficiency associated to a polymalformative syndrome

Author

Lydie Da Costa, Fanny Fouyssac, Michel Bahuau, Lucille Altounian, Bruno Leheup, Philippe Jonveaux, Odile Fenneteau, Jean-François Lesesve, and Julien Perrin

Subjects
Male, Anemia, Hemolytic, medicine.medical_specialty, Pyrimidine, Pancytopenia, business.industry, Erythrocytes, Abnormal, General Medicine, Young Adult, chemistry.chemical_compound, Endocrinology, Pyrimidine-5'-Nucleotidase Deficiency, chemistry, Internal medicine, Nucleotidase, Humans, Medicine, business, 5'-Nucleotidase
Abstract

A pyrimidine 5'-nucleotidase deficiency in an adult is reported. Interestingly, the P5'N-1 deficiency was associated to a polymalformative syndrome and was characterized by a chronic, pancytopenic evolution with concomitant dyserythropoiesis.

Published
2015

26. WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation

Author

Nicolas Lebrun, Thierry Bienvenu, Stéphane Auvin, Aissa Moustaïne, Lila Allou, Jean-Louis Guéant, Laurent Pasquier, Philippe Jonveaux, Andrée Delahaye-Duriez, Eva Pipiras, Anne-Isabelle Vermersch, Bénédicte Héron, Cyril Mignot, Laetitia Lambert, Aline Saunier, Christophe Philippe, Marie-Laure Moutard, Marie-Christine Nougues, Jeremie Lefranc, Virginie Roth, Catherine Barrey, Boris Keren, Mylène Valduga, Laurence Olivier-Faivre, Sandra Chantot-Bastaraud, Delphine Héron, Service de génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Unité de Génétique Clinique [CHRU Nancy], Service de Médecine Néonatale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CHU Pontchaillou [Rennes], CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Laboratoire de Biochimie et Génétique Moléculaire, CHU Cochin [AP-HP], Hôpital Jean Verdier, CHRU de Brest - Département de Pédiatrie ( CHU BREST Pédiatrie ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Service de neuropédiatrie [Debré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Hôpital Saint Camille, Service de Génétique et d'Embryologie Médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service de Neuropédiatrie [CHU Trousseau], Service de neurophysiologie [CHU Trousseau], Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique des Anomalies du Développement (GAD), and IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB)

Subjects
WWOX, Microcephaly, [SDV]Life Sciences [q-bio], Nonsense mutation, Mutation, Missense, Biology, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Spinocerebellar Ataxias, Missense mutation, Allele, Genetics (clinical), infantile, 030304 developmental biology, Comparative Genomic Hybridization, 0303 health sciences, [ SDV ] Life Sciences [q-bio], Tumor Suppressor Proteins, Chromosomal fragile site, High-Throughput Nucleotide Sequencing, genotype/phenotype correlations, medicine.disease, Null allele, 3. Good health, Phenotype, WW Domain-Containing Oxidoreductase, Codon, Nonsense, intellectual disability, Spinocerebellar ataxia, Oxidoreductases, Spasms, Infantile, high throughput data mining, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND:Homozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy (IEE), including one who deceased prior to DNA sampling.METHODS:By combining array comparative genomic hybridisation, targeted Sanger sequencing and next generation sequencing, we identified five further patients from four families with IEE due to biallelic alterations of WWOX.RESULTS:We identified eight deleterious WWOX alleles consisting in four deletions, a four base-pair frameshifting deletion, one missense and two nonsense mutations. Genotype-phenotype correlation emerges from the seven reported families. The phenotype in four patients carrying two predicted null alleles was characterised by (1) little if any psychomotor acquisitions, poor spontaneous motility and absent eye contact from birth, (2) pharmacoresistant epilepsy starting in the 1st weeks of life, (3) possible retinal degeneration, acquired microcephaly and premature death. This contrasted with the less severe autosomal recessive spinocerebellar ataxia type 12 phenotype due to hypomorphic alleles. In line with this correlation, the phenotype in two siblings carrying a null allele and a missense mutation was intermediate.CONCLUSIONS:Our results obtained by a combination of different molecular techniques undoubtedly incriminate WWOX as a gene for recessive IEE and illustrate the usefulness of high throughput data mining for the identification of genes for rare autosomal recessive disorders. The structure of the WWOX locus encompassing the FRA16D fragile site might explain why constitutive deletions are recurrently reported in genetic databases, suggesting that WWOX-related encephalopathies, although likely rare, may not be exceptional.

Published
2014

27. An adult patient with 49, XXXXY syndrome: further clinical and biological delineation

Author

Jérôme Chatelin, Mylène Valduga, Philippe Jonveaux, Agnès Collet, Lila Allou, Laetitia Lambert, Céline Bonnet, Georges Weryha, Razvan Nicolaie Gospodaru, and M. Agopiantz

Subjects
Male, Pediatrics, medicine.medical_specialty, Deep vein, Aneuploidy, Deafness, Blindness, XXXY syndrome, Klinefelter Syndrome, Hypergonadotropic hypogonadism, Intellectual Disability, medicine, Humans, Hypertelorism, business.industry, Hypogonadism, Eyelids, Facies, General Medicine, Middle Aged, medicine.disease, medicine.anatomical_structure, Palpebral fissure, Microorchidism, 49, XXXXY syndrome, medicine.symptom, business
Abstract

49, XXXXY syndrome is a rare sex chromosome aneuploidy occurring in 1:80 000-1:100 000 male births. Data on this aneuploidy in adulthood are limited, with most of the literature data based on paediatric patients. We report a new male patient whose 49, XXXXY diagnosis was formally made at the age of 54 years. So far, no medical follow-up was performed specifically for his condition. This man presented with facial features (epicanthus, hypertelorism, up-slanting palpebral fissures), microorchidism and features of chronic hypoandrogenism with muscular weakness, sparse body hair, dry skin with abnormal healing of skin wounds. Endocrine evaluation confirmed a hypergonadotropic hypogonadism. He had moderate intellectual deficiency with more affected verbal skills. A recent deep vein thrombosis was diagnosed in his left leg. Unusually, in addition to moderate deafness, he developed progressively a severe vision impairment leading to blindness. There have been very few reports of adult individuals with 49, XXXXY syndrome and this kind of report may contribute to improved management of prospective medical healthcare associated with this condition in older individuals.

Published
2014

28. No chromosome arm unturned: in memory of Roland Berger 1934–2012

Author

M Le Coniat-Busson, Anne Hagemeijer, H. Van den Berghe, Alain Bernheim, M Gautier, Florence Nguyen-Khac, Serge Romana, Nicole Dastugue, Janet D. Rowley, Philippe Jonveaux, Christine J. Harrison, M Martineau, Olivier Bernard, Leukaemia Research Cytogenetics Group [Northern Institute for Cancer Research - Newcastle University], Northern Institute for Cancer Research [Newcastle] (NICR), Newcastle University [Newcastle]-Newcastle University [Newcastle], Section of Hematology/Oncology [Chicago], The University of Chicago Medicine, Center for the Biology of Disease, and KU Leuven (VIB), Génétique des tumeurs (U985), Institut Gustave Roussy (IGR)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Sciences Unit, Faculty of Medicine, University of Southampton, UK, Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'hématologie biologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique et d'Embryologie Médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]

Subjects
Chromosome Aberrations, 0303 health sciences, Cancer Research, Leukemia, business.industry, [SDV]Life Sciences [q-bio], Hematology, History, 20th Century, History, 21st Century, Pediatrics, Genealogy, 03 medical and health sciences, 0302 clinical medicine, Oncology, Physicians, 030220 oncology & carcinogenesis, Chromosome Arm, Medicine, France, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2014

29. Dialogical history of a logical fallacy spontaneously produced during a predictive medicine consultation. Role of the causal connective Puisque in a discussion

Author

Philippe Jonveaux, Thérèse Rivasseau Jonveaux, Alain Trognon, Martine Batt, Denis Vernant, Laboratoire de psychologie de l'interaction et des relations intersubjectives (INTERPSY), Université de Lorraine (UL), Maison des Sciences de l'Homme Lorraine (MSH Lorraine), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)

Subjects
Puisque, Santé mentale, Fallacy, Linguistics and Language, Interaction, Psychologie sociale et du travail, Antecedent (logic), media_common.quotation_subject, [SHS.PSY]Humanities and Social Sciences/Psychology, Psychologie du développement et de l’éducation, Psychologie de la cognition, Psychologie clinique et psychopathologie, 050105 experimental psychology, Language and Linguistics, Predictive medicine, Psychologie de l’interaction et de la communication, Artificial Intelligence, Affirming the consequent, Natural (music), 0501 psychology and cognitive sciences, Dialogue, media_common, 060201 languages & linguistics, Intersubjectivity, Conditional reasoning, 05 social sciences, Dialogical self, 06 humanities and the arts, Epistemology, 0602 languages and literature, Rhetoric, Psychology, Construct (philosophy), Genetic counseling
Abstract

International audience; This article presents the dialogical history of the production and the contesting of logical fallacies in a natural dialogue stemming from a Genetic Counseling for Predictive Testing consultation. These logical fallacies are errors in reasoning that are well-known in psychology and rhetoric: « affirming the consequent » and « negating the antecedent ». The authors construct a formal model of this dialogue which explains why the fallacy appears and why corrective attempts ultimately fail. They show that the causal connective puisque is an essential operator of the studied dialogue.

Published
2014

30. Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy

Author

Catherine Nowak, Kamiar Mireskandari, Masano Amamoto, Jean-Baptiste Rivière, Amber Begtrup, Thibaud Jouan, Laurence Faivre, Aline Saunier, Nicolas Chatron, Noriko Miyake, Mitsuhiro Kato, Dorothée Ville, Jessica Douglas, Stéphane Auvin, Bertrand Isidor, Guylène Lemeur, Stylianos E. Antonarakis, Naomichi Matsumoto, Mathieu Milh, Philippe Jonveaux, Hanan Hamamy, Neal Sondheimer, Mirna Assoum, Paolo Milani, Mitsuko Nakashima, Amira Masri, Gaetan Lesca, Julien Thevenon, Yannis Duffourd, Laurence Perrin, Caroline Paris, Christel Thauvin-Robinet, Christophe Philippe, Periklis Makrythanasis, Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP), University of Geneva, Division of Clinical and Metabolic Genetics [Toronto], The Hospital for sick children [Toronto] ( SickKids ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Boston Children's Hospital, Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon, Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), GeneDx, Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] ( HFME ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service de Neurologie Pédiatrique, HFME, Bron, France, Service d'ophtalmologie [Nantes], Hôtel-Dieu, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Pediatric Emergency Centre, Kitakyushu Municipal Yahata Hospital, Yokohama City University School of Medecine ( YCUSM ), University School of Medecine, University of Amman, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Regional Council of Burgundy Dijon University Hospital Association Française du Syndrome de Rett, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre hospitalier universitaire de Nantes (CHU Nantes), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children [Toronto] (SickKids), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), GeneDx [Gaithersburg, MD, USA], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Yokohama City University School of Medecine (YCUSM), Yokohama University School of Medecine, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Microcephaly, Developmental Disabilities, Postnatal microcephaly, copper-metabolism, Epilepsy, 0302 clinical medicine, expansion, hermansky-pudlak-syndrome, ddc:576.5, Age of Onset, Child, disorders, Genetics (clinical), seizures, Genetics, MEDNIK syndrome, Syndrome, 3. Good health, Pedigree, intellectual disability, Child, Preschool, mednik syndrome, Female, Developmental regression, Adaptor Protein Complex 3, Genes, Recessive, Biology, AP3B1, 03 medical and health sciences, Atrophy, Report, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Humans, Adaptor Protein Complex beta Subunits, mouse, disease, ap-4 deficiency, Infant, Newborn, Infant, medicine.disease, Optic Atrophy, 030104 developmental biology, Mutation, Hermansky–Pudlak syndrome, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing. The targeted sequencing of AP3B2 in 86 unrelated individuals with EOEE led to the identification of an additional family. We gathered five additional families with eight affected individuals through the Matchmaker Exchange initiative by matching autosomal- recessive mutations in AP3B2. Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly. No spasticity, albinism, or hematological symptoms were reported. AP3B2 encodes the neuron-specific subunit of the AP-3 complex. Autosomal-recessive variations of AP3B1, the ubiquitous isoform, cause Hermansky-Pudlak syndrome type 2. The only isoform for the delta subunit of the AP-3 complex is encoded by AP3D1. Autosomal-recessive mutations in AP3D1 cause a severe disorder cumulating the symptoms of the AP3B1 and AP3B2 defects.

Published
2016

31. GENESIS: a French national resource to study the missing heritability of breast cancer

Author

Sylvie Mazoyer, Valérie Layet, Carole Verny-Pierre, Claude Adenis, Marie-Gabrielle Dondon, Isabelle Mortemousque, Morgane Marcou, Olga M. Sinilnikova, Philippe Jonveaux, Anne Floquet, François Eisinger, Yves-Jean Bignon, Catherine Noguès, Laurence Gladieff, Capucine Delnatte, Olivier Caron, Bruno Buecher, Pascaline Berthet, Anne Fajac, Clotilde Penet, Séverine Eon-Marchais, Sandra Fert-Ferrer, Florent Soubrier, Dominique Stoppa-Lyonnet, Chrystelle Colas, Isabelle Coupier, Christine Lasset, Emmanuelle Barouk-Simonet, Michel Longy, Jean-Pierre Fricker, Jean Chiesa, Sophie Giraud, Dominique Leroux, Catherine Dugast, Sophie Lejeune-Dumoulin, Hélène Dreyfus, Annie Chevrier, Odile Cohen-Haguenauer, Thierry Frebourg, Liliane Demange, Julie Tinat, Fabienne Lesueur, Pascal Pujol, Emmanuelle Mouret-Fourme, Elisabeth Luporsi, Christine Maugard, Dorothée Le Gal, Noura Mebirouk, Séverine Audebert-Bellanger, Laure Barjhoux, Muriel Belotti, Eve Cavaciuti, Marion Gauthier-Villars, Marie-Agnès Collonge-Rame, Paul Gesta, Jean-Marc Limacher, Odile Bera, Lucie Toulemonde, Anne Tardivon, Fabienne Prieur, Laurence Faivre, Juana Beauvallet, Alain Lortholary, Nadine Andrieu, François Cornelis, Marc Frenay, Valérie Sornin, Laurence Venat-Bouvet, Francesca Damiola, Valérie Bonadona, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Service de génétique, Institut Curie Paris, Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Catherine-de-Sienne [Nantes] (CCS), CRLCC Eugène Marquis (CRLCC), Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), CRLCC Paul Strauss, CRLCC René Huguenin, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'oncogénétique [Centre georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), CRLCC René Gauducheau, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Bergonié [Bordeaux], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Polyclinique de Courlancy, Institut Sainte Catherine [Avignon], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Claudius Regaud, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Jeanne de Flandre [Lille], Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital pasteur [Colmar], Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Métropole Savoie [Chambéry], CRLCC Jean Godinot, Institut du cancer Courlancy-Reims, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Gustave Flaubert, Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Viggo-Petersen, Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), CHU de la Martinique [Fort de France], Institut Curie, Département d'Imagerie Médicale (Curie Institute, Department of Medical Imaging), F-75005 Paris, France., Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), UL, NGERE, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Lille Nord de France (COMUE)-UNICANCER, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Oncology, Cancer Research, [SDV]Life Sciences [q-bio], Genome-wide association study, Identifies 2, Genome-Wide Association, 0302 clinical medicine, Missing heritability problem, Confer Susceptibility, Susceptibility Loci, 10. No inequality, skin and connective tissue diseases, education.field_of_study, medicine.diagnostic_test, BRCA1 Protein, Middle Aged, 16. Peace & justice, 3. Good health, Neoplasm Proteins, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Female, France, Research Article, Adult, Risk, medicine.medical_specialty, Population, Breast Neoplasms, 03 medical and health sciences, Germline mutation, Breast cancer, Internal medicine, medicine, Genetics, Humans, Genetic Predisposition to Disease, Genetic Testing, education, Germ-Line Mutation, Alleles, Genetic testing, Aged, Gynecology, BRCA2 Protein, Common Variants, business.industry, Genetic heterogeneity, Cancer, medicine.disease, 030104 developmental biology, business
Abstract

Background Less than 20 % of familial breast cancer patients who undergo genetic testing for BRCA1 and BRCA2 carry a pathogenic mutation in one of these two genes. The GENESIS (GENE SISter) study was designed to identify new breast cancer susceptibility genes in women attending cancer genetics clinics and with no BRCA1/2 mutation. Methods The study involved the French national network of family cancer clinics. It was based on enrichment in genetic factors of the recruited population through case selection relying on familial criteria, but also on the consideration of environmental factors and endophenotypes like mammary density or tumor characteristics to assess potential genetic heterogeneity. One of the initial aims of GENESIS was to recruit affected sibpairs. Siblings were eligible when index cases and at least one affected sister were diagnosed with infiltrating mammary or ductal adenocarcinoma, with no BRCA1/2 mutation. In addition, unrelated controls and unaffected sisters were recruited. The enrolment of patients, their relatives and their controls, the collection of the clinical, epidemiological, familial and biological data were centralized by a coordinating center. Results Inclusion of participants started in February 2007 and ended in December 2013. A total of 1721 index cases, 826 affected sisters, 599 unaffected sisters and 1419 controls were included. 98 % of participants completed the epidemiological questionnaire, 97 % provided a blood sample, and 76 % were able to provide mammograms. Index cases were on average 59 years old at inclusion, were born in 1950, and were 49.7 years of age at breast cancer diagnosis. The mean age at diagnosis of affected sisters was slightly higher (51.4 years). The representativeness of the control group was verified. Conclusions The size of the study, the availability of biological specimens and the clinical data collection together with the detailed and complete epidemiological questionnaire make this a unique national resource for investigation of the missing heritability of breast cancer, by taking into account environmental and life style factors and stratifying data on endophenotypes to decrease genetic heterogeneity.

Published
2016

32. Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

Author

Charles Coutant, Laurent Arnould, Christophe Philippe, Patrick Callier, Pierre Fumoleau, Myriam Bronner, Emmanuelle Ferrant, Sarab Lizard, Amandine Baurand, Jean-Louis Jouve, Laurence Faivre, Carole Chery, Gérard Couillault, Alexandra Delignette, Catherine Loustalot, Caroline Chapusot, Côme Lepage, Thierry Frebourg, Emilie Degrolard-Courcet, Laurent Martin, Francine Mugneret, Marie-Martine Padeano, Salima El Chehadeh, Séverine Guiu, Philippe Jonveaux, Fanny Coron, Joanna Sokolowska, Cyril Hatem, Service de Pathologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de chirurgie [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Département d'oncologie médicale [Centre Georges-François Leclerc], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Polyclinique du Parc - Clinique Drevon [Dijon], Service d'Hématologie Clinique (CHU de Dijon), Service de pédiatrie (CHU de Dijon), Service de radiologie [Centre Georges-François Leclerc], Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], UNICANCER, Laboratoire de cytogénétique (CHU de Dijon), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)

Subjects
Adult, Biallelic Mutation, RNA Splicing, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Biology, medicine.disease_cause, Article, Frameshift mutation, Genetics, medicine, Humans, Missense mutation, Age of Onset, Gene, Alleles, Genetics (clinical), BRCA2 Protein, Mutation, Point mutation, Computational Biology, Chromosome Breakage, Pedigree, 3. Good health, Amino Acid Substitution, Female, RNA Splice Sites, Chromosome breakage, Colorectal Neoplasms
Abstract

International audience; Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.

Published
2013

33. Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests

Author

Sophie Grandjouan, Pascaline Berthet, Rosette Lidereau, E. Nogue, M. C. Picot, C. Bara, S. Giraud, Frédérique Nowak, J. Blin, Catherine Noguès, Bruno Buecher, D. Khayat, B. Bressac de Paillerets, Florent Soubrier, Virginie Galibert, Thierry Frebourg, Sylviane Olschwang, Hagay Sobol, D. Stoppa Lyonnet, Pascal Pujol, Philippe Jonveaux, Catherine Dugast, Christine Lasset, Claude Houdayer, Rosine Guimbaud, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Proband, Cancer Research, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Genes, BRCA2, Genes, BRCA1, Genetic Carrier Screening, DNA Mismatch Repair, 0302 clinical medicine, Referral and Consultation, Ovarian Neoplasms, Genetics, 0303 health sciences, medicine.diagnostic_test, 030305 genetics & heredity, Nuclear Proteins, Lynch syndrome, 3. Good health, DNA-Binding Proteins, MutS Homolog 2 Protein, Oncology, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Female, France, MutL Protein Homolog 1, medicine.medical_specialty, Genetic counseling, Breast Neoplasms, Genetic Counseling, Cancer Care Facilities, 03 medical and health sciences, Breast cancer, Neoplastic Syndromes, Hereditary, Internal medicine, medicine, Humans, Genetic Testing, Adaptor Proteins, Signal Transducing, Genetic testing, Family Health, business.industry, Cancer, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Mutation, Laboratories, business
Abstract

Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with BRCA1/2 or MMR genes mutation. Genetic testing and consultations for familial high-risk individuals are exclusively funded and monitored by the INCa in France. All nationwide cancer genetics centers reported annually standardized parameters of activity from 2003 to 2011. The analysis included a total of 240,134 consultations and 134,652 genetic tests enabling to identify 32,494 mutation carriers. Referral for hereditary breast and ovarian cancer (HBOC) or colorectal cancer predisposition syndromes represented 59 % (141,639) and 23.2 % (55,698) consultations, respectively. From 2003 to 2011, we found a dramatic and steady increase of tests performed for BRCA1/2 (from 2,095 to 7,393 tests/year, P < 0.0001) but not for MMR genes (from 1,144 to 1,635/year, P = NS). The overall percentage of deleterious mutations identified in the probands tested was 13.8 and 20.9 % in HBOC and Lynch syndromes, respectively. Pooled analysis for BRCA1/2 and Lynch syndrome tests showed an inverse relationship between the percentage of mutation detected and the absolute number of tests performed over the time (overall Cochran-Armitage test for trend: P < 0.001). In families with BRCA1/2 or MMR identified mutations, there was an average number of 2.94 and 3.28 relatives performing targeted tests, respectively. This nationwide study shows a lack of referral and genetic testing in Lynch as compared to HBOC syndromes. Only a third of relatives of a proband with a predisposing mutation performed a targeted test. Enhanced information about benefit of genetic testing should be given to clinicians and patients for Lynch syndrome and relatives of a proband carrying an identified predisposing mutation.

Published
2013

34. Extended spectrum of MBD5 mutations in neurodevelopmental disorders

Author

Emmanuel Bresso, Bruno Leheup, Sarah Lejczak, Charlène Vigouroux, Joris Andrieux, Irina Giurgea, Asma A. Khan, Anne Moncla, Philippe Jonveaux, Marie-Dominique Devignes, Mylène Beri, Bénédicte Deemer, Céline Bonnet, Christophe Philippe, Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Déficiences Mentales et Anomalies de Structure du Génome (DMASG), Université Henri Poincaré - Nancy 1 (UHP), Knowledge representation, reasonning (ORPAILLEUR), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Natural Language Processing & Knowledge Discovery (LORIA - NLPKD), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Pédiatrie, CHU Amiens, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Computational Algorithms for Protein Structures and Interactions (CAPSID), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], and UL, NGERE

Subjects
Male, Developmental Disabilities, [SDV]Life Sciences [q-bio], Nonsense mutation, Short Report, Biology, medicine.disease_cause, 03 medical and health sciences, Exon, Neurodevelopmental disorder, Genes, Duplicate, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Child, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, 030305 genetics & heredity, Microdeletion syndrome, medicine.disease, Phenotype, 3. Good health, [SDV] Life Sciences [q-bio], DNA-Binding Proteins, Codon, Nonsense, Child, Preschool, Female, Haploinsufficiency
Abstract

International audience; Intellectual disability (ID) is a clinical sign reflecting diverse neurodevelopmental disorders that are genetically and phenotypically heterogeneous. Just recently, partial or complete deletion of methyl-CpG-binding domain 5 (MBD5) gene has been implicated as causative in the phenotype associated with 2q23.1 microdeletion syndrome. In the course of systematic whole-genome screening of individuals with unexplained ID by array-based comparative genomic hybridization, we identified de novo intragenic deletions of MBD5 in three patients leading, as previously documented, to haploinsufficiency of MBD5. In addition, we described a patient with an unreported de novo MBD5 intragenic duplication. Reverse transcriptase-PCR and sequencing analyses showed the presence of numerous aberrant transcripts leading to premature termination codon. To further elucidate the involvement of MBD5 in ID, we sequenced ten coding, five non-coding exons and an evolutionary conserved region in intron 2, in a selected cohort of 78 subjects with a phenotype reminiscent of 2q23.1 microdeletion syndrome. Besides variants most often inherited from an healthy parent, we identified for the first time a de novo nonsense mutation associated with a much more damaging phenotype. Taken together, these results extend the mutation spectrum in MBD5 gene and contribute to refine the associated phenotype of neurodevelopmental disorder.

Published
2013

35. Mutations inWNT10Aare frequently involved in oligodontia associated with minor signs of ectodermal dysplasia

Author

Encarna Guillén-Navarro, Sabine Sigaudy, Christine Coubes, Ghislaine Plessis, Dominique Martin-Coignard, Marc Abramowicz, Philippe Jonveaux, Catherine Vincent-Delorme, Frédéric Vaysse, Isabelle Bailleul-Forestier, Estelle Colin, V. Gaston, Nicolas Chassaing, Didier Lacombe, Bénédicte Demeer, Muriel Holder-Espinasse, Patrick Calvas, Julie Plaisancié, Hélène Dollfus, Eric Bieth, Alain Verloes, and Laurence Faivre

Subjects
Male, Ectodermal dysplasia, Genotype, Molecular Sequence Data, medicine.disease_cause, Compound heterozygosity, Ectodermal Dysplasia, Genetics, medicine, Humans, Amino Acid Sequence, Hypohidrotic ectodermal dysplasia, Genetic Association Studies, Genetics (clinical), Anodontia, Mutation, EDARADD, Edar Receptor, Genetic heterogeneity, business.industry, medicine.disease, Wnt Proteins, Hypodontia, Phenotype, Female, Ectodysplasin A, business, Sequence Alignment
Abstract

Ectodermal dysplasias (ED) are a clinically and genetically heterogeneous group of hereditary disorders that have in common abnormal development of ectodermal derivatives. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of eccrine sweat glands, hair, and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of patients with the hypohidrotic form. Autosomal dominant and autosomal recessive forms are occasionally seen, and result from mutations in at least three genes (WNT10A, EDAR, or more rarely EDARADD). We have screened for mutations in EDAR (commonly involved in the hypohidrotic form) and WNT10A (involved in a wide spectrum of ED and in isolated hypodontia) in a cohort of 36 patients referred for EDA molecular screening, which failed to identify any mutation. We identified eight EDAR mutations in five patients (two with homozygous mutations, one with compound heterozygous mutations, and two with heterozygous mutation), four of which were novel variants. We identified 28 WNT10A mutations in 16 patients (5 with homozygous mutations, 7 with compound heterozygous mutations, and 4 with heterozygous mutations), seven of which were novel variants. Our study allows a more precise definition of the phenotypic spectrum associated with EDAR and WNT10A mutations and underlines the importance of the implication of WNT10A among patients with ED. © 2013 Wiley Periodicals, Inc.

Published
2013

36. Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders

Author

Paquita Nurden, Sylvie Daliphard, Pascale Cornillet-Lefebvre, Anne Bauters, Paola Ballerini, Thomas Lecompte, Philippe Jonveaux, Rémi Favier, Guy Leverger, Aline Renneville, Véronique Latger-Cannard, Alexandre Bouquet, Claude Preudhomme, Véronique Baccini, Sophie Bayart, Marie-Joelle Mozziconacci, Christophe Philippe, Marie-Christine Alessi, Hagay Sobol, Annick Ankri, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'hématologie, Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Service d'Oncologie Génétique, de Prévention et Dépistage, Service de Génétique Médicale [CHRU Nancy], IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Division of Haematology (Div Haemato - GENEVE), Hôpitaux Universitaires de Genève (HUG), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2, CHU Marseille, and ALESSI, Marie-Christine

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, [SDV]Life Sciences [q-bio], 0302 clinical medicine, hemic and lymphatic diseases, Medicine, Missense mutation, Leukaemia, Genetics(clinical), Pharmacology (medical), Child, Genetics (clinical), Blood Platelet Disorders, Medicine(all), Comparative Genomic Hybridization, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, Middle Aged, 3. Good health, Pedigree, Leukemia, Myeloid, Acute, 030220 oncology & carcinogenesis, Child, Preschool, Core Binding Factor Alpha 2 Subunit, Female, Adult, RUNX1, Adolescent, Platelet disorder, Genetic counseling, Familial platelet disorder with predisposition to acute myeloid leukaemia, Frameshift mutation, δ-granule release defect, 03 medical and health sciences, Young Adult, Blood Coagulation Disorders, Inherited, Humans, Allele, Mean platelet volume, Genetic Association Studies, business.industry, Research, Infant, Thrombocytopenia, Transplantation, Immunology, Mutation, business, 030215 immunology
Abstract

Less than 50 patients with FPD/AML (OMIM 601309) have been reported as of today and there may an underestimation. The purpose of this study was to describe the natural history, the haematological features and the genotype-phenotype correlations of this entity in order to, first, screen it better and earlier, before leukaemia occurrence and secondly to optimize appropriate monitoring and treatment, in particular when familial stem cell transplantation is considered., We have investigated 41 carriers of RUNX1 alteration belonging to nine unrelated French families with FPD/AML and two syndromic patients, registered in the French network on rare platelet disorders from 2005 to 2015., Five missense, one non-sense, three frameshift mutations and two large deletions involving several genes including RUNX1 were evidenced. The history of familial leukaemia was suggestive of FPD/AML in seven pedigrees, whereas an autosomal dominant pattern of lifelong thrombocytopenia was the clinical presentation of two. Additional syndromic features characterized two large sporadic deletions. Bleeding tendency was mild and thrombocytopenia moderate (>50 x10(9)/L), with normal platelet volume. A functional platelet defect consistent with a δ-granule release defect was found in ten patients regardless of the type of RUNX1 alteration. The incidence of haematological malignancies was higher when the mutated RUNX1 allele was likely to cause a dominant negative effect (19/34) in comparison with loss of function alleles (3/9). A normal platelet count does not rule out the diagnosis of FPD/AML, since the platelet count was found normal for three mutated subjects, a feature that has a direct impact in the search for a related donor in case of allogeneic haematopoietic stem cell transplantation., Platelet dysfunction suggestive of defective δ-granule release could be of values for the diagnosis of FPD/AML particularly when the clinical presentation is an autosomal dominant thrombocytopenia with normal platelet size in the absence of familial malignancies. The genotype-phenotype correlations might be helpful in genetic counselling and appropriate optimal therapeutic management.

Published
2016

37. Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk

Author

Delphine Bonnet, Rosine Guimbaud, Pascaline Berthet, Anne-Françoise Cailleux, Marie-Pierre Buisine, Jacques Mauillon, Paul Gesta, David Malka, Stéphanie Baert-Desurmont, Estelle Cauchin, Estelle Houivet, Marine Lebrun, Caroline Abadie, Salima El Chehadeh, Isabelle Coupier, Lorena Ippolito, Julie Tinat, Philippe Jonveaux, Qing Wang, Marie Agnès Collonge-Rame, Françoise Desseigne, Sylvie Manouvrier, Jean-Christophe Saurin, Marion Gauthier-Villars, Jean-Marc Rey, Catherine Dugast, Laurence Brugières, Christine Toulas, Brigitte Bressac-de Paillerets, Pierre Laurent-Puig, Pascal Pujol, Sophie Giraud, Fabienne Prieur, Florence Polycarpe-Osaer, Jean Chiesa, Jacques Benichou, Dominique Leroux, Bruno Buecher, Ludovic Mansuy, Marie-Emmanuelle Morin-Meschin, Joanna Sokolowska, Marion Bougeard, Sophie Lejeune, Myriam Bronner, Jacqueline Duffour, Agnès Hardouin, Hakim Sebaoui, Valérie Bonadona, Julien Blot, Chrystelle Colas, Aziz Zaanan, Olivier Caron, Françoise Charbonnier, François Duhoux, Thierry Frebourg, Laurence Faivre, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Cancéropole Nord-Ouest, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Eugène Marquis (CRLCC), Oncologie thoracique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre Léon Bérard [Lyon], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Institut Curie Paris, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Institut Claudius Regaud, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Génétique [CHU HEGP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique Clinique [CHRU Nïmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Onco-génétique, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de génétique [Cliniques Universitaires Saint-Luc, Bruxelles], Cliniques Universitaires Saint-Luc [Bruxelles], Génétique biologique histologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Hépatologie et de Gastroentérologie [Lyon], Unité de recherche clinique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU), and UL, NGERE

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Genotyping Techniques, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Gene Frequency, Risk Factors, Internal medicine, Odds Ratio, Genetics, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Prospective cohort study, Alleles, Genetics (clinical), Chromosomes, Human, Pair 15, business.industry, Case-control study, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Lynch syndrome, 3. Good health, SNP genotyping, [SDV] Life Sciences [q-bio], 030104 developmental biology, Genetic Loci, Case-Control Studies, Female, Chromosomes, Human, Pair 18, Colorectal Neoplasms, business, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract

International audience; To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case-control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's chi(2) test, Cochran-Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30-2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11-1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13-1.98; P=0.007 and OR: 1.49, CI: 1.14-1.95; P=0.0035). We found a significant (P

Published
2016

38. The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients

Author

Marie-Ange Delrue, Nathalie Golovkine, Annick Toutain, Marie-Jose Gregoire, Christel Thauvin-Robinet, Nicolas Gruchy, Cédric Le Caignec, Emilie Landais, Bruno Delobel, Olivier Tassy, Pascal Sabouraud, Laurence Taine, Caroline Fiquet, Nathalie Leporrier, Agathe Paubel, Dominique Gaillard, Philippe Jonveaux, Nathalie Bednarek, Jacques Motte, Bruno Leheup, Olivier Brichet, Albert David, Didier Lacombe, Martine Doco-Fenzy, Stéphanie Arpin, Mylène Beri, Sylvain Briault, Monique Mozelle-Nivoix, Camille Leroy, Francine Mugneret, Service de Génétique, Centre Hospitalier Universitaire de Reims ( CHU Reims ) -Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne ( URCA ) -Université de Reims Champagne-Ardenne ( URCA ), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne ( URCA ) -Université de Picardie Jules Verne ( UPJV ), Centre de génétique et Centre de référence maladies rares et anomalies du développement et syndromes malformatifs du Centre Est, Département de Génétique et Procréation UF-Hôpital Couple Enfant de Grenoble-CHU Grenoble, Plateforme Régionale de Biologie Innovante, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Immunologie et Neurogénétique Expérimentales et Moléculaires ( INEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Service de génétique médicale [CHU Nantes], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Génétique Clinique [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Laboratoire de cytogénétique et génétique moléculaire [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Université de Lorraine ( UL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Maladies Rares - Génétique et Métabolisme ( MRGM ), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Service de génétique [Tours], Hôpital Bretonneau-CHRU Tours, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, American Memorial Hospital (Reims), Service de génétique [Reims], Service de psychothérapie de l’enfant et l’adolescent [CHU Reims], Université de Reims Champagne-Ardenne ( URCA ), Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Centre Hospitalier Universitaire de Reims (CHU Reims), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Maladies Rares - Génétique et Métabolisme (MRGM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Université de Reims Champagne-Ardenne (URCA), UL, NGERE, Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
Adult, Male, Candidate gene, Adolescent, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Chromosome Disorders, Locus (genetics), Biology, Fibrous Dysplasia, Polyostotic, Bioinformatics, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, Humans, Child, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, KIF1A, Behavior, Comparative Genomic Hybridization, 0303 health sciences, [ SDV ] Life Sciences [q-bio], medicine.diagnostic_test, Brachydactyly, Chromosome Mapping, Overweight, Subtelomere, medicine.disease, [SDV] Life Sciences [q-bio], Child, Preschool, Chromosomes, Human, Pair 2, Autism, Female, Chromosome Deletion, 030217 neurology & neurosurgery, Comparative genomic hybridization, Fluorescence in situ hybridization
Abstract

International audience; The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable ‘2q37-deletion syndrome’ or Albright’s hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8 Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype–phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1.

Published
2012

39. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

Author

Laurent Pasquier, Anne V. Snow, David T. Miller, Louise Harewood, Christina Triantafallou, Timothy P.L. Roberts, Leighton B. Hinkley, Zili Chu, Louis Vallée, Alyss Lian Cavanagh, Evica Rajcan-Separovic, Patricia Blanchet, Fiona Miller, Robin P. Goin-Kochel, Beau Reilly, Bettina Cerban, Vanessa Siffredi, Bridget A. Fernandez, Roger Vaughan, Brianna M. Paul, Fanny Morice-Picard, Elisabeth Flori, Dominique Campion, Gérard Didelot, Anne Philippe, Christa Lese Martin, Srikantan S. Nagarajan, Joris Andrieux, Jacques Puechberty, Marie Pierre Cordier, Jill V. Hunter, Ellen van Binsbergen, Catherine Vincent-Delorme, Vivek Swarnakar, Jean Marie Cuisset, Monica Proud, Patrick Callier, Bert B.A. de Vries, Jeffrey I. Berman, Sarah J. Spence, Alexandra Bowe, Wendy K. Chung, Katy Ankenman, Katherine Hines, Sarah E. Gobuty, Philippe Jonveaux, Lisa Blaskey, Alice Goldenberg, Sylvie Jaillard, Alessandra Renieri, Anne M. Maillard, Tracy Luks, Lee Anne Green Snyder, Elliott H. Sherr, Sarah Y. Khan, Fabienne Prieur, Simon A. Zwolinski, Andres Metspalu, Ghislaine Plessis, Jean Chiesa, Rita J. Jeremy, Valérie Malan, Michèle Mathieu-Dramard, Loyse Hippolyte, Bethanny Smith-Packard, Andrea M. Paal, Bénédicte Duban Bedu, Claudine Rieubland, Jordan Burko, Sylvie Joriot, Philippe Conus, Dominique Bonneau, Benoit Arveiler, Nicole de Leeuw, Allison G. Dempsey, John E. Spiro, Julia Wenegrat, Bertrand Isidor, Cédric Le Caignec, Kyle J. Steinman, Bruno Delobel, Ashlie Llorens, Jacques S. Beckmann, Kelly Johnson, Sean Ackerman, Polina Bukshpun, Silvia Garza, Alexandre Reymond, Damien Sanlaville, Ellen Hanson, Martine Doco-Fenzy, Jacques Thonney, Mari Wakahiro, Juliane Hoyer, Jacqueline Vigneron, Katrin Õunap, Arthur L. Beaudet, Mandy Barker, Nicole Visyak, Sonia Bouquillon, W. Andrew Faucett, Raphael Bernier, Sudha Kilaru Kessler, Audrey Lynn Bibb, Dennis Shaw, R. Frank Kooy, Suzanne M E Lewis, Anna L. Laakman, Nicholas J. Pojman, Hubert Journel, Laura Bernardini, Arianne Stevens, Julia P. Owen, Rebecca Mc Nally Keehn, Stéphanie Selmoni, Sébastien Lebon, Aurélien Macé, Bruno Leheup, Saba Qasmieh, Zoltán Kutalik, Anita Rauch, Yiping Shen, Elysa J. Marco, Nathalie Van der Aa, Carina Ferrari, Noam D. Beckmann, Delphine Héron, Jennifer Tjernage, Benjamin Aaronson, Albert David, Marie Pierre Lemaitre, Muriel Holder, Eve Õiglane-Shlik, Anneke T. Vulto-van Silfhout, Flore Zufferey, Constance Atwell, Marta Benedetti, Ellen Grant, Jenna Elgin, Patricia Z. Page, Caroline Rooryck, Randy L. Buckner, Qixuan Chen, Laurence Faivre, Sébastien Jacquemont, Kerri P. Nowell, Florence Fellmann, Disciglio Vittoria, Katharina Magdalena Rötzer, Hana Lee, Alastair J. Martin, Marion Greenup, David H. Ledbetter, Katrin Männik, Morgan W. Lasala, Jennifer Gerdts, Hanalore Alupay, Florence Petit, Elizabeth Aylward, Gerald D. Fischbach, Mafalda Mucciolo, Maxwell Cheong, Gabriela Marzano, Frédérique Béna, Danielle Martinet, Timothy J. Moss, Odile Boute, Jennifer Olson, Marco Belfiore, Christina Fagerberg, Corby L. Dale, Robert M. Witwicki, Yolanda L. Evans, Melissa B. Ramocki, Marie-Claude Addor, Christèle Dubourg, Mariken Ruiter, Tuhin K. Sinha, Mieke M. van Haelst, Alan Packer, Kathleen E. McGovern, Christie M. Brewton, Stephen M. Kanne, Richard I. Fisher, Tracey Ward, Sophie Dupuis-Girod, Pratik Mukherjee, Simons VIP Consortium, 16p11.2 European Consortium, Addor, MC., Arveiler, B., Belfiore, M., Bena, F., Bernardini, L., Blanchet, P., Bonneau, D., Boute, O., Callier, P., Campion, D., Chiesa, J., Cordier, MP., Cuisset, JM., David, A., de Leeuw, N., de Vries, B., Didelot, G., Doco-Fenzy, M., Bedu, BD., Dubourg, C., Dupuis-Girod, S., Fagerberg, CR., Faivre, L., Fellmann, F., Fernandez, BA., Fisher, R., Flori, E., Goldenberg, A., Heron, D., Holder, M., Hoyer, J., Isidor, B., Jaillard, S., Jonveaux, P., Joriot, S., Journel, H., Kooy, F., le Caignec, C., Leheup, B., Lemaitre, MP., Lewis, S., Malan, V., Mathieu-Dramard, M., Metspalu, A., Morice-Picard, F., Mucciolo, M., Oiglane-Shlik, E., Ounap, K., Pasquier, L., Petit, F., Philippe, A., Plessis, G., Prieur, F., Puechberty, J., Rajcan-Separovic, E., Rauch, A., Renieri, A., Rieubland, C., Rooryck, C., Rötzer, KM., Ruiter, M., Sanlaville, D., Selmoni, S., Shen, Y., Siffredi, V., Thonney, J., Vallée, L., van Binsbergen, E., Van der Aa, N., van Haelst MM., Vigneron, J., Vincent-Delorme, C., Vittoria, D., Vulto-van Silfhout AT., Witwicki, RM., Zwolinski, SA., Bowe, A., Beaudet, AL., Brewton, CM., Chu, Z., Dempsey, AG., Evans, YL., Garza, S., Kanne, SM., Laakman, AL., Lasala, MW., Llorens, AV., Marzano, G., Moss, TJ., Nowell, KP., Proud, MB., Chen, Q., Vaughan, R., Berman, J., Blaskey, L., Hines, K., Kessler, S., Khan, SY., Qasmieh, S., Bibb, AL., Paal, AM., Page, PZ., Smith-Packard, B., Buckner, R., Burko, J., Cavanagh, AL., Cerban, B., Snow, AV., Snyder, LG., Keehn, RM., Miller, DT., Miller, FK., Olson, JE., Triantafallou, C., Visyak, N., Atwell, C., Benedetti, M., Fischbach, GD., Greenup, M., Packer, A., Bukshpun, P., Cheong, M., Dale, C., Gobuty, SE., Hinkley, L., Jeremy, RJ., Lee, H., Luks, TL., Marco, EJ., Martin, AJ., McGovern, KE., Nagarajan, SS., Owen, J., Paul, BM., Pojman, NJ., Sinha, T., Swarnakar, V., Wakahiro, M., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Elgin, J., Gerdts, J., Johnson, K., Reilly, B., Shaw, D., Stevens, A., Ward, T., Wenegrat, J., Other departments, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), CHU Pontchaillou [Rennes], Department of Medical Genetics, Université de Lausanne (UNIL), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Texas Children's Hospital [Houston, USA], Department of pediatrics, Primary palliative Care Research Group, Community Health Sciences, General Practice Section, University of Edinburgh, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developmental Brain and Behaviour Unit, University of Southampton, Institute of Molecular and Cell Biology, University of Tartu, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Lausanne = University of Lausanne (UNIL), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California (UC)-University of California (UC)-Semel Institute, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Kooy, Frank

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Heterozygote, Adolescent, [SDV]Life Sciences [q-bio], Developmental Disabilities, Biology, Body Mass Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Order, Genetics, medicine, Humans, Copy-number variation, Clinical genetics, Obesity, Young adult, Child, Genetics (clinical), 030304 developmental biology, Child Development Disorders, Pervasive/diagnosis, Child Development Disorders, Pervasive/genetics, Chromosome Deletion, Chromosomes, Human, Pair 16, Developmental Disabilities/diagnosis, Developmental Disabilities/genetics, Female, Intelligence Tests, Phenotype, Syndrome, 2. Zero hunger, Psychiatry, 0303 health sciences, Intelligence quotient, Neuropsychology, Complex traits, medicine.disease, Comorbidity, 3. Good health, Autism spectrum disorder, Child Development Disorders, Pervasive, Autism, Medical genetics, Human medicine, Copy-Number Variation, 030217 neurology & neurosurgery
Abstract

Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Published
2012

40. What can we learn from old microdeletion syndromes using array-CGH screening?

Author

Nathalie Marle, Muriel Holder-Espinasse, C. Ragon, P. Callier, Anne Dieux-Coeslier, Anne-Laure Mosca-Boidron, Philippe Jonveaux, Joris Andrieux, Catherine Vincent-Delorme, Muriel Payet, Brigitte Benzacken, Francine Mugneret, E Questiaux, Ghislaine Plessis, Eva Pipiras, C. Thauvin-Robinet, Alice Masurel-Paulet, Sonia Bouquillon, Andrée Delahaye, C Bonnet, Sylvie Manouvrier-Hanu, M Berri, and Laurence Faivre

Subjects
Adult, Adolescent, Genotype, Chromosomes, Human, Pair 22, Karyotype, Biology, Bioinformatics, Intellectual Disability, Variable phenotype, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), Comparative Genomic Hybridization, medicine.disease, Phenotype, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 7, Modifier Genes, Comparative genomic hybridization
Abstract

Most microdeletion syndromes identified before the implementation of array-comparative genomic hybridization (array-CGH) were presumed to be well-defined clinical entities. However, the introduction of whole-genome screening led not only to the description of new syndromes but also to the recognition of a broader spectrum of features for well-known syndromes. Here, we report on 10 patients presenting with mental retardation associated with atypical features not suggestive of a known microdeletion and a normal standard karyotype. Array-CGH analyses revealed five microdeletions in the DiGeorge region, three microdeletions in the Williams-Beuren region and two microdeletions in the Smith-Magenis region. Reevaluation in these patients confirmed that the diagnosis remained difficult on clinical grounds and emphasized that well-known genomic disorders can have a phenotype that is heterogeneous and more variable than originally thought. The widespread use of array-CGH shows that such patients may be more readily achieved on the basis of genotype rather than phenotype.

Published
2011

41. IgG deficiency and expansion of CTG repeats in myotonic dystrophy

Author

Jean François Lesesve, Pierre Kaminsky, Philippe Jonveaux, and Lelia Pruna

Subjects
Adult, Male, musculoskeletal diseases, Immunoglobulin A, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, CD3 Complex, T-Lymphocytes, Lymphocyte, Myotonic dystrophy, Immunoglobulin G, Young Adult, Trinucleotide Repeats, medicine, Humans, Myotonic Dystrophy, Lymphocyte Count, IgG Deficiency, Aged, biology, business.industry, General Medicine, Middle Aged, Myotonia, medicine.disease, CD4 Lymphocyte Count, medicine.anatomical_structure, Immunoglobulin M, Immunology, biology.protein, Female, Surgery, IgG deficiency, Neurology (clinical), Antibody, business
Abstract

Objectives Expansion of CTG repeats in myotonic dystrophy (DM1) alters the regulated expression of numerous genes. It is considered to explain the major clinical features of DM1. IgG deficiency is common in DM1 and is due to altered FcRn-related hypercatabolism. We hypothesized that the IgG catabolic rate is correlated with CTG repeat expansion. Methods Correlations between serum immunoglobulin levels, peripheral lymphocyte subset counts and CTG repeat numbers were performed in 52 DM1 patients. Results Serum IgG and IgG1 levels were below the normal limit respectively in 54% and 72% of patients. Increasing CTG repeat numbers were significantly correlated with decreasing serum IgG and IgG1 levels, and with decreasing CD3+ T-cell and CD3+–CD8+ cell counts. An abnormal immunoglobulin profile at protein electrophoresis was found in 4 patients. Conclusion We conclude that the catabolic rate of IgG is linked to expanded CTG repeats, possibly involving an altered immune response.

Published
2011

42. De Novo 21q22.1q22.2 deletion including RUNX1 mimicking a congenital infection

Author

Mylène Béri-Dexheimer, Sylvie Falcon-Eicher, Christel Thauvin-Robinet, Julien Thevenon, Frédéric Huet, Philippe Jonveaux, Laurence Faivre, Francine Mugneret, Patrick Callier, Marc Maynadié, N. Méjean, Samuel Bidot, and Emmanuel de Maistre

Subjects
Genetics, chemistry.chemical_compound, Text mining, RUNX1, chemistry, business.industry, Medicine, business, Genetics (clinical)
Published
2010

43. Clinical and molecular characterization of a large family with an interstitial 15q11q13 duplication

Author

Claire Beneteau, Marie-José Grégoire, Christophe Philippe, Marie Marvier, Juliette Piard, M. Béri, Philippe Jonveaux, Virginie Roth, B. Leheup, Céline Bonnet, and M. Valduga

Subjects
Male, Adolescent, Psychometrics, Biology, Polymerase Chain Reaction, Genomic Imprinting, Gene Duplication, Intellectual Disability, Angelman syndrome, Gene duplication, Genetics, medicine, Humans, Clinical significance, Autistic Disorder, Child, In Situ Hybridization, Fluorescence, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Chromosomes, Human, Pair 15, Comparative Genomic Hybridization, medicine.diagnostic_test, Infant, DNA Methylation, medicine.disease, Penetrance, Pedigree, Phenotype, Child, Preschool, Autism, Female, Angelman Syndrome, Abnormality, Prader-Willi Syndrome, Fluorescence in situ hybridization, Comparative genomic hybridization
Abstract

The clinical significance of an interstitial duplication of chromosome 15q11q13 is still not well documented. This abnormality has been associated with autistic spectrum disorders (ASD) and varying degrees of mental retardation. The clinical variability appears to be influenced by the parental origin of the duplication. We present here the clinical evaluation and psychological assessment of the largest reported family with 12 carriers on three generations. Patients exhibit mental retardation, motor and visuo-motor skills impairments and adaptive functioning deficit without formal diagnosis of autism. There appeared to be evidence in the family of reduced penetrance in duplication of paternal origin. This familial 15q11q13 duplication was precisely investigated by cytogenetic and molecular techniques including fluorescence in situ hybridization (FISH), PCR analysis of microsatellite markers, array-comparative genomic hybridization analysis (Array-CGH) and semi-quantitative methylation-sensitive PCR. Results showed an inherited 15q11q13 duplication of maternal origin in 10 patients and of paternal origin in the remaining two. The size of the duplicated area was around 6 Mb with breakpoints in accordance with those previously reported. This report extends the clinical spectrum of the 15q11q13 duplication, and we recommend the investigation of 15q11q13 duplication not only in subjects with autistic spectrum disorder but also in patients with low normal intelligence and dyspraxia.

Published
2010

44. A retrospective study by oligonucleotide array-CGH analysis in 50 fetuses with multiple malformations

Author

A. Miton, M. Valduga, M. Béri, Christophe Nemos, B. Foliguet, Philippe Jonveaux, P. Bach Segura, O. Thiebaugeorges, Christophe Philippe, and Céline Bonnet

Subjects
Fetus, Pathology, medicine.medical_specialty, Obstetrics and Gynecology, Prenatal diagnosis, Biology, medicine.disease, Corpus callosum, Agenesis, Tetrasomy, medicine, Copy-number variation, Trisomy, Genetics (clinical), Comparative genomic hybridization
Abstract

Objective To retrospectively define the frequency and the nature of submicroscopic chromosomal imbalances among fetuses with multiple congenital anomalies (MCA). Methods We used oligonucleotide arrays to perform comparative genomic hybridization after termination of pregnancy in 50 polymalformated fetuses with a normal karyotype. These fetuses presented with at least three significant malformations (42 cases) or a severe brain anomaly (eight cases). Results We identified a deleterious copy number variation (CNV) in five fetuses (10%). De novo genomic imbalances identified in this study consisted of a 6qter deletion in a fetus with brain and renal malformations, a mosaicism for a 8p tetrasomy in a fetus with agenesis of corpus callosum, growth retardation, mild facial dysmorphic features, and vertebral anomalies, a 17p13.3 deletion in a fetus with a complex brain malformation, and a partial 11p trisomy in a fetus with severe growth retardation and oligoamnios. In one case, we identified a partial 17q trisomy resulting from malsegregation of a cryptic-balanced translocation. Conclusions This study shows that array comparative genomic hybridization (aCGH) is particularly effective for identifying the molecular basis of the disease phenotype in fetuses with multiple anomalies. Our study should help to define clinical relevant regions that would need to be included in targeted arrays designed for prenatal testing. Copyright © 2010 John Wiley & Sons, Ltd.

Published
2010

45. Mutational spectrum ofCDKL5in early-onset encephalopathies: a study of a large collection of French patients and review of the literature

Author

Philippe Jonveaux, Alice Goldenberg, Christophe Philippe, Fabienne Giuliano, Bérénice Doray, F Verneau, Valérie Layet, Aline Saunier, MA N’guyen, Christophe Nemos, Bruno Delobel, Laetitia Lambert, and Agathe Roubertie

Subjects
Blotting, Western, CDKL5, Rett syndrome, Protein Serine-Threonine Kinases, Bioinformatics, Aicardi syndrome, Epilepsy, Neurodevelopmental disorder, Gene Frequency, Seizures, Gene duplication, Rett Syndrome, Genetics, medicine, Humans, Genetic Predisposition to Disease, Atypical Rett syndrome, Genetic Testing, Cells, Cultured, Genetics (clinical), DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, business.industry, Infant, Newborn, Infant, Flow Cytometry, medicine.disease, Hypotonia, Pedigree, Phenotype, Child, Preschool, Mutation, Female, France, medicine.symptom, business
Abstract

The CDKL5 gene has been implicated in the molecular etiology of early-onset intractable seizures with infantile spasms (IS), severe hypotonia and atypical Rett syndrome (RTT) features. So far, 48 deleterious alleles have been reported in the literature. We screened the CDKL5 gene in a cohort of 177 patients with early-onset seizures, including 30 men and 10 girls with Aicardi syndrome. The screening was negative for all men as well as for women with Aicardi syndrome, excluding the CDKL5 gene as a candidate for this neurodevelopmental disorder. We report 11 additional de novo mutations in CDKL5 in female patients. For the first time, the MLPA approach allowed the identification of a partial deletion encompassing the promoter and the first two exons of CDKL5. The 10-point mutations consist of five missenses (with recurrent amino acid changes at p.Ala40 and p.Arg178), four splicing variants and a 1-base pair duplication. We present a review of all mutated alleles published in the literature. In our study, the overall frequency of mutations in CDKL5 in women with early-onset seizures is around 8.6%, a result comparable with previous reports. Noteworthy, the CDKL5 mutation rate is high (28%) in women with early-onset seizures and IS.

Published
2009

46. AberrantGRIA3transcripts with multi-exon duplications in a family with X-linked mental retardation

Author

B. Leheup, M. Béri, Céline Bonnet, Philippe Jonveaux, Marie-José Grégoire, and Christophe Philippe

Subjects
Male, Genetics, Polymorphism, Genetic, Base Sequence, biology, Molecular Sequence Data, Phenotype, Pedigree, Frameshift mutation, Young Adult, Exon, X Chromosome Inactivation, Gene Duplication, Gene duplication, Mental Retardation, X-Linked, biology.protein, Humans, Female, Receptors, AMPA, Tandem exon duplication, Allele, GRIA3, Genetics (clinical), X chromosome
Abstract

Investigation of chromosomal rearrangements in patients with mental retardation (MR) is particularly informative in the search for novel genes involved in MR. We report on a family with a genomic duplication at Xq25 identified by oligo array-CGH. Further characterization showed a partial tandem duplication of GRIA3 extending from exon 1 to exon 12. This duplication is present in two brothers with MR and on one allele in their sister with normal phenotype and completely skewed X-chromosome inactivation. The duplication is inherited from the mother, whose cognitive level is low and X-chromosome inactivation is random. This is the second family with partial duplication of GRIA3 associated with MR. GRIA3 expression studies in our case demonstrated a new mechanism for GRIA3 dysfunction with the presence of aberrant GRIA3 transcripts carrying multi-exon duplications leading to a frameshift. Our study gives additional support to the implication of GRIA3 in X-linked MR.

Published
2009

47. Gestion des variations du nombre de séquences génomiques (CNV) en génétique humaine constitutionnelle utilisant l’hybridation génomique comparative en microréseau d’ADN (HGCM)

Author

Anne-Claire Bursztejn, Philippe Jonveaux, and Christophe Nemos

Subjects
General Medicine, Biology, Molecular biology
Abstract

Resume Ces dernieres annees, la technologie d’hybridation genomique comparative en microreseau d’ADN (HGCM) a connu une progression majeure en terme de resolution. Cette avancee technologique a permis de detecter un grand nombre de variations structurales dans le genome humain qui peuvent avoir une incidence sur la survenue de phenotypes deleteres. Cette revue a pour objectif d’eclaircir la terminologie relative aux variations structurales a l’echelle des variations en nombre de copies (CNV), de determiner les champs d’application de l’HGCM et d’aborder l’interpretation des associations qui peuvent exister et qui restent a realiser dans l’avenir entre les CNV et les anomalies genetiques generant un phenotype deletere.

Published
2008

48. Cryptic 7q21 and 9p23 deletions in a patient with apparently balanced de novo reciprocal translocation t(7;9)(q21;p23) associated with a dystonia-plus syndrome: paternal deletion of the epsilon-sarcoglycan (SGCE) gene

Author

Céline Bonnet, Marie-José Grégoire, E. Raffo, B. Leheup, Mireille Vibert, and Philippe Jonveaux

Subjects
Male, Myoclonus, Developmental Disabilities, Chromosome 9, Chromosomal translocation, Biology, Translocation, Genetic, Fathers, SGCE, Sarcoglycans, Genetics, Humans, Allele, In Situ Hybridization, Fluorescence, Genetics (clinical), Chromosome 7 (human), Infant, Syndrome, Molecular biology, Chromosome Banding, Dystonic Disorders, Chromosome Deletion, Chromosomes, Human, Pair 9, Genomic imprinting, Haploinsufficiency, Chromosomes, Human, Pair 7, Dystonic disorder
Abstract

We report on a boy with myoclonus-dystonia (M-D), language delay, and malformative anomalies. Genetic investigations allowed the identification of an apparently balanced de novo reciprocal translocation, t(7;9)(q21;p23). Breakpoint-region mapping using fluorescent in situ hybridization (FISH) analysis of bacterial artificial chromosome (BAC) clone probes identified microdeletions of 3.7 and 5.2 Mb within 7q21 and 9p23 breakpoint regions, respectively. Genotyping with microsatellite markers showed that deletions originated from paternal alleles. The deleted region on chromosome 7q21 includes a large imprinted gene cluster. SGCE and PEG10 are two maternally imprinted genes. SGCE mutations are implicated in M-D. In our case, M-D is due to deletion of the paternal allele of the SGCE gene. PEG10 is strongly expressed in the placenta and is essential for embryo development. Prenatal growth retardation identified in the patient may be due to deletion of the paternal allele of the PEG10 gene. Other genes in the deleted region on chromosome 7 are not imprinted. Nevertheless, a phenotype can be due to haploinsufficiency of these genes. KRIT1 is implicated in familial forms of cerebral cavernous malformations, and COL1A2 may be implicated in very mild forms of osteogenesis imperfecta. The deleted region on chromosome 9 overlaps with the candidate region for monosomy 9p syndrome. The proband shows dysmorphic features compatible with monosomy 9p syndrome, without mental impairment. These results emphasize that the phenotypic abnormalities of apparently balanced de novo translocations can be due to cryptic deletions and that the precise mapping of these aneusomies may improve clinical management.

Published
2008

49. Clinical phenotype of germline RUNX1 haploinsufficiency: from point mutations to large genomic deletions

Author

Véronique Latger-Cannard, Marie-José Grégoire, Thomas Lecompte, Mylène Béri-Dexheimer, Céline Bonnet, Pierre Bordigoni, Virginie Roth, Pascal Chambon, Philippe Jonveaux, Christophe Philippe, and Bruno Leheup

Subjects
Male, Myeloid, Chromosomes, Human, Pair 21, Genetic counseling, Platelet disorder, Biology, Polymerase Chain Reaction, Short stature, Germline, chemistry.chemical_compound, Intellectual Disability, hemic and lymphatic diseases, Genetics, medicine, Humans, Point Mutation, Child, Genetics (clinical), Sequence Deletion, Genome, Human, Point mutation, DNA, Thrombocytopenia, Phenotype, medicine.anatomical_structure, RUNX1, chemistry, Child, Preschool, Core Binding Factor Alpha 2 Subunit, Cancer research, Female, Blood Platelet Disorders, medicine.symptom, Haploinsufficiency
Abstract

Germline RUNX1 mutations result in a rare autosomal dominant condition characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies (familial platelet disorder with propensity to acute myeloid leukaemia, FPD/AML). Only 13 pedigrees have previously been described so far. We report on two novel germline RUNX1 mutations: (1) an out-of-frame 8 bp heterozygous deletion (c.442_449del) in an FPD/AML pedigree and (2) a de novo 3.5 Mb deletion in the 21q22.11.21q22.12 region encompassing the RUNX1 gene in a mentally retarded female patient with short stature and thrombocytopenia. Interestingly, a similar de novo submicroscopic deletion has been recently reported in the literature in a mentally retarded patient. Mental retardation is one of the most common disorders and primary causes of thrombocytopenia are rare. When occurring together, these features should prompt to test for 21q22 deletion for comprehensive genetic counselling and clinical management.

Published
2008

50. Prenatal diagnosis of mosaicism for 11q terminal deletion

Author

A. Miton, Philippe Jonveaux, T. Lecompte, B. Foliguet, S. Romana, Christophe Philippe, M. Valduga, P. Droulle, and V. Latger Cannard

Subjects
Adult, Pathology, medicine.medical_specialty, Down syndrome, Monosomy, Genetic counseling, Prenatal diagnosis, Ultrasonography, Prenatal, Pregnancy, Prenatal Diagnosis, Genetics, medicine, Humans, Jacobsen syndrome, In Situ Hybridization, Fluorescence, Genetics (clinical), Chromosomal Deletion, medicine.diagnostic_test, Mosaicism, business.industry, Chromosomes, Human, Pair 11, Paris-Trousseau syndrome, General Medicine, medicine.disease, Karyotyping, Amniocentesis, Female, Chromosome Deletion, business
Abstract

The phenotype of 11q terminal deletion also known as Jacobsen syndrome is a clinically well known entity whose diagnosis in infancy and childhood is based on clinical examination, hematological and cytogenetic findings. Hematological features in Jacobsen syndrome are very similar to those reported in Paris-Trousseau syndrome (PTS) which is also associated with11q terminal deletion. Karyotype analysis shows a variable terminal deletion from 11q23 sub-band extending to the telomere. Most often in patients with Jacobsen syndrome, this chromosomal deletion is present in all metaphases. We report on the identification of a distal 11q deletion in mosaic (20% of deleted cells) in a fetus ascertained after amniocentesis for maternal serum screening test indicative for Down syndrome. The present case is the third prenatal diagnosis of a mosaic for a distal 11q deletion with the lowest mosaicism rate. The 2D-ultrasound examination and cord blood hematological studies were useful to estimate the prognosis at term, considering the contribution of the mosaicism rate to the phenotypic variability in Jacobsen syndrome. The identification of mosaicism for distal 11q deletion is a very rare event in prenatal diagnosis. This case illustrates the complexity in genetic counselling for prenatally ascertained partial monosomy 11qter in mosaic.

Published
2007

Catalog

Books, media, physical & digital resources
See catalog results