87 results on '"Yves Sznajer"'
Search Results
2. Novel RPL13 variants and evidence for incomplete penetrance in a human ribosomopathy with spondyloepimetaphyseal dysplasia
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Alice Costantini, Jessica J. Alm, Francesca Tonelli, Helena Valta, Céline Huber, Anh N. Tran, Valentina Daponte, Nadi Kirova, Yong-Uk Kwon, Jung Yun Bae, Woo Yeong Chung, Shengjiang Tan, Yves Sznajer, Gen Nishimura, Tuomas Näreoja, Alan J. Warren, Valérie Cormier-Daire, Ok-Hwa Kim, Antonella Forlino, Tae-Joon Cho, and Outi Mäkitie
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Diseases of the musculoskeletal system ,RC925-935 - Published
- 2020
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3. Patient with confirmed LEOPARD syndrome developing multiple melanoma
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Colmant Caroline, Deborah Franck, Liliane Marot, Gert Matthijs, Yves Sznajer, Sandrine Blomme, and Isabelle Tromme
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LEOPARD syndrome ,melanomas ,dermoscopy ,Dermatology ,RL1-803 - Abstract
LEOPARD syndrome, also known as Gorlin syndrome II, cardiocutaneous syndrome, lentiginosis profusa syndrome, Moynahan syndrome, was more recently coined as Noonan syndrome with multiple lentigines (NSML), inside the RASopathies. Historically, the acronym LEOPARD refers to the presence of distinctive clinical features such as: lentigines (L), electrocardiographic/conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), genital abnormalities (A), retardation of growth (R), and sensorineural deafness (D). This condition is identified in 85% of patients with phenotype hallmarks caused by presence a germline point mutation in PTPN11 gene. Association of melanoma to NSML seems to be rare: to our knowledge, two patients so far were reported in the literature. We herein present a patient diagnosed with LEOPARD syndrome, in whom molecular investigation confirmed the presence of the c.1403C>T mutation in exon 12 of the PTPN11 gene, who developed four superficial spreading melanomas and three atypical lentiginous hyperplasias. Three of the melanomas were achromic or hypochromic, three were in situ, and one had a Breslow index under 0.5 mm. Dermoscopic examination showed some characteristic white structures in most of the lesions, which were a signature pattern and a key for the diagnosis.
- Published
- 2018
4. ISID0852 - Olmsted syndrome due to PERP mutations shows activation of the EGFR pathway and is improved by oral erlotinib
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Stéphanie Mallet, Yves Sznajer, An Van Damme, Valérie Dekeuleneer, Lucile MARCHAL, Justine Basset, and Hovnanian Alain
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- 2023
5. Outcome of publicly funded nationwide first-tier noninvasive prenatal screening
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Leonor Palmeira, Lore Lannoo, Anne De Leener, Eva Sammels, Julie Désir, Nathalie Brison, Guillaume Smits, Vincent Bours, Annelies Dheedene, Annelies Fieuw, Kris Van Den Bogaert, Marjan De Rademaeker, Elise Vantroys, Jean-Stéphane Gatot, Laura Bourlard, Vincent Gatinois, Colombine Meunier, Koenraad Devriendt, Armelle Duquenne, François Boemer, Bettina Blaumeiser, Axel Marichal, Katrien Janssens, Joris Vermeesch, Nathalie Fieremans, Bruno Pichon, Yves Sznajer, Björn Menten, Sandra Janssens, Bernard Grisart, Machteld Baetens, Damien Lederer, UCL - SSS/IREC/SLUC - Pôle St.-Luc, and UCL - (SLuc) Centre de génétique médicale UCL
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0301 basic medicine ,Down syndrome ,medicine.medical_specialty ,Noninvasive Prenatal Testing ,Population ,MEDLINE ,Chromosome Disorders ,Trisomy ,Prenatal care ,030105 genetics & heredity ,03 medical and health sciences ,Pregnancy ,Prenatal Diagnosis ,medicine ,Humans ,Genomic medicine ,education ,Genetics (clinical) ,education.field_of_study ,business.industry ,Obstetrics ,Incidence (epidemiology) ,Aneuploidy ,medicine.disease ,030104 developmental biology ,Prenatal screening ,Female ,Human medicine ,Down Syndrome ,business - Abstract
Purpose Noninvasive prenatal screening (NIPS) using cell-free DNA has transformed prenatal care. Belgium was the first country to implement and fully reimburse NIPS as a first-tier screening test offered to all pregnant women. A consortium consisting of all Belgian genetic centers report the outcome of two years genome-wide NIPS implementation. Methods The performance for the common trisomies and for secondary findings was evaluated based on 153,575 genome-wide NIP tests. Furthermore, the evolution of the number of invasive tests and the incidence of Down syndrome live births was registered. Results Trisomies 21, 18, and 13 were detected in respectively 0.32%, 0.07%, and 0.06% of cases, with overall positive predictive values (PPVs) of 92.4%, 84.6%, and 43.9%. Rare autosomal trisomies and fetal segmental imbalances were detected in respectively 0.23% and 0.07% of cases with PPVs of 4.1% and 47%. The number of invasive obstetric procedures decreased by 52%. The number of trisomy 21 live births dropped to 0.04%. Conclusion Expanding the scope of NIPS beyond trisomy 21 fetal screening allows the implementation of personalized genomic medicine for the obstetric population. This genome-wide NIPS approach has been embedded successfully in prenatal genetic care in Belgium and might serve as a framework for other countries offering NIPS.
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- 2021
6. Novel <scp> RPL13 </scp> Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia
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Outi Mäkitie, Gen Nishimura, Yves Sznajer, Valérie Cormier-Daire, Francesca Tonelli, Tuomas Näreoja, Yong Uk Kwon, Anh Nhi Tran, Valentina Daponte, Ok Hwa Kim, Helena Valta, Tae Joon Cho, Alan J. Warren, Jung Yun Bae, Antonella Forlino, Alice Costantini, Nadi Kirova, Jessica J. Alm, Woo Yeong Chung, Shengjiang Tan, Céline Huber, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de référence neuromusculaire, UCL - SSS/IREC/SLUC - Pôle St.-Luc, HUS Children and Adolescents, Children's Hospital, University of Helsinki, Helsinki University Hospital Area, Clinicum, Lastentautien yksikkö, CAMM - Research Program for Clinical and Molecular Metabolism, and Research Programs Unit
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0301 basic medicine ,WEB TOOL ,Ribosomopathy ,Endocrinology, Diabetes and Metabolism ,0302 clinical medicine ,Missense mutation ,Orthopedics and Sports Medicine ,ENCODES ,Zebrafish ,Genetics ,CHOPCHOP ,Phenotype ,Penetrance ,Neoplasm Proteins ,Pedigree ,3. Good health ,CRISPR-CAS9 ,Original Article ,medicine.symptom ,Ribosomal Proteins ,030209 endocrinology & metabolism ,Biology ,Osteochondrodysplasias ,Short stature ,RPL13 ,03 medical and health sciences ,SKELETAL ,Spondyloepimetaphyseal dysplasia ,Variable expressivity ,INCOMPLETE PENETRANCE ,medicine ,Animals ,Humans ,Incomplete penetrance ,MUTATIONS ,SPONDYLOEPIMETAPHYSEAL DYSPLASIA ,ZEBRAFISH ,RIBOSOMOPATHY ,Original Articles ,medicine.disease ,biology.organism_classification ,GENE ,Spine ,030104 developmental biology ,Biological Variation, Population ,VARIABLE EXPRESSIVITY ,Dysplasia ,3121 General medicine, internal medicine and other clinical medicine ,CRISPR‐CAS9 - Abstract
Spondyloepimetaphyseal dysplasias (SEMDs) are a heterogeneous group of disorders with variable growth failure and skeletal impairments affecting the spine and long bone epiphyses and metaphyses. Here we report on four unrelated families with SEMD in which we identified two monoallelic missense variants and one monoallelic splice site variant in RPL13, encoding the ribosomal protein eL13. In two out of four families, we observed autosomal dominant inheritance with incomplete penetrance and variable clinical expressivity; the phenotypes of the mutation‐positive subjects ranged from normal height with or without hip dysplasia to severe SEMD with severe short stature and marked skeletal dysplasia. In vitro studies on patient‐derived dermal fibroblasts harboring RPL13 missense mutations demonstrated normal eL13 expression, with proper subcellular localization but reduced colocalization with eL28 (p
- Published
- 2020
7. Phenotypic spectrum of patients with Poretti-Boltshauser syndrome: Patient report of antenatal ventriculomegaly and esophageal atresia
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Chloé Geerts, Yves Sznajer, Erika D'haenens, Dana Dumitriu, and Marie-Cécile Nassogne
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Genetics ,General Medicine ,Genetics (clinical) - Abstract
Poretti-Boltshauser syndrome (PTBHS) is an autosomal recessive disorder characterized by cerebellar dysplasia with cysts and an abnormal shape of the fourth ventricle on neuroimaging, due to pathogenic variants in the LAMA1 gene. The clinical spectrum mainly consists of neurological and ophthalmological manifestations, including non-progressive cerebellar ataxia, oculomotor apraxia, language impairment, intellectual disability, high myopia, abnormal eye movements and retinal dystrophy. We report a patient presenting with ventriculomegaly on antenatal neuroimaging and a neonatal diagnosis of Type III esophageal atresia. She subsequently developed severe myopia and strabismus with retinal dystrophy, mild developmental delay, and cerebellar dysplasia. Genetic investigations confirmed PTBHS. This report confirms previous reports of antenatal ventriculomegaly in PTBHS patients and documents a so far unreported occurrence of esophageal atresia in PTBHS. We additionally gathered phenotype and genotype descriptions of published cases in an effort to better define the spectrum of PTBHS.
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- 2022
8. Null variants and deletions in BRWD3 cause an X‐linked syndrome of mild–moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients
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Sahar Mansour, Sarah F. Smithson, Gillian Rea, Anna Zachariou, Philip J. Ostrowski, Edward Blair, Alison Foster, Sofia Douzgou, Katrina Tatton-Brown, Trevor Cole, Chey Loveday, Elizabeth Thompson, Swati Naik, Diana Baralle, Katherine Lachlan, Michael Field, Claire Kyle, and Yves Sznajer
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Male ,0301 basic medicine ,Joint hypermobility ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Context (language use) ,030105 genetics & heredity ,Severity of Illness Index ,03 medical and health sciences ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Humans ,Prognathism ,Obesity ,Child ,Genetics (clinical) ,business.industry ,Macrocephaly ,Genetic Diseases, X-Linked ,Syndrome ,medicine.disease ,Megalencephaly ,Chin ,030104 developmental biology ,medicine.anatomical_structure ,Neonatal hypotonia ,medicine.symptom ,Differential diagnosis ,business ,Gene Deletion ,Transcription Factors - Abstract
BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and two partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (
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- 2019
9. Fetal Vesicoallantoic Cyst and Intraabdominal Defects: An Unusual Case and Review of the Literature
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Jean Marc Biard, Corinne Hubinont, Etienne Marbaix, Mathieu Delvaux, Yves Sznajer, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de référence neuromusculaire, UCL - (SLuc) Service d'oto-rhino-laryngologie, UCL - SST/ELI/ELIE - Environmental Sciences, UCL - SSS/DDUV/CELL - Biologie cellulaire, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Centre labio-palatin Albert de Coninck, and UCL - (SLuc) Service d'obstétrique
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medicine.medical_specialty ,Fetus ,business.industry ,Pediatrics, Perinatology and Child Health ,medicine ,Obstetrics and Gynecology ,Cyst ,General Medicine ,medicine.disease ,business ,Surgery - Abstract
no abstract available
- Published
- 2021
10. Wieacker‐Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a 'de novo' ZC4H2 gene partial deletion
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Yves Sznajer, Armelle Duquenne, Charlotte Deneufbourg, and Jean-Marc Biard
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Arthrogryposis ,Genetics ,Medicine (General) ,Fetus ,Arthrogryposis multiplex congenita ,business.industry ,Genetic counseling ,Case Report ,General Medicine ,Phenotype ,DNA sequencing ,ZC4H2 gene ,Wieacker‐Wolff syndrome ,R5-920 ,arthrogryposis multiplex congenita ,Medicine ,Xq11.2 deletion ,medicine.symptom ,business ,WIEACKER-WOLFF SYNDROME ,Gene - Abstract
Unusual fetal arthrogryposis on ultrasound should draw attention to look for additional lower limb anomalies. Precise genetic counseling may be obtained from deletion on Xq11.2 as for ZC4H2 gene sequencing diagnostic for Wieacker‐Wolff syndrome.
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- 2021
11. ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants
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Bernd Wissinger, Thomy de Ravel de l'Argentière, Frans P.M. Cremers, Jim Bauwens, Bart P. Leroy, Riccardo Sangermano, Caroline Van Cauwenbergh, Julie De Zaeytijd, Ana Fakin, Sarah De Jaegere, Toon Rosseel, Mubeen Khan, Gavin Arno, Susanne Kohl, Andrew R. Webster, Meindert De Vries, Elfride De Baere, Rob W.J. Collin, Alejandro Garanto, Irina Balikova, Keren J. Carss, Thalia Van Laethem, Miriam Bauwens, Kim De Leeneer, Marnik Vuylsteke, Sarah Naessens, Yves Sznajer, Timothy J. Cherry, Françoise Sadler, Nicole Weisschuh, Software Languages Lab, Informatics and Applied Informatics, Faculty of Sciences and Bioengineering Sciences, UCL - (SLuc) Centre de génétique médicale UCL, and UCL - SSS/IREC/SLUC - Pôle St.-Luc
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DEEP-INTRONIC VARIANTS ,Male ,ABCA4 ,PHENOTYPE ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Cohort Studies ,0302 clinical medicine ,Gene Frequency ,Missing heritability problem ,STARGARDT-DISEASE ,Medicine and Health Sciences ,Genetics(clinical) ,Genetics (clinical) ,Genetics ,0303 health sciences ,biology ,noncoding ,deep-intronic ,Exons ,DYSTROPHY ,Middle Aged ,Phenotype ,3. Good health ,Pedigree ,Female ,Adult ,Genes, Recessive ,ANTISENSE OLIGONUCLEOTIDES ,Article ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,AON ,Retinitis pigmentosa ,RETINITIS-PIGMENTOSA ,REVEALS ,Retinal Dystrophies ,medicine ,non-coding ,Humans ,splice ,Allele ,Gene ,Alleles ,030304 developmental biology ,SPECTRUM ,TRANSPORTER GENE ABCR ,MUTATIONS ,Biology and Life Sciences ,ABCA4-associated disease ,Oligonucleotides, Antisense ,medicine.disease ,Introns ,Stargardt disease ,HEK293 Cells ,missing heritability ,Mutation ,030221 ophthalmology & optometry ,biology.protein ,ATP-Binding Cassette Transporters - Abstract
PURPOSE: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. METHODS: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. RESULTS: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. CONCLUSION: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders. ispartof: GENETICS IN MEDICINE vol:21 issue:8 pages:1761-1771 ispartof: location:United States status: published
- Published
- 2019
12. The Belgian MicroArray Prenatal (BEMAPRE) database: A systematic nationwide repository of fetal genomic aberrations
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Joris Vermeesch, Benoit Parmentier, Julie Désir, Mauricette Jamar, Damien Lederer, Winnie Courtens, Anne De Leener, Sandra Janssens, Philip Holmgren, Nathalie Brison, Kathelijn Keymolen, Claude Bandelier, Annelies Dheedene, Yves Jacquemyn, Koenraad Devriendt, Marjan De Rademaeker, Bruno Pichon, Erik Fransen, Jean-Stéphane Gatot, Marije Meuwissen, Sonia Rombout, Anne Destree, Olivier Vanakker, J. Muys, Bettina Blaumeiser, Katrien Janssens, Patrizia Chiarappa, Björn Menten, Annelies Fieuw, Kris Van Den Bogaert, Yves Sznajer, Saskia Bulk, Ann Van Den Bogaert, Clinical sciences, Reproduction and Genetics, Medical Genetics, and Faculty of Medicine and Pharmacy
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Adult ,0301 basic medicine ,Ichthyosis, X-Linked ,DNA Copy Number Variations ,Microarray ,Population ,Prenatal diagnosis ,Haploinsufficiency ,030105 genetics & heredity ,computer.software_genre ,Congenital Abnormalities ,03 medical and health sciences ,0302 clinical medicine ,Belgium ,Charcot-Marie-Tooth Disease ,Pregnancy ,Prenatal Diagnosis ,Obstetrics and Gynaecology ,Databases, Genetic ,DiGeorge Syndrome ,Humans ,Medicine ,Genetics(clinical) ,Genetic Predisposition to Disease ,Copy-number variation ,education ,Uncertain significance ,Genetics (clinical) ,Arthrogryposis ,Chromosome Aberrations ,Comparative Genomic Hybridization ,education.field_of_study ,Fetus ,030219 obstetrics & reproductive medicine ,Database ,business.industry ,Obstetrics and Gynecology ,Microarray Analysis ,Pathogenicity ,Karyotyping ,Female ,National database ,Hereditary Sensory and Motor Neuropathy ,business ,computer - Abstract
OBJECTIVE: With the replacement of karyotyping by chromosomal microarray (CMA) in invasive prenatal diagnosis, new challenges have arisen. By building a national database, we standardize the classification and reporting of prenatally detected copy number variants (CNVs) across Belgian genetic centers. This database, which will link genetic and ultrasound findings with postnatal development, forms a unique resource to investigate the pathogenicity of variants of uncertain significance and to refine the phenotypic spectrum of pathogenic and susceptibility CNVs. METHODS: The Belgian MicroArray Prenatal (BEMAPRE) consortium is a collaboration of all genetic centers in Belgium. We collected data from all invasive prenatal procedures performed between May 2013 and July 2016. RESULTS: In this three-year period, 13 266 prenatal CMAs were performed. By national agreement, a limited number of susceptibility CNVs and no variants of uncertain significance were reported. Added values for using CMA versus conventional karyotyping were 1.8% in the general invasive population and 2.7% in cases with an ultrasound anomaly. Of the reported CNVs, 31.5% would have remained undetected with non-invasive prenatal test as the first-tier test. CONCLUSION: The establishment of a national database for prenatal CNV data allows for a uniform reporting policy and the investigation of the prenatal and postnatal genotype-phenotype correlation. ispartof: PRENATAL DIAGNOSIS vol:38 issue:13 pages:1120-1128 ispartof: location:England status: published
- Published
- 2018
13. Performance and diagnostic value of genome-wide noninvasive prenatal testing in multiple gestations
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Bernard Grisart, Armelle Duquenne, Naïri Khudashvili, Margot van Riel, Eva Sammels, Leonor Palmeira, Elise Vantroys, Leen Vancoillie, Bruno Pichon, Nathalie Brison, Annelies Dheedene, Bettina Blaumeiser, Kris Van Den Bogaert, Katrien Janssens, Sandra Janssens, Axel Marichal, François Boemer, Machteld Baetens, Joris Vermeesch, Ilse Parijs, Yves Sznajer, Jean-Stéphane Gatot, Koenraad Devriendt, Annelies Fieuw, Laura Bourlard, Nathalie Fieremans, Julie Désir, Guillaume Smits, Saskia Bulk, Ellen Roets, Colombine Meunier, Marion Suenaert, Lore Lannoo, Anne De Leener, Lotte Vandeputte, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de référence neuromusculaire, and UCL - (SLuc) Centre des maladies neuro-cutanées congénitales
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medicine.medical_specialty ,Trisomy 13 Syndrome ,Noninvasive Prenatal Testing ,Aneuploidy ,Trisomy ,Sensitivity and Specificity ,Multiple Gestation ,Pregnancy, Quadruplet ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,medicine ,Humans ,Amnion ,030212 general & internal medicine ,Diagnostic Errors ,False Negative Reactions ,Twin Pregnancy ,Retrospective Studies ,030219 obstetrics & reproductive medicine ,medicine.diagnostic_test ,Genome, Human ,Obstetrics ,business.industry ,Obstetrics and Gynecology ,Retrospective cohort study ,Chorion ,Fetal Resorption ,Pregnancy, Triplet ,medicine.disease ,Cohort ,Amniocentesis ,Pregnancy, Twin ,Gestation ,Female ,Human medicine ,Down Syndrome ,Pregnancy, Multiple ,business ,Cell-Free Nucleic Acids ,Trisomy 18 Syndrome - Abstract
OBJECTIVE: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic-diamniotic twin pregnancies. METHODS: We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography. Follow-up invasive testing was carried out in the event of positive NIPT results. Sensitivity and specificity were calculated for the detection of trisomy 21, 18, and 13 in the dichorionic-diamniotic twin cohort. RESULTS: Unique NIPT analyses were performed for 4,150 pregnant women with a multiple gestation and an additional 767 with vanishing gestations. The failure rate in multiple gestations excluding vanishing gestations ranged from 0% to 11.7% among the different genetic centers. Overall, the failure rate was 4.8%, which could be reduced to 1.2% after single resampling. There were no common fetal trisomies detected among the 86 monochorionic-monoamniotic and 25 triplet cases. Two monochorionic-diamniotic twins had an NIPT result indicative of a trisomy 21, which was confirmed in both fetuses. Among 2,716 dichorionic-diamniotic twin gestations, a sensitivity of 100% (95% CI 74.12-100%) and a specificity of 100% (95% CI 99.86-100%) was reached for trisomy 21 (n=12). For trisomy 18 (n=3), the respective values were 75% (95% CI 30.06-95.44%) sensitivity and 100% (95% CI 99.86-100%) specificity, and for trisomy 13 (n=2), 100% (95% CI 20.65-100%) sensitivity and 99.96% (95% CI 99.79-99.99%) specificity. In the vanishing gestation group, 28 NIPT results were positive for trisomy 21, 18, or 13, with only five confirmed trisomies. CONCLUSION: Genome-wide NIPT performed accurately for detection of aneuploidy in dichorionic-diamniotic twin gestations.
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- 2021
14. Digenic Inheritance Involving a Muscle Specific Protein Kinase and the Giant Titin Protein Causes a Skeletal Muscle Myopathy
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Ana Topf, Irina Zaharieva, Valeria Di Leo, Anna Vihola, Neha Wali, Marco Savarese, Kristen Laricchia, Cristina Venturini, Bas Vroling, Beryl Cummings, Rita Barresi, Elizabeth Harris, Chiara Marini Bettolo, Dan Cox, Jennifer Duff, Eleina England, Jane Patrick, Valerie Biancalana, Shobhana Bommireddipalli, Carsten Bonnemann, Anita Cairns, Mei Chiew, Kristl G. Claeys, Sandra Cooper, Mark R. Davis, Sandra Donkervoort, Corrie E. Erasmus, Carla Grosmann, Heinz Jungbluth, Erik-Jan Kamsteeg, Xaviere Lornage, Wolfgang Löscher, Edoardo Malfatti, Adnan Manzur, Pilar Marti, Tiziana Mongini, Nuria Muelas, Atsuko Nishikawa, Narumi Ogonuki, Gina O'Grady, Stephanie Paquay, Rahul Phadke, Beth Pletcher, Norma Romero, Meyke Schouten, Snehal Shah, Yves Sznajer, Giorgio Tasca, Allysa Tuite, Peter van den Bergh, Nicol Voermans, Julia Wanschitz, Elizabeth Wraige, Kimihiko Yoshimura, Emily Oates, Osamu Nakagawa, Ichizo Nishino, Jocelyn Laporte, Juan Vilchez, Daniel Macarthur, Anna Sarkozy, Bjarne Udd, Elisabeth Busch-Nentwich, Francesco Muntoni, and Volker Straub
- Published
- 2021
15. Defining a Centiloid scale threshold predicting long-term progression to dementia in patients attending the memory clinic: an [18F] flutemetamol amyloid PET study
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Yves Sznajer, Jiri Cerman, Gill Farrar, Christopher Buckley, John L. Woodard, Adrian Ivanoiu, Laurence Dricot, Lisa Quenon, Bernard Hanseeuw, Renaud Lhommel, Vincent Malotaux, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IONS/COSY - Systems & cognitive Neuroscience, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de neurologie, UCL - (SLuc) Centre de génétique médicale UCL, and UCL - (SLuc) Service de médecine nucléaire
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medicine.medical_specialty ,Receiver operating characteristic ,business.industry ,Memory clinic ,Amyloid pet ,Cognition ,General Medicine ,medicine.disease ,Predictive value ,Radiology Nuclear Medicine and imaging ,Internal medicine ,Research studies ,Medicine ,Dementia ,Radiology, Nuclear Medicine and imaging ,In patient ,business - Abstract
Purpose To evaluate cerebral amyloid-β(Aβ) pathology in older adults with cognitive complaints, visual assessment of PET images is approved as the routine method for image interpretation. In research studies however, Aβ-PET semi-quantitative measures are associated with greater risk of progression to dementia; but until recently, these measures lacked standardization. Therefore, the Centiloid scale, providing standardized Aβ-PET semi-quantitation, was recently validated. We aimed to determine the predictive values of visual assessments and Centiloids in non-demented patients, using long-term progression to dementia as our standard of truth. Methods One hundred sixty non-demented participants (age, 54–86) were enrolled in a monocentric [18F] flutemetamol Aβ-PET study. Flutemetamol images were interpreted visually following the manufacturers recommendations. SUVr values were converted to the Centiloid scale using the GAAIN guidelines. Ninety-eight persons were followed until dementia diagnosis or were clinically stable for a median of 6 years (min = 4.0; max = 8.0). Twenty-five patients with short follow-up (median = 2.0 years; min = 0.8; max = 3.9) and 37 patients with no follow-up were excluded. We computed ROC curves predicting subsequent dementia using baseline PET data and calculated negative (NPV) and positive (PPV) predictive values. Results In the 98 participants with long follow-up, Centiloid = 26 provided the highest overall predictive value = 87% (NPV = 85%, PPV = 88%). Visual assessment corresponded to Centiloid = 40, which predicted dementia with an overall predictive value = 86% (NPV = 81%, PPV = 92%). Inclusion of the 25 patients who only had a 2-year follow-up decreased the PPV = 67% (NPV = 88%), reflecting the many positive cases that did not progress to dementia after short follow-ups. Conclusion A Centiloid threshold = 26 optimally predicts progression to dementia 6 years after PET. Visual assessment provides similar predictive value, with higher specificity and lower sensitivity. Trial registration Eudra-CT number: 2011-001756-12
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- 2021
16. Antenatal diagnosis of CHARGE syndrome: Prenatal ultrasound findings and crucial role of fetal dysmorphic signs. About a series of 10 cases and review of literature
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Pamela Baldin, Yves Sznajer, Philippe Clapuyt, Valérie Benoit, Stéphanie Payrat, Catherine Barrea, Pierre Bernard, Benedicte Van Grambezen, and Jean-Marc Biard
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0301 basic medicine ,Male ,Polyhydramnios ,medicine.medical_specialty ,Prenatal diagnosis ,Choanal atresia ,030105 genetics & heredity ,Ultrasonography, Prenatal ,03 medical and health sciences ,CHARGE syndrome ,Fetus ,Temporal bone ,otorhinolaryngologic diseases ,Genetics ,Medicine ,Humans ,Genetic Testing ,Genetics (clinical) ,Exome sequencing ,business.industry ,Obstetrics ,DNA Helicases ,Infant, Newborn ,General Medicine ,Sequence Analysis, DNA ,medicine.disease ,Magnetic Resonance Imaging ,DNA-Binding Proteins ,030104 developmental biology ,Agenesis ,Atresia ,Karyotyping ,Female ,CHARGE Syndrome ,business ,Tomography, X-Ray Computed - Abstract
Although the prognosis of CHARGE syndrome can be highly variable from mild until severe, final diagnosis is difficult to establish in utero. The aim of our study is to compare antenatal and postnatal findings in a retrospective cohort of 10 successive patients with a positive CHD7 gene variant in order to identify the specific prenatal features for CHARGE syndrome diagnosis. Fetal ultrasound, follow-up and supplementary investigations are collected and compared to postnatal findings. Congenital heart defect (7/10), choanal atresia (7/10) and tracheoesophageal atresia (4/10) are the most frequent fetal anomalies found. Inner and external ear anomalies appear as the keystone (constant features) for prenatal diagnosis of CHARGE syndrome in fetuses with multiple anomalies and normal microarray karyotype. External ear malformations are identified in all cases by 3D ultrasound when carefully evaluated. MRI and temporal bone CT-Scan are second line useful tools to assess the diagnosis when looking for semicircular canal agenesis, arhinencephaly and/or choanal atresia. Before availability of prenatal exome sequencing in clinical routine, present findings lead to the recommendation that fetuses, with congenital heart defect (mainly septal and conotruncal), cleft lip/palate or unexplained polyhydramnios should carefully be screened for clues suggesting CHARGE syndrome using 2D and 3D ultrasound, MRI and temporal bone CT-Scan. When CHARGE syndrome is suspected with normal molecular karyotype, CHD7 gene sequencing must be offered.
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- 2020
17. Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders
- Author
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Perrine Pennamen, Caroline Rooryck, Yves Sznajer, Anne-Karin Kahlert, Isolina Riaño-Galán, Denny Schanze, David J. Amor, Eva Bermejo-Sánchez, Maie Walsh, Ariana Kariminejad, Siavash Ghaderi-Sohi, Mohamad Hasan Kariminejad, Ian P Hayes, Sönke Weinert, Patrick J. Morrison, Patrick Shannon, Martin Zenker, Gemma Poke, Annick Toutain, Suonavy Khung‐Savatovsky, Heinrich Sticht, David Chitayat, Fatima Abdelfattah, Evren Gumus, Marie-Laure Vuillaume, Katherine D. Mathews, Sabine Weidensee, Luisa Weiß, Benjamin W. Darbro, German Federal Ministry of Education and Research, Instituto de Salud Carlos III, and Fundación 1000 sobre Defectos Congénitos
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Male ,Neu–Laxova syndrome ,Mutant ,Autosomal recessive ,Limb Deformities, Congenital ,Biology ,medicine.disease_cause ,Serine ,03 medical and health sciences ,Fetus ,Genotype ,Genetics ,medicine ,Neu-Laxova syndrome ,Humans ,Abnormalities, Multiple ,Phosphoglycerate dehydrogenase ,Gene ,PHGDH ,Genetics (clinical) ,Genetic Association Studies ,Phosphoglycerate Dehydrogenase ,Transaminases ,030304 developmental biology ,0303 health sciences ,Mutation ,Brain Diseases ,Fetal Growth Retardation ,Genotype–phenotype correlation ,030305 genetics & heredity ,Infant, Newborn ,L-Serine biosynthesis ,Ichthyosis ,medicine.disease ,Phenotype ,PSAT1 ,Microcephaly ,Female - Abstract
Financial assistance was received in support of the study by grants from the German Federal Ministry of Education and Research (BMBF) (GeNeRARe, FKZ: 01GM1519D) to M. Z. and from the Institute of Health Carlos III: Convenio ISCIII‐ASEREMAC, and Fundación 1000 sobre Defectos Congénitos, of Spain to E. B.‐S. and I. R. G., Abdelfattah, F., Kariminejad, A., Kahlert, A.-K., Morrison, P.J., Gumus, E., Mathews, K.D., Darbro, B.W., Amor, D.J., Walsh, M., Sznajer, Y., Weiß, L., Weidensee, S., Chitayat, D., Shannon, P., Bermejo-Sánchez, E., Riaño-Galán, I., Hayes, I., Poke, G., Rooryck, C., Pennamen, P., Khung-Savatovsky, S., Toutain, A., Vuillaume, M.-L., Ghaderi-Sohi, S., Kariminejad, M.H., Weinert, S., Sticht, H., Zenker, M., Schanze, D.
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- 2020
18. Prenatally detected copy number variants in a national cohort: A postnatal follow-up study
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Sandra Janssens, Koenraad Devriendt, Joris Vermeesch, Julie Désir, J. Muys, Erik Fransen, Marjan De Rademaeker, Bettina Blaumeiser, Saskia Bulk, Katrien Janssens, Damien Lederer, Armelle Duquenne, Laura Bourlard, Björn Menten, Kathelijn Keymolen, Mauricette Jamar, Nathalie Brison, Ann Van Den Bogaert, Annelies Dheedene, Yves Sznajer, Yves Jacquemyn, Jean-Stéphane Gatot, Anne Destree, Bruno Pichon, Patrizia Chiarappa, Jorien Kerstjens, Annelies Fieuw, Kris Van Den Bogaert, Anne De Leener, Sonia Rombout, Clinical sciences, and Medical Genetics
- Subjects
Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,DNA Copy Number Variations ,Context (language use) ,030105 genetics & heredity ,Congenital Abnormalities ,National cohort ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Belgium ,Pregnancy ,Prenatal Diagnosis ,medicine ,Humans ,Copy-number variation ,Genetics (clinical) ,Chromosome Aberrations ,030219 obstetrics & reproductive medicine ,business.industry ,Significant difference ,Infant, Newborn ,Pregnancy Outcome ,Follow up studies ,Infant ,Obstetrics and Gynecology ,Microarray Analysis ,medicine.disease ,Child development ,eye diseases ,Patient population ,Case-Control Studies ,Child, Preschool ,Female ,Human medicine ,business ,Follow-Up Studies - Abstract
OBJECTIVE: Belgian genetic centers established a database containing data on all chromosomal microarrays (CMA) performed in a prenatal context. A study was initiated to evaluate postnatal development in children diagnosed prenatally with a non-benign copy number variant (CNV). METHODS: All children diagnosed with a prenatally detected non-benign CNV in a Belgian genetic center between May 2013 and February 2015 were included in the patient population. The control population consisted of children who had undergone an invasive procedure during pregnancy, with no or only benign CNVs. Child development was evaluated at 36 months using three (3) questionnaires: Ages and Stages Questionnaire Third edition, Ages and Stages Questionnaire Social-Emotional Second Edition and a general questionnaire. RESULTS: A significant difference in communication and personal-social development was detected between children with a reported susceptibility CNV and both children with an unreported susceptibility CNV and the control population. The outcome of children with a particular CNV is discussed in a case-by-case manner. CONCLUSION: Our postnatal follow-up project of children with a prenatally detected non-benign CNV is the first nationwide project of its kind. A higher number of cases for each CNV category is however needed to confirm our findings.
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- 2020
19. Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness
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Ana Töpf, Katherine Johnson, Adam Bates, Lauren Phillips, Katherine R. Chao, Eleina M. England, Kristen M. Laricchia, Thomas Mullen, Elise Valkanas, Liwen Xu, Marta Bertoli, Alison Blain, Ana B. Casasús, Jennifer Duff, Magdalena Mroczek, Sabine Specht, Monkol Lek, Monica Ensini, Daniel G. MacArthur, Ela Akay, Jorge Alonso-Pérez, Jonathan Baets, Nina Barisic, Alexandra Bastian, Sabine Borell, Teodora Chamova, Kristl Claeys, Jaume Colomer, Sandra Coppens, Nicolas Deconinck, Willem de Ridder, Jordi Díaz-Manera, Cristina Domínguez-González, Alexis Duncan, Hacer Durmus, Nagia A. Fahmy, Maria Elena Farrugia, Roberto Fernández-Torrón, Lidia Gonzalez-Quereda, Jana Haberlova, Maja von der Hagen, Andreas Hahn, Antonia Jakovčević, Ivonne Jerico Pascual, Solange Kapetanovic, Viktorija Kenina, Janbernd Kirschner, Andrea Klein, Heike Kölbel, Anna Kostera-Pruszczyk, Richa Kulshrestha, Jaana Lähdetie, Mahsa Layegh, Cheryl Longman, Adolfo López de Munain, Wolfgang Loscher, Anna Lusakowska, Paul Maddison, Armelle Magot, Anirban Majumdar, Pilar Martí, Amaia Martínez Arroyo, Radim Mazanec, Sandra Mercier, Tiziana Mongini, Nuria Muelas, Andrés Nascimento, Shahriar Nafissi, Shirin Omidi, Carlos Ortez, Stéphanie Paquay, Yann Pereon, Stojan Perić, Valentina Ponzalino, Vidosava Rakočević Stojanović, Gauthier Remiche, Aida Rodríguez Sainz, Sabine Rudnik, Iciar Sanchez Albisua, Manuela Santos, Ulrike Schara, Andriy Shatillo, Jadranka Sertić, Ulrich Stephani, Sonja Strang-Karlsson, Yves Sznajer, Ani Tanev, Ivailo Tournev, Peter Van den Bergh, Vinciane Van Parijs, Juan Vílchez, Katharina Vill, John Vissing, Carina Wallgren-Pettersson, Julia Wanschitz, Tracey Willis, Nanna Witting, Miren Zulaica, Volker Straub, MYO-SEQ Consortium, HUSLAB, HUS Children and Adolescents, Clinicum, Medicum, and Claeys, Kristl
- Subjects
0301 basic medicine ,targeted exome analysis ,Neuromuscular disease ,Medizin ,Anoctamins ,030105 genetics & heredity ,Bioinformatics ,3124 Neurology and psychiatry ,DNA sequencing ,Article ,03 medical and health sciences ,genetic diagnosis ,limb-girdle weakness ,neuromuscular disease ,next-generation sequencing ,3123 Gynaecology and paediatrics ,Exome Sequencing ,Medicine ,Humans ,Exome ,Gene ,Genetics (clinical) ,Exome sequencing ,SGCA ,RYR1 ,Genetic heterogeneity ,business.industry ,Sciences bio-médicales et agricoles ,medicine.disease ,Phenotype ,3. Good health ,030104 developmental biology ,Muscular Dystrophies, Limb-Girdle ,Glucosyltransferases ,Human medicine ,business - Abstract
Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology., info:eu-repo/semantics/published
- Published
- 2020
20. Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series
- Author
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Konstanze Hörtnagel, Amaury Delestienne, Constanza Navarro Moreno, Philippe A. Lysy, Sarah Lechner, Selda Aydin, Véronique Beauloye, Dominique Maiter, Yves Sznajer, Etienne Marbaix, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/CELL - Biologie cellulaire, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service d'endocrinologie et de nutrition, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de cardiologie pédiatrique, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, and UCL - (SLuc) Centre du cancer
- Subjects
Adrenal Cortex Diseases ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Carney complex ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Short stature ,03 medical and health sciences ,Cushing syndrome ,0302 clinical medicine ,Endocrinology ,medicine ,Humans ,Child ,Cushing Syndrome ,PRKAR1A gene ,business.industry ,Middle Aged ,medicine.disease ,Dermatology ,Child, Preschool ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Female ,Primary pigmented nodular adrenocortical disease ,medicine.symptom ,business ,Skin lesion ,Rare disease - Abstract
Cushing syndrome (CS) is a rare disease in children, frequently associated with subtle or periodic symptoms that may delay its diagnosis. Weight gain and growth failure, the hallmarks of hypercortisolism in pediatrics, may be inconsistent, especially in ACTH-independent forms of CS. Primary pigmented nodular adrenocortical disease (PPNAD) is the rarest form of ACTH-independent CS, and can be associated with endocrine and nonendocrine tumors, forming the Carney complex (CNC). Recently, phenotype/genotype correlations have been described with particular forms of CNC where PPNAD is isolated or associated only with skin lesions. We present four familial series of CS due to isolated PPNAD, and compare them to available data from the literature. We discuss the clinical and molecular findings, and underline challenges in diagnosing PPNAD in childhood.
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- 2018
21. Childhood hearing loss is a key feature of CAPOS syndrome: A case report
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Naima Deggouj, Elsa Wiame, Antonella Boschi, Marie-Cécile Nassogne, Stéphanie Paquay, Romolo Daniele De Siati, Yves Sznajer, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de neurologie pédiatrique, UCL - (SLuc) Service d'ophtalmologie, UCL - (SLuc) Service d'oto-rhino-laryngologie, and UCL - (SLuc) Centre de génétique médicale UCL
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Pes cavus ,Areflexia ,Cerebellar Ataxia ,Foot Deformities, Congenital ,Hearing loss ,Hearing Loss, Sensorineural ,Neurological disorder ,Audiology ,Auditory neuropathy ,Diagnosis, Differential ,CAPOS ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,ATP1A3 ,otorhinolaryngologic diseases ,medicine ,Humans ,Optic atrophy ,Child ,Reflex, Abnormal ,Cerebellar ataxia ,business.industry ,Hearing Tests ,General Medicine ,medicine.disease ,Optic Atrophy ,030104 developmental biology ,Otorhinolaryngology ,Mutation ,Pediatrics, Perinatology and Child Health ,Female ,Ataxia ,Sensorineural hearing loss ,Sodium-Potassium-Exchanging ATPase ,medicine.symptom ,Differential diagnosis ,business ,030217 neurology & neurosurgery - Abstract
CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare neurological disorder, recently associated with the c.2452G > A hotspot mutation in the ATP1A3 gene, with sensorineural hearing loss as a prominent feature. We herein report on a girl who has experienced hearing loss for three years following an initial encephalitic episode when aged 15 months old. CAPOS was diagnosed only when she was six years old by targeted testing whilst she displayed optic atrophy, cerebellar signs and areflexia. CAPOS syndrome should be considered in the differential diagnosis of acquired childhood deafness, prompting clinicians to search for associated neurological features.
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- 2018
22. Patient with confirmed LEOPARD syndrome developing multiple melanoma
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Isabelle Tromme, Deborah Franck, Gert Matthijs, Caroline Colmant, Liliane Marot, Sandrine Blomme, and Yves Sznajer
- Subjects
medicine.medical_specialty ,Dermatology ,LEOPARD Syndrome ,Germline ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Genetics ,Medicine ,Sex organ ,Hypertelorism ,Molecular Biology ,LEOPARD syndrome ,business.industry ,Melanoma ,Articles ,medicine.disease ,PTPN11 ,Oncology ,RL1-803 ,030220 oncology & carcinogenesis ,medicine.symptom ,dermoscopy ,business ,Noonan Syndrome with Multiple Lentigines ,melanomas - Abstract
LEOPARD syndrome, also known as Gorlin syndrome II, cardiocutaneous syndrome, lentiginosis profusa syndrome, Moynahan syndrome, was more recently coined as Noonan syndrome with multiple lentigines (NSML), inside the RASopathies. Historically, the acronym LEOPARD refers to the presence of distinctive clinical features such as: lentigines (L), electrocardiographic/conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), genital abnormalities (A), retardation of growth (R), and sensorineural deafness (D). This condition is identified in 85% of patients with phenotype hallmarks caused by presence a germline point mutation in PTPN11 gene. Association of melanoma to NSML seems to be rare: to our knowledge, two patients so far were reported in the literature. We herein present a patient diagnosed with LEOPARD syndrome, in whom molecular investigation confirmed the presence of the c.1403C>T mutation in exon 12 of the PTPN11 gene, who developed four superficial spreading melanomas and three atypical lentiginous hyperplasias. Three of the melanomas were achromic or hypochromic, three were in situ, and one had a Breslow index under 0.5 mm. Dermoscopic examination showed some characteristic white structures in most of the lesions, which were a signature pattern and a key for the diagnosis. ispartof: Dermatology practical & conceptual vol:8 issue:1 pages:59-62 ispartof: location:Austria status: published
- Published
- 2018
23. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies
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Pierre Sarda, Yves Sznajer, Florence Riant, Claire-Sophie Davoine, Christelle Tesson, Cyril Goizet, François Tison, Anthony Behin, Mélanie Fradin, Marie-Lorraine Monin, Giovanni Stevanin, Claire Ewenczyk, Rémi Valter, Pierre Labauge, Marie Coutelier, Urielle Ullmann, Didier Hannequin, Giulia Coarelli, Giovanni Castelnovo, Lionel Van Maldergem, Albert David, Mathieu Anheim, Alexis Brice, Perrine Charles, Alexandra Durr, Juliette Konop, Fanny Mochel, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/IREC/SLUC - Pôle St.-Luc, and UCL - (SLuc) Centre de génétique médicale UCL
- Subjects
Adult ,Male ,0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Ataxia ,Adolescent ,Cerebellar Ataxia ,Genotype ,Genetic counseling ,Biology ,CACNA1A ,SPG7 ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Genetic variation ,medicine ,Humans ,Spinocerebellar ataxia type 6 ,Age of Onset ,Child ,Aged ,Genes, Dominant ,Aged, 80 and over ,Genetics ,Cerebellar ataxia ,Metalloendopeptidases ,Middle Aged ,channelopathies ,medicine.disease ,Phenotype ,030104 developmental biology ,Child, Preschool ,Spinocerebellar ataxia ,ATPases Associated with Diverse Cellular Activities ,Female ,Calcium Channels ,Neurology (clinical) ,Age of onset ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype-phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more 'conventional' ataxias. After exclusion of CAG/polyglutamine expansions in spinocerebellar ataxia genes in 412 index cases with dominantly inherited cerebellar ataxias, we aimed to establish the relative frequencies of mutations in other genes, with an approach combining panel sequencing and TaqMan® polymerase chain reaction assay. We found relevant genetic variants in 59 patients (14.3%). The most frequently mutated were channel genes [CACNA1A (n = 16), KCND3 (n = 4), KCNC3 (n = 2) and KCNA1 (n = 2)]. Deletions in ITPR1 (n = 11) were followed by biallelic variants in SPG7 (n = 9). Variants in AFG3L2 (n = 7) came next in frequency, and variants were rarely found in STBN2 (n = 2), ELOVL5, FGF14, STUB1 and TTBK2 (n = 1 each). Interestingly, possible risk factor variants were detected in SPG7 and POLG. Clinical comparisons showed that ataxias due to channelopathies had a significantly earlier age at onset with an average of 24.6 years, versus 40.9 years for polyglutamine expansion spinocerebellar ataxias and 37.8 years for SPG7-related forms (P = 0.001). In contrast, disease duration was significantly longer in the former (20.5 years versus 9.3 and 13.7, P=0.001), though for similar functional stages, indicating slower progression of the disease. Of interest, intellectual deficiency was more frequent in channel spinocerebellar ataxias, while cognitive impairment in adulthood was similar among the three groups. Similar differences were found among a single gene group, comparing 23 patients with CACNA1A expansions (spinocerebellar ataxia 6) to 22 patients with CACNA1A point mutations, which had lower average age at onset (25.2 versus 47.3 years) with longer disease duration (18.7 versus 10.9), but lower severity indexes (0.39 versus 0.44), indicating slower progression of the disease. In conclusion, we identified relevant genetic variations in up to 15% of cases after exclusion of polyglutamine expansion spinocerebellar ataxias, and confirmed CACNA1A and SPG7 as major ataxia genes. We could delineate firm genotype-phenotype correlations that are important for genetic counselling and of possible prognostic value.
- Published
- 2017
24. EDNRBmutations cause Waardenburg syndrome type II in the heterozygous state
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Laurence Jonard, Veronique Pingault, Emmanuelle Faubert, Naima Deggouj, Laure Lecerf, Patricia Blanchet, Yves Sznajer, Sandrine Marlin, Sylvain Poisson, Natalie Loundon, Sarah Issa, Albert David, Patrick Nitschké, and Nadege Bondurand
- Subjects
0301 basic medicine ,Neurocristopathy ,Genetics ,Mutation ,Waardenburg syndrome ,SOX10 ,Genetic disorder ,Biology ,medicine.disease ,medicine.disease_cause ,Penetrance ,03 medical and health sciences ,030104 developmental biology ,medicine ,Exome ,Genetics (clinical) ,Exome sequencing - Abstract
Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss and pigmentation anomalies. The clinical definition of four WS types is based on additional features due to defects in structures mostly arising from the neural crest, with type I and type II being the most frequent. While type I is tightly associated to PAX3 mutations, WS type II (WS2) remains partly enigmatic with mutations in known genes (MITF, SOX10) accounting for only 30% of the cases. We performed exome sequencing in a WS2 index case and identified a heterozygous missense variation in EDNRB. Interestingly, homozygous (and very rare heterozygous) EDNRB mutations are already described in type IV WS (i.e., in association with Hirschsprung disease [HD]) and heterozygous mutations in isolated HD. Screening of a WS2 cohort led to the identification of an overall of six heterozygous EDNRB variations. Clinical phenotypes, pedigrees and molecular segregation investigations unraveled a dominant mode of inheritance with incomplete penetrance. In parallel, cellular and functional studies showed that each of the mutations impairs the subcellular localization of the receptor or induces a defective downstream signaling pathway. Based on our results, we now estimate EDNRB mutations to be responsible for 5%-6% of WS2.
- Published
- 2017
25. 'Serpentine-like syndrome'–A very rare multiple malformation syndrome characterised by brachioesophagus and vertebral anomalies
- Author
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Pierre Bernard, Philippe Clapuyt, Christian Debauche, Yves Sznajer, Catheline Hocq, Patricia Steenhaut, and Ana Beleza-Meireles
- Subjects
Adult ,Heart Defects, Congenital ,Rachischisis ,Short neck ,Biology ,Vertebral anomalies ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Diaphragmatic hernia ,Connective Tissue Diseases ,Median cleft lip ,Genetics (clinical) ,Infant, Newborn ,General Medicine ,Anatomy ,medicine.disease ,Spine ,Natural history ,030220 oncology & carcinogenesis ,Gestation ,Female ,Presentation (obstetrics) ,Hernias, Diaphragmatic, Congenital ,Digestive System Abnormalities ,Intestinal Volvulus - Abstract
“Serpentine-like syndrome” is a severe and rare association of multiple congenital malformations, characterised by brachioesophagus, secondary intrathoracic stomach, and vertebral anomalies. Other associated anomalies have been described, such as malposition and herniation of abdominal organs. We report the natural history of a baby girl born at 29 weeks of gestation with intra uterine growth restriction, short neck, large rachischisis from cervical to thoracic spine, a very short oesophagus, thoracic stomach associated with a midline diaphragmatic hernia, malrotated gut and median cleft lip. Most of these anomalies were detected antenatally. Molecular karyotype was normal. She died at age 12 days. To our knowledge, the present patient represents the 8th report of a case of “Serpentine-like syndrome”. Brachioesophagus and congenital vertebral anomalies, in particular rachischisis, are the cardinal features of this condition. All reported cases have been sporadic and the cause is still unknown. We believe that the specificity of the presentation as well as the similarities between available descriptions of patients suggests a common, yet to identify, molecular cause, possibly involving a developmental “toolkit”/homeobox gene or related pathways.
- Published
- 2017
26. Phenotype description in KIF5C gene hot-spot mutations responsible for malformations of cortical development (MCD)
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Marie-Cécile Nassogne, Katrien Stouffs, Philippe Clapuyt, Yves Sznajer, Sophie Duquesne, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/IMAG - Pôle d'imagerie médicale, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de radiologie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de pédiatrie générale, UCL - (SLuc) Service de neurologie pédiatrique, Clinical sciences, Medical Genetics, and Reproduction and Genetics
- Subjects
0301 basic medicine ,Intellectual disability ,Lissencephaly ,Kinesins ,030105 genetics & heredity ,Biology ,Gene mutation ,03 medical and health sciences ,Epilepsy ,Genotype ,Genetics ,medicine ,Cortical malformations ,Humans ,Child ,Gene ,Genetics (clinical) ,Pachygyria ,Brain ,General Medicine ,Kinesin ,medicine.disease ,Phenotype ,KIF5C gene ,Malformations of Cortical Development ,030104 developmental biology ,Clinical diagnosis ,Mutation ,Female - Abstract
Malformations of cortical development (MCD) represent a large group of brain cortical anomalies characterized by distinctive MRI findings. This 'radiologically-based' classification required re evaluation over time on identified underlying mechanisms (cytogenetic and/or molecular). The understanding of genotype findings (nature of cytogenetic/molecular mutation, cellular pathways consequences, timing, …) draw line of evidence on these distinctive group of conditions whereas sometimes precise and constant recurrent genotype/phenotype correlation may not be present. The clinical diagnosis of MCD is often difficult due to variability and rarity of individual types of malformations. Recent studies have established a relationship between lissencephaly and pathogenic variants in genes involved in the kinesin/tubulin pathways, as the KIF5C gene. Pathogenic variants in the KIF5C gene are a more recently discovered cause of severe developmental delay with epilepsy, characterized by specific malformation of cortical development such as pachygyria. Only seven children have been described to date. We report the natural history of a sixteen years old patient identified carrier of a KIF5C gene mutation who developed infantile epilepsy. We then gather phenotype description and molecular results of all reported patients so far in order to better define this entity.
- Published
- 2019
27. Antenatal diagnosis of cardio-facio-cutaneous syndrome: Prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. About a case and review of literature
- Author
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Valerie Race, Jean-Marc Biard, Patricia Steenhaut, Yves Sznajer, and Pierre Bernard
- Subjects
Adult ,Heart Defects, Congenital ,Proto-Oncogene Proteins B-raf ,Pediatrics ,medicine.medical_specialty ,DNA Copy Number Variations ,Genetic counseling ,RASopathy ,Ultrasonography, Prenatal ,03 medical and health sciences ,0302 clinical medicine ,Costello syndrome ,Ectodermal Dysplasia ,Pregnancy ,Prenatal Diagnosis ,medicine ,Humans ,030212 general & internal medicine ,Hypertelorism ,Legius syndrome ,030219 obstetrics & reproductive medicine ,business.industry ,Macrocephaly ,Obstetrics and Gynecology ,Cystic hygroma ,Facies ,medicine.disease ,Failure to Thrive ,Reproductive Medicine ,Mutation ,Noonan syndrome ,Female ,medicine.symptom ,business - Abstract
Antenatal diagnosis of cardio-facio-cutaneous syndrome: prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. This paper is a case study and review of literature. “RASopathies” is the term coined for a group of genetic diseases that share modulation inside the MAPKinase pathway. Mutations inside the coding sequence of any of these genes may be responsible for the upregulation of the RAS pathway, leading on the clinical level to Type 1 Neurofibromatosis (NF1), Noonan syndrome (NS), Costello syndrome (CS), Multiple Lentigines, Loose Anagen Hair syndrome, Cardio-Facio-Cutaneous syndrome (CFCS), and, more recently, Legius syndrome. While the postnatal presentation of this group is well-known, prenatal findings are less well recognized. The presence of a RASopathy during the prenatal period can be suspected on account of non-specific abnormalities: polyhydramnios, cystic hygroma or high nuchal translucency, macrosomia with proportionate short long bones, macrocephaly, renal, lymphatic, or cardiac defects. The current case report underlines the characteristic dysmorphic facial features on 3D-ultrasound (hypertelorism, down-slanting palpebral fissures, a long and marked philtrum, and low-set posteriorly rotated ears) that allow for a “RASopathy” to be postulated. After detecting a copy number variation (CNV) absence on a CGH array, we performed a RASopathy gene panel analysis, which identified a so-far unreported heterozygous de novo mutation in the BRAF gene (namely NM_004333.4 : c.1396 G > C ; p.Gly466Arg). Genetic counseling has, therefore, focused on the diagnosis of a RASopathy and predictable phenotype of CFCS, a distinct entity characterized by an increased risk of intellectual disability and early-onset feeding problems. We suggest that a more detailed prenatal facial evaluation should be performed in fetuses presenting high nuchal thickness, heart defects, or unusual findings, along with the absence of a CNV on a CGH array. Due to the dysmorphic facial features, targeted RASopathy genes are presumed to likely to be responsible for NS, CFCS, and CS.
- Published
- 2019
28. Panel-based exome sequencing for neuromuscular disorders as a diagnostic service
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Nicol C. Voermans, Nanna Witting, Yves Sznajer, Ingrid P.C. Krapels, Anneke J. van der Kooi, Benno Küsters, Amanda Krause, Bitten Schönewolf-Greulich, Karin Y. van Spaendonck-Zwarts, Corien C. Verschuuren-Bemelmans, Corrie E. Erasmus, Baziel G.M. van Engelen, Meyke Schouten, Suzanne C E H Sallevelt, Anneke J.A. Kievit, Rowdy Meijer, Christine E. M. de Die-Smulders, Marjolein Kriek, Daniela Q.C.M. Barge-Schaapveld, Dineke Westra, Christian Gillissen, Brian H.Y. Chung, Isabelle Maystadt, Christa de Geus, Sophelia H. S. Chan, Saskia Bulk, Bas C. Stunnenberg, Erica H. Gerkes, P. A. van der Zwaag, Magnhild Rasmussen, Maartje Pennings, Christiaan G J Saris, Erik-Jan Kamsteeg, Neurology, Amsterdam Neuroscience - Neuroinfection & -inflammation, Clinical Genetics, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de référence neuromusculaire, UCL - (SLuc) Service d'oto-rhino-laryngologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Neurology ,Adolescent ,Whole Exome Sequencing/methods ,Neuromuscular Diseases/diagnosis ,Genetic counseling ,Functional testing ,Population ,Other Research Donders Center for Medical Neuroscience [Radboudumc 0] ,Muscle disorder ,Bioinformatics ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Exome Sequencing ,medicine ,Humans ,genetics ,Preschool ,education ,Child ,Exome sequencing ,Aged ,education.field_of_study ,Genetic heterogeneity ,business.industry ,Infant, Newborn ,Infant ,Neuromuscular Diseases ,Middle Aged ,Newborn ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Neuromuscular diseases ,030104 developmental biology ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Child, Preschool ,myopathies ,Female ,Neurology (clinical) ,Age of onset ,business ,exome sequencing ,030217 neurology & neurosurgery ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Contains fulltext : 204157.pdf (Publisher’s version ) (Closed access) BACKGROUND: Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous. Accurate molecular genetic diagnosis can improve clinical management, provides appropriate genetic counseling and testing of relatives, and allows potential therapeutic trials. OBJECTIVE: To establish the clinical utility of panel-based whole exome sequencing (WES) in NMDs in a population with children and adults with various neuromuscular symptoms. METHODS: Clinical exome sequencing, followed by diagnostic interpretation of variants in genes associated with NMDs, was performed in a cohort of 396 patients suspected of having a genetic cause with a variable age of onset, neuromuscular phenotype, and inheritance pattern. Many had previously undergone targeted gene testing without results. RESULTS: Disease-causing variants were identified in 75/396 patients (19%), with variants in the three COL6-genes (COL6A1, COL6A2 and COL6A3) as the most common cause of the identified muscle disorder, followed by variants in the RYR1 gene. Together, these four genes account for almost 25% of cases in whom a definite genetic cause was identified. Furthermore, likely pathogenic variants and/or variants of uncertain significance were identified in 95 of the patients (24%), in whom functional and/or segregation analysis should be used to confirm or reject the pathogenicity. In 18% of the cases with a disease-causing variant of which we received additional clinical information, we identified a genetic cause in genes of which the associated phenotypes did not match that of the patients. Hence, the advantage of panel-based WES is its unbiased approach. CONCLUSION: Whole exome sequencing, followed by filtering for NMD genes, offers an unbiased approach for the genetic diagnostics of NMD patients. This approach could be used as a first-tier test in neuromuscular disorders with a high suspicion of a genetic cause. With uncertain results, functional testing and segregation analysis are needed to complete the evidence.
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- 2019
29. PEDIA: Prioritization of Exome Data by Image Analysis
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Eamonn Sheridan, Alfredo Orrico, Ivan Ivanovski, Saskia Biskup, Alexej Knaus, Marzena Wiśniewska, Anna Keryan, Bernd Wollnik, Gundula Thiel, Gorazd Rudolf, Max Zhao, Malte Spielmann, Yaron Gurovich, Sandra Wilson, Uwe Kornak, Pola Smirin-Yosef, Yair Hanani, Christina Fagerberg, Christian Thiel, Peter N. Robinson, Diana Mitter, Annick Raas-Rothschild, Gholson J. Lyon, Na Zhu, Dagmar Wahl, Nechama Haddad, Claus-Eric Ott, Antonio Martinez Carrascal, Janelle Howell, Nadja Ehmke, Irena Vrecar, Purificación Marín Reina, Oleg V. Borisov, Konstanze Hoertnagel, Denise Horn, Nurulhuda Hajjir, Sabine Rudnik, Sebastian Köhler, Marie Coutelier, Nicole Revencu, Ingrid Weber, Stanislav Rosnev, Johannes Zschocke, Claudia Ciaccio, Or Shanoon, Nicole Fleischer, Anna Schossig, Luitgard Graul-Neumann, Guy Nadav, Dione Aguilar, Susanne B. Kamphausen, Markus M. Nöthen, Allan Bayat, Borut Peterlin, Heidi Beate Bentzen, Øivind Braaten, Eun Kyung Suk, Magdalena Danyel, Ming W. Yeung, Catherine Karimov, Angela M. Kaindl, Luis Becerra-Solano, Tzung-Chien Hsieh, Svenja Daschkey, Laura Morlan Herrador, Christine Fauth, Stefan Mundlos, Ulrich A. Schatz, Jean Tori Pantel, Alain Verloes, Heinz Gabriel, Kirsten Cremer, Alexander Lavrov, Karen W. Gripp, Martin A. Mensah, Kristen Park, Yves Sznajer, Jakob Hertzberg, Korina Winter, Max Schubach, Sofia Douzgou, Peter Krawitz, Hadil Kathom, Linda M. Randolph, Björn Fischer-Zirnsak, Maximilian Leitheiser, Tom Kamphans, Asya Gusina, Omri Bar, Hilda David Eden, Koenraad Devriendt, Dejan Đukić, Elisabeth Mangold, Laura Pölsler, UCL - SSS/IREC/SLUC - Pôle St.-Luc, and UCL - (SLuc) Centre de génétique médicale UCL
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Male ,0301 basic medicine ,Computer science ,030105 genetics & heredity ,computer.software_genre ,computer vision ,Databases, Genetic ,Image Processing, Computer-Assisted ,Exome ,Genetics (clinical) ,Exome sequencing ,variant prioritization ,0303 health sciences ,030305 genetics & heredity ,dysmorphology ,Genomics ,3. Good health ,Phenotype ,Cohort ,Medical genetics ,Female ,exome diagnostics ,Algorithms ,Natural language processing ,deep learning ,Prioritization ,medicine.medical_specialty ,Article ,Image (mathematics) ,03 medical and health sciences ,Similarity (network science) ,Similarity (psychology) ,medicine ,Humans ,Gene ,030304 developmental biology ,business.industry ,Deep learning ,Computational Biology ,Sequence Analysis, DNA ,030104 developmental biology ,Artificial intelligence ,business ,computer ,Software - Abstract
PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis. ispartof: GENETICS IN MEDICINE vol:21 issue:12 pages:2807-2814 ispartof: location:United States status: published
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- 2018
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30. Novel RPL13 variants and evidence for incomplete penetrance in a human ribosomopathy with spondyloepimetaphyseal dysplasia
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Helena Valta, Yong Uk Kwon, Jessica J. Alm, Outi Mäkitie, Céline Huber, Francesca Tonelli, Alan J. Warren, Jung Yun Bae, Tuomas Näreoja, Tae Joon Cho, Gen Nishimura, Yves Sznajer, Alice Costantini, Nadi Kirova, Shengjiang Tan, Anh Nhi Tran, Woo Yeong Chung, Ok Hwa Kim, Antonella Forlino, Valérie Cormier-Daire, and Valentina Daponte
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Genetics ,Spondyloepimetaphyseal dysplasia ,lcsh:Diseases of the musculoskeletal system ,business.industry ,Ribosomopathy ,Endocrinology, Diabetes and Metabolism ,medicine ,Orthopedics and Sports Medicine ,lcsh:RC925-935 ,medicine.disease ,business ,Penetrance - Published
- 2020
31. Exploring the genetic basis of 3MC syndrome: Findings in 12 further families
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Nicole Revencu, Jill E. Urquhart, Deepthi De Silva, Sheela Nampoothiri, Sanjeev S. Bhaskar, Simon G. Williams, Jill Clayton-Smith, Elena Chervinsky, Mohnish Suri, Rebecca Roberts, Stavit A. Shalev, Yves Sznajer, Romesh Gunasekera, and Jamie M Ellingford
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0301 basic medicine ,Genetics ,Mutation ,Genetic heterogeneity ,3MC syndrome ,business.industry ,Genitourinary Tract Anomalies ,030105 genetics & heredity ,medicine.disease_cause ,medicine.disease ,03 medical and health sciences ,Postnatal growth deficiency ,030104 developmental biology ,medicine ,Tail ,Hypertelorism ,medicine.symptom ,business ,Genetics (clinical) ,Michels syndrome - Abstract
The 3MC syndromes are a group of rare autosomal recessive disorders where the main clinical features are cleft lip and palate, hypertelorism, highly arched eyebrows, caudal appendage, postnatal growth deficiency, and genitourinary tract anomalies. Ophthalmological abnormalities, most notably anterior chamber defects may also be seen. We describe the clinical and molecular findings in 13 individuals with suspected 3MC syndrome from 12 previously unreported families. The exclusion of the MASP1 and COLEC11 Loci in two individuals from different consanguineous families and the absence of mutations in four further individuals sequenced for both genes raises the possibility that that there is further genetic heterogeneity of 3MC syndrome.
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- 2016
32. Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins
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David Francis, Yves Sznajer, Lieve Vanwalleghem, Jennifer Kussmann, David A. Bateman, Gael E. Phillips, Scott A. Anderson, Elizabeth K. Fiorino, Przemyslaw Szafranski, Kamilla Schlade-Bartusiak, Neil J. Sebire, Pablo Lapunzina, Maya Chopra, Urvashi Surti, Isabelle Maystadt, Oliver Quarrell, Partha Sen, Jill Slamon, Avinash V. Dharmadhikari, Philippe Moerman, Liesbeth Spruijt, Dick Tibboel, Susan Arbuckle, Glenda Hendson, Jennifer Schuette, Nicole de Leeuw, Melissa Lees, Namasivayam Ambalavanan, Annelies de Klein, Svetlana A. Yatsenko, Joel Reiter, Joseph T. Shieh, Sandra Janssens, Gregory Peters, Jessica Sebastian, David R. Kelly, Eitan Kerem, Janet Lioy, Martina Owens, Gary Tsz Kin Mok, Carlos A. Bacino, Amy S. Lay, Shalini N. Jhangiani, Suneeta Madan-Khetarpal, Björn Menten, Elizabeth Roeder, Kadir C. Akdemir, Denise A. Hayes, Laurie A. Steiner, Taryn C. Rosenthal, Richard Sayers, Fernando Santos-Simarro, Ashley Wilson, Joyce E. Fox, Yoyo W. Y. Chu, Richard Fisher, Rebecca O. Littlejohn, Daynna J. Wolff, Wai Lap Wong, Timothy Thiruchelvam, Kristin Scheible, Zoe Mead, Eileen McKay, M. Anwar Iqbal, Erwin Brosens, Melinda H. Markham, Julián Nevado, Anne Loccufier, Rosanna G. Abellar, Tomasz Gambin, Charles Shaw-Smith, Alison Yeung, Pawel Stankiewicz, Nihal Godiwala, Elfride De Baere, Ilse Feenstra, Diane J. Payton, Girvan Malcolm, María Palomares, Morris Edelman, Claire Langston, Thomas S. DeNapoli, Margaret L. McKinnon, Carol L. Wagner, Brian H.Y. Chung, James R. Lupski, Dawn English, Alison Male, Edwina J. Popek, Frances Elmslie, Jasneek Chawla, Sara Jane Hamilton, Jason Pinner, Clinical Genetics, and Pediatric Surgery
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0301 basic medicine ,Alveolar capillary dysplasia ,Male ,Locus (genetics) ,Biology ,Persistent Fetal Circulation Syndrome ,Article ,03 medical and health sciences ,symbols.namesake ,Genomic Imprinting ,0302 clinical medicine ,Chromosome 16 ,Genetics ,medicine ,Humans ,Copy-number variation ,Genetics (clinical) ,Exome sequencing ,Sequence Deletion ,Sanger sequencing ,Comparative Genomic Hybridization ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Genome, Human ,Infant, Newborn ,High-Throughput Nucleotide Sequencing ,Forkhead Transcription Factors ,medicine.disease ,Molecular biology ,Uniparental disomy ,Pedigree ,Pulmonary Alveoli ,030104 developmental biology ,Pulmonary Veins ,030220 oncology & carcinogenesis ,symbols ,Female ,Genes, Lethal ,Genomic imprinting ,Chromosomes, Human, Pair 16 ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Contains fulltext : 168023.pdf (Publisher’s version ) (Closed access) Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.
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- 2016
33. Corrigendum to 'A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy' [Neuromuscular disorders 27/11 (2017) 1043-1046]
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L. Phillips, Daniel G. MacArthur, Dirk Lefeber, P. Van den Bergh, Ana Töpf, Ron A. Wevers, Katherine Johnson, Yves Sznajer, L. Xu, Monkol Lek, Volker Straub, W. van Tol, V. Van Parys, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, and UCL - (SLuc) Service de neurologie
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Pathology ,medicine.medical_specialty ,Neurology ,business.industry ,Alpha-Dystroglycan ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,medicine ,Neurology (clinical) ,business ,medicine.disease ,Genetics (clinical) ,Limb-girdle muscular dystrophy - Abstract
The authors regret that in the Abstract and in the Molecular Analysis paragraphs of the above paper, the following was incorrect: “a homozygous c.131T > G (p.Leu44Pro) substitution”. This should read “a homozygous c.131T > C (p.Leu44Pro) substitution”. The authors would like to apologise for any inconvenience caused. They would like to thank Sally Heywood, Research Assistant, Human Gene Mutation Database, Institute of Medical Genetics, Cardiff University for bringing this error to their attention.
- Published
- 2018
34. Improved diagnosis in nonimmune hydrops fetalis using a standardized algorithm
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Marie Laterre, Yves Sznajer, Miikka Vikkula, and Pierre Bernard
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0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,030219 obstetrics & reproductive medicine ,business.industry ,Hydrops Fetalis ,Obstetrics and Gynecology ,Retrospective cohort study ,030105 genetics & heredity ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Pregnancy ,Hydrops fetalis ,Medicine ,Humans ,Female ,business ,Genetics (clinical) ,Algorithms ,Retrospective Studies - Published
- 2017
35. The diagnostic value of next generation sequencing in familial nonsyndromic congenital heart defects
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Jeroen Breckpot, Yaojuan Jia, Jacoba Louw, Luc Dehaspe, Yves Sznajer, Catherine Barrea, Koenraad Devriendt, Anniek Corveleyn, Diether Lambrechts, Marc Gewillig, Erika Souche, Joris Vermeesch, and Bert Callewaert
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Heart Defects, Congenital ,Male ,Genetics ,Holt–Oram syndrome ,Massive parallel sequencing ,medicine.diagnostic_test ,business.industry ,Disease ,medicine.disease ,DNA sequencing ,Pedigree ,medicine ,Humans ,Coding region ,Female ,business ,Gene ,Supravalvular aortic stenosis ,Genetics (clinical) ,Genetic testing - Abstract
To determine the diagnostic value of massive parallel sequencing of a panel of known cardiac genes in familial nonsyndromic congenital heart defects (CHD), targeted sequencing of the coding regions of 57 genes previously implicated in CHD was performed in 36 patients from 13 nonsyndromic CHD families with probable autosomal dominant inheritance. Following variant analysis and Sanger validation, we identified six potential disease causing variants in three genes (MYH6, NOTCH1, and TBX5), which may explain the defects in six families. Several problematic situations were encountered when performing genotype-phenotype correlations in the families to confirm the causality of these variants. In conclusion, by screening known CHD-associated genes in well-selected nonsyndromic CHD families and cautious variant interpretation, potential causative variants were identified in less than half of the families (6 out of 13; 46%). Variant interpretation remains a major challenge reflecting the complex genetic cause of CHD.
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- 2015
36. ‘De novo’ Col4A2 mutation in a patient with migraine, leukoencephalopathy, and small carotid aneurysms
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Olivier Vanakker, Yves Sznajer, Paul Kollmann, and André Peeters
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0301 basic medicine ,Intracerebral hemorrhage ,medicine.medical_specialty ,Pathology ,Neurology ,medicine.diagnostic_test ,business.industry ,030105 genetics & heredity ,medicine.disease ,Magnetic resonance angiography ,Surgery ,Leukoencephalopathy ,03 medical and health sciences ,Migraine ,Mutation (genetic algorithm) ,Medicine ,Neurology (clinical) ,business ,Stroke ,Neuroradiology - Published
- 2016
37. Autosomal recessive primary microcephaly due to ASPM mutations: An update
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Martine Doco-Fenzy, Monique Elmaleh-Bergès, Berten Ceulemans, Sandrine Passemard, David Geneviève, Anita Rauch, Daniel Amram, Anais Ernault, Bernd Wollnick, Christine Francannet, Alain Verloes, Abdelaziz Sefiani, Pascaline Letard, Julie Désir, Marc Abramowicz, Brigitte Benzacken, Clothilde Rivier-Ringenbach, Toni Kasole Lubala, Yusuf Tunca, Vincent El Ghouzzi, Mathilde Nizon, Laurence Faivre, Marion Gérard, Koenraad Devriendt, Nathalie Pouvreau, Sophie Guilmin Crepon, Massimiliano Rossi, Hélène Maurey, C. Geoffrey Woods, Julia Metreau, Séverine Drunat, Michèle Mathieu-Dramard, Yves Sznajer, Cyril Gitiaux, Tiffany Busa, Geneviève Pierquin, Corinne Alberti, Sabine Sigaudy, Elise Schaefer, Stéphanie Arpin, Sébastien Lebon, Marta Bertoli, Pierre Gressens, Sophie Julia, Siham Chafai Elalaoui, Sarah Duerinckx, Sanaa Nasserereddine, Yoann Vial, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université libre de Bruxelles (ULB), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Mohamed V, Rabat, Maroc, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), 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), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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), Université de Lubumbashi (UNILU), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Ibn Rochd [Casablanca], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Liège (CHU-Liège), L'Hôpital Nord-Ouest [Villefranche sur Saône], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (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), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Université Catholique de Louvain = Catholic University of Louvain (UCL), Gülhane School of Medicine, Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Georg-August-University = Georg-August-Universität Göttingen, University of Cambridge [UK] (CAM), University hospital of Zurich [Zurich], Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Paris 13 (UP13), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), 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), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), CHU Clermont-Ferrand, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Toulouse [Toulouse], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), 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), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Lubumbashi, Georg-August-University [Göttingen], Richard, Nicolas, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Jean Verdier, UFR Santé, Médecine et Biologie Humaine ( UFR SMBH ), Université Paris 13 ( UP13 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Hôpital Bretonneau-CHRU Tours, 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 Hospitalier Universitaire de Reims ( CHU Reims ), Université de Reims Champagne-Ardenne ( URCA ) -Université de Picardie Jules Verne ( UPJV ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de Génétique Clinique [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Hospices Civils de Lyon ( HCL ), 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 d'Investigation Clinique 1426 ( CIC 1426 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Passemard, Sandrine [0000-0002-0242-4566], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Male ,Microcephaly ,MESH: Geography ,Intellectual disability ,ASPM ,brain development ,brain imaging ,MESH: Cognition ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Spindle pole body ,MESH: Magnetic Resonance Imaging ,Cohort Studies ,Neurodevelopmental disorder ,Cognition ,MESH: Nerve Tissue Proteins ,MESH: Cohort Studies ,Genetics (clinical) ,MESH: Genetic Association Studies ,Genetics ,0303 health sciences ,Geography ,primary microcephaly ,030305 genetics & heredity ,Brain development ,MESH: Infant ,Magnetic Resonance Imaging ,3. Good health ,intellectual disability ,Child, Preschool ,Autosomal Recessive Primary Microcephaly ,Brain size ,Female ,MESH: Mutation ,Brain imaging ,Nerve Tissue Proteins ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,Biology ,MESH: Microcephaly ,Primary microcephaly ,03 medical and health sciences ,medicine ,Humans ,Family ,Gene ,MESH: Family ,Genetic Association Studies ,030304 developmental biology ,Centrosome ,MCPH ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,MESH: Humans ,Genetic heterogeneity ,MESH: Child, Preschool ,Infant ,medicine.disease ,MESH: Male ,030104 developmental biology ,centrosome ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Mutation ,Human medicine ,[ SDV.GEN ] Life Sciences [q-bio]/Genetics ,MESH: Female - Abstract
Autosomal recessive microcephaly or MicroCephaly Primary Hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The Abnormal SPindle-like Microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities. This article is protected by copyright. All rights reserved. ispartof: Human Mutation vol:39 issue:3 pages:319-332 ispartof: location:United States status: published
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- 2017
38. A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy
- Author
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Ron A. Wevers, Ana Töpf, W. van Tol, Dirk Lefeber, Volker Straub, L. Phillips, V. Van Parys, L. Xu, Katherine Johnson, Daniel G. MacArthur, Yves Sznajer, P. Van den Bergh, Monkol Lek, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, and UCL - (SLuc) Centre de génétique médicale UCL
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Cardiomyopathy ,medicine.disease_cause ,Dolichol-P-mannose synthase ,Mannosyltransferases ,03 medical and health sciences ,Limb girdle muscular dystrophy ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,Medicine ,Humans ,Disorders of movement Radboud Institute for Molecular Life Sciences [Radboudumc 3] ,Dystroglycans ,Muscle, Skeletal ,Wasting ,Genetics (clinical) ,Exome sequencing ,Mutation ,business.industry ,Homozygote ,Skeletal muscle ,Membrane Proteins ,DPM3 ,Anatomy ,Middle Aged ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,medicine.disease ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Muscular Dystrophies, Limb-Girdle ,Pediatrics, Perinatology and Child Health ,Congenital muscular dystrophy ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Alpha-dystroglycan ,Limb-girdle muscular dystrophy - Abstract
Defects of O-linked glycosylation of alpha-dystroglycan cause a wide spectrum of muscular dystrophies ranging from severe congenital muscular dystrophy associated with abnormal brain and eye development to mild limb girdle muscular dystrophy. We report a female patient who developed isolated pelvic girdle muscle weakness and wasting, which became symptomatic at age 42. Exome sequencing uncovered a homozygous c.131T > G (p.Leu44Pro) substitution in DPM3, encoding dolichol-P-mannose (DPM) synthase subunit 3, leading to a 50% reduction of enzymatic activity. Decreased availability of DPM as an essential donor substrate for protein O-mannosyltransferase (POMT) 1 and 2 explains defective skeletal muscle alpha-dystroglycan O-glycosylation. Our findings show that DPM3 mutations may lead to an isolated and mild limb girdle muscular dystrophy phenotype without cardiomyopathy.
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- 2017
39. Neurobehavioural vulnerability and autistic traits in RASopathies
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Yves Sznajer, UCL - SSS/IREC/SLUC - Pôle St.-Luc, and UCL - (SLuc) Centre de génétique médicale UCL
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0301 basic medicine ,Vulnerability ,MEDLINE ,030105 genetics & heredity ,03 medical and health sciences ,0302 clinical medicine ,Autistic traits ,Phenotype ,Sex Factors ,Developmental Neuroscience ,Sex factors ,Pediatrics, Perinatology and Child Health ,Humans ,Neurology (clinical) ,Autistic Disorder ,Psychology ,030217 neurology & neurosurgery ,Clinical psychology - Published
- 2017
40. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency
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Jacek Majewski, A. Madrid, Babak Oskouian, Yves Sznajer, Julie Désir, Julie Patat, York Pei, Megan A. Cooper, Weizhen Tan, Elisabet Ars, Monica Furlano, Anne-Sophie Truant, Alain Schmitt, Rainer Wilcken, Won-Il Choi, Navina Kuss, Carolin E. Sadowski, Corinne Antignac, Jillian S. Parboosingh, Vilain Catheline, Marcia C. Willing, Christelle Arrondel, Jia Rao, Vikas R. Dharnidharka, Johanna Magdalena Schmidt, Nicola A.M. Wright, Thomas Giese, Martin Zenker, Brigitte Adams, Franz Schaefer, Richard P. Lifton, Noelle Lachaussée, Merlin Airik, Ingolf Franke, Klaus Schwarz, Julie D. Saba, David Schapiro, Guido Capitani, Seema Hashmi, Howard Riezman, Ronald Biemann, Johann Greil, Vladimir Girik, Anne M Connolly, Shazia Ashraf, Nuria Lloberas, Julian P. Midgley, Denny Schanze, Svjetlana Lovric, Matias Simons, Friedhelm Hildebrandt, Sara Gonçalves, Vincent Vuiblet, Heon Yung Gee, Eugen Widmeier, Tilman Jobst-Schwan, Francois P. Bernier, A. Micheil Innes, Olivier Gribouval, Olivia Boyer, Jung H. Suh, Ryan E. Lamont, Honnappa Srinivas, Daniela A. Braun, Shirlee Shril, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, and UCL - (SLuc) Service de néonatologie
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0301 basic medicine ,Male ,medicine.medical_specialty ,Nephrotic Syndrome ,Nephrosis ,030232 urology & nephrology ,Síndrome nefròtica ,Biology ,medicine.disease_cause ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Movement ,Internal medicine ,medicine ,Chronic renal failure ,Animals ,Drosophila Proteins ,Humans ,Exome sequencing ,Immunodeficiency ,Aldehyde-Lyases ,Mice, Knockout ,Mutation ,Ichthyosis ,General Medicine ,medicine.disease ,Phenotype ,3. Good health ,Rats ,Protein Transport ,030104 developmental biology ,Endocrinology ,Drosophila melanogaster ,ddc:540 ,Mesangial Cells ,Slit diaphragm ,Insuficiència renal crònica ,Female ,Nephrotic syndrome ,Ichthyosis, Lamellar ,Research Article - Abstract
Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1. yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.
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- 2017
41. Search forReCQL4mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes
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Nadège Gigot, Valeria Capra, Annick Toutain, Alice Goldenberg, Geneviève Pierquin, Nicole Philip, Odile Boute, S. Gauthier, Mariam Tajir, Yves Sznajer, Muriel Holder-Espinasse, Loreto Martorell, Laurence Faivre, J. Piard, Jean-Benoît Courcet, Christine Francannet, Cédric Baumann, Philippe Parent, Valérie Cormier-Daire, Michael Wright, N. Didonato, Marie-Pierre Cordier, David Geneviève, Didier Bessis, Ana Berta Sousa, Laurent Pasquier, Angela F. Brady, F. Boralevi, Siham Chafai Elalaoui, André Mégarbané, Bernard Aral, Edward Blair, Christine Bodemer, Eve Puzenat, B. Demeer, M. Tardieu, Corinne Collet, V. Barlogis, C. Thauvin-Robinet, Marlène Rio, Christine Coubes, Pierre Vabres, Geneviève Baujat, J. Franques, Patrick Callier, Jean-Baptiste Rivière, María Antonia González-Enseñat, Julien Thevenon, Olga Domnica Moldovan, and A. Rodríguez
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Genetics ,medicine.medical_specialty ,business.industry ,Poikiloderma ,Consanguinity ,Baller–Gerold syndrome ,medicine.disease ,Dermatology ,3. Good health ,Hereditary sclerosing poikiloderma ,Genotype ,medicine ,business ,Rothmund–Thomson syndrome ,Genetics (clinical) ,Comparative genomic hybridization ,Porokeratosis - Abstract
Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.
- Published
- 2014
42. EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state
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Sarah, Issa, Nadege, Bondurand, Emmanuelle, Faubert, Sylvain, Poisson, Laure, Lecerf, Patrick, Nitschke, Naima, Deggouj, Natalie, Loundon, Laurence, Jonard, Albert, David, Yves, Sznajer, Patricia, Blanchet, Sandrine, Marlin, and Veronique, Pingault
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Adult ,Male ,Heterozygote ,Adolescent ,DNA Mutational Analysis ,Intracellular Space ,Computational Biology ,High-Throughput Nucleotide Sequencing ,Iris ,Receptor, Endothelin B ,Pedigree ,Protein Transport ,Young Adult ,Phenotype ,Amino Acid Substitution ,Mutation Rate ,Child, Preschool ,Mutation ,Humans ,Exome ,Female ,Waardenburg Syndrome ,RNA Splice Sites ,Child ,Genetic Association Studies - Abstract
Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss and pigmentation anomalies. The clinical definition of four WS types is based on additional features due to defects in structures mostly arising from the neural crest, with type I and type II being the most frequent. While type I is tightly associated to PAX3 mutations, WS type II (WS2) remains partly enigmatic with mutations in known genes (MITF, SOX10) accounting for only 30% of the cases. We performed exome sequencing in a WS2 index case and identified a heterozygous missense variation in EDNRB. Interestingly, homozygous (and very rare heterozygous) EDNRB mutations are already described in type IV WS (i.e., in association with Hirschsprung disease [HD]) and heterozygous mutations in isolated HD. Screening of a WS2 cohort led to the identification of an overall of six heterozygous EDNRB variations. Clinical phenotypes, pedigrees and molecular segregation investigations unraveled a dominant mode of inheritance with incomplete penetrance. In parallel, cellular and functional studies showed that each of the mutations impairs the subcellular localization of the receptor or induces a defective downstream signaling pathway. Based on our results, we now estimate EDNRB mutations to be responsible for 5%-6% of WS2.
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- 2016
43. Autosomal insertional translocation mimicking an X-linked mode of inheritance
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Cédric Le Caignec, Albert David, Gaelle Thierry, Yves Sznajer, Annaig Briand, Olivier Pichon, and Damien Poulain
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Male ,Microcephaly ,X-linked intellectual disability ,Genetic counseling ,Inheritance Patterns ,Chromosomal translocation ,Biology ,Short stature ,Translocation, Genetic ,Intellectual Disability ,Gene duplication ,Genetics ,medicine ,Humans ,Metaphase ,In Situ Hybridization, Fluorescence ,Genetics (clinical) ,Comparative Genomic Hybridization ,General Medicine ,medicine.disease ,Mutagenesis, Insertional ,Chromosomes, Human, Pair 6 ,medicine.symptom ,Chromosomes, Human, Pair 8 ,Comparative genomic hybridization - Abstract
Unbalanced insertional translocations are a rare cause of intellectual disability. An unbalanced insertional translocation is a rare chromosomal imbalance, which may result from a balanced insertional translocation present in a phenotypically normal parent. We report here three brothers with intellectual disability, short stature, microcephaly, craniofacial anomalies and small testes. Since their parents and their sister were all phenotypically normal, the pattern of the family suggested an X-linked mode of inheritance. Surprisingly, we identified by array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) in the three brothers an 8q22.3q23.2 deletion resulting from a balanced insertional translocation present in their healthy father. The deletion encompassed the ZFPM2 gene known to be involved in gonadal development, which is consistent with the small testes and abnormal endocrine dosages in the affected brothers. The present report also illustrates that parental analyses by aCGH or qPCR methods are not sufficient when a de novo deletion or duplication is identified in an affected child and that FISH analysis should be performed on metaphase spreads in both parents to deliver an accurate genetic counseling.
- Published
- 2013
44. Eight Novel Mutations Confirm the Role of AAGAB in Punctate Palmoplantar Keratoderma Type 1 (Buschke-Fischer-Brauer) and Show Broad Phenotypic Variability
- Author
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Yves Sznajer, Kathrin A. Giehl, Regina C. Betz, Stefan Rapprich, Gertrud Eckstein, Miklós Sárdy, Markus Braun-Falco, Valérie Dekeuleneer, Tanja von Braunmühl, Tim M. Strom, Thomas Herzinger, Hans Wolff, Nicola Wagner, Thomas Ruzicka, Pascaline Boes, Dominique Tennstedt, UCL - (SLuc) Service de dermatologie, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, and UCL - (SLuc) Centre de génétique médicale UCL
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0301 basic medicine ,Adult ,Male ,Heredity ,Adolescent ,DNA Mutational Analysis ,Dermatology ,medicine.disease_cause ,Punctate palmoplantar keratoderma type 1 ,Polymorphism, Single Nucleotide ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Gene Frequency ,Polymorphism (computer science) ,Keratoderma, Palmoplantar ,Risk Factors ,Genotype ,medicine ,Humans ,Genetic Predisposition to Disease ,Keratoderma ,Punctate Palmoplantar Keratoderma ,Ppkp1 ,Aagab ,Phenotype-genotype Correlation ,Allele frequency ,Genetic Association Studies ,Aged ,Genetics ,Aged, 80 and over ,Mutation ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Phenotype ,Pedigree ,Adaptor Proteins, Vesicular Transport ,030104 developmental biology ,Female ,business - Abstract
Punctate palmoplantar keratoderma (PPKP1; Buschke-Fischer-Brauer) is a rare autosomal dominant inherited skin disease characterized by multiple hyperkeratotic papules involving the palms and soles. Mutations have been found at 2 loci, on chromosomes 15q22-15q24 and 8q24.13-8q24.21. We recently identified mutations in 3 families, in the AAGAB gene on 15q, which encodes the alpha- and gamma-adaptin-binding protein p34. The current study examined 14 additional families, comprising a total of 26 affected individuals and identified 8 novel mutations in 9 families. In one family a mutation representing a known SNP that was present only in the affected individuals was found, and in 4 other families, previously reported mutations were found (1, 2). These results confirm the role of AAGAB in PPKP1. Our findings suggest that there is no correlation with age, but with mechanical factors. No additional obvious genotype phenotype correlation was observed, even when comparing different types of mutations. Rather, identical genotypes presented a very broad interfamilial and intrafamilial variability of phenotypes.
- Published
- 2016
45. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies
- Author
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S. Kitsiou Tzeli, Hülya Kayserili, L. Giordano, B. Rodriguez, P. Collignon, V. Sabolic Avramovska, Silvana Briuglia, Christopher A. Walsh, Laila Bastaki, Amy Goldstein, Francesca Faravelli, F. Papadia, A. Permunian, Alessandro Simonati, S. Halldorsson, Gian Marco Ghiggeri, David G. Brooks, Clara Barbot, Kathryn J. Swoboda, Chiara Pantaleoni, O. D'Addato, Jason W. Caldwell, Maria Roberta Cilio, Soumaya Mougou-Zerelli, M. Vascotto, Andreas Zankl, Gaetano Tortorella, Julia Tantau, Elliott H. Sherr, Patrizia Accorsi, Maurizio Genuardi, Carmelo Salpietro, G. Marra, Pierangela Castorina, Petter Strømme, J. Johannsdottir, Bruno Dallapiccola, Kenton R. Holden, Donatella Greco, Maria Spanò, Pasquale Parisi, Roberta Battini, Paola Grammatico, P. Ludvigsson, Dorit Lev, Daria Riva, C. Ae Kim, WB Dobyns, L. Martorell Sampol, Robert P. Cruse, H. Raynes, Sabrina Signorini, A. Seward, Raoul C.M. Hennekam, Elena Andreucci, Manuela Priolo, Banu Anlar, Bernard Stuart, Christopher P. Bennett, S. Comu, Christopher Geoffrey Woods, Vlatka Mejaški-Bošnjak, J. Milisa, Eamonn Sheridan, Melissa Lees, C. Moco, Ender Karaca, Miriam Iannicelli, Annalisa Mazzotta, C. Dacou-Voutetakis, Tania Attié-Bitach, Philippe Loget, D. Petkovic, L. Demerleir, Loredana Boccone, Meriem Tazir, Kalpathy S. Krishnamoorthy, Damir Lončarević, Dominika Swistun, Yves Sznajer, Stefano D'Arrigo, Ginevra Zanni, Angela Barnicoat, Marina Michelson, L. I. Al Gazali, Vincenzo Leuzzi, G. Uziel, A. Adami, B. Gener Querol, V. Udani, M. Di Giacomo, Maryse Bonnière, Enrico Bertini, K. Dias, Edward Blair, Johannes M. Penzien, M. Cazzagon, Susana Quijano-Roy, Trine Prescott, Barbara Scelsa, Giuseppina Vitiello, Francesco Brancati, Gilda Stringini, Trudy McKanna, Roser Pons, Renato Borgatti, M. Gentile, Dean Sarco, C. Von Der Lippe, Eugen Boltshauser, Luigina Spaccini, A. Pessagno, Alex Magee, Marilena Briguglio, Margherita Silengo, Lena Starck, M. L. Di Sabato, Roshan Koul, Nicole I. Wolf, A. M. Laverda, Elizabeth Flori, Clotilde Lagier-Tourenne, A. Matuleviciene, Matloob Azam, Kathrin Ludwig, Ghada M H Abdel-Salam, Atıl Yüksel, Johannes R. Lemke, Stefania Bigoni, Elizabeth Said, Anna Rajab, Mary Kay Koenig, Andreas R. Janecke, Asma A. Al-Tawari, Agnese Suppiej, Henry Sanchez, Wendy K. Chung, P. Guanciali, Heike Philippi, Silvia Majore, E. DeMarco, J. Hahn, Gianluca Caridi, Marc D'Hooghe, M. M. De Jong, M. Akcakus, Franco Stanzial, Silvia Battaglia, Gian Luigi Ardissino, Giangennaro Coppola, Jane A. Hurst, Terry D. Sanger, Alessandra Renieri, Nadia Elkhartoufi, Rita Fischetto, Alex E. Clark, S. Strozzi, S. Romano, Alain Verloes, Marzia Pollazzon, Elisa Fazzi, L. Yates, Faustina Lalatta, Sabine Sigaudy, Alessandra D'Amico, Brigitte Leroy, Joel Victor Fluss, David Viskochil, Alice Abdel-Aleem, Darryl C. De Vivo, Padraic Grattan-Smith, Corrado Romano, D. Nicholl, Regine Schubert, A. Moreira, Claudia Izzi, Barbara Gentilin, Gustavo Maegawa, Céline Gomes, László Sztriha, C. Donahue, Luciana Rigoli, Jean Messer, Sophie Thomas, E. Del Giudice, R. Van Coster, André Mégarbané, Ignacio Pascual-Castroviejo, Alessandra Ferlini, Topcu, R. Touraine, Ginevra Guanti, Lorena Travaglini, L. Ali Pacha, R. De Vescovi, Enza Maria Valente, Filippo Bernardi, L. Carr, Shubha R. Phadke, S. Bernes, Maria Teresa Divizia, C. Daugherty, M. Akgul, C. Macaluso, Maha S. Zaki, E. Finsecke, Itxaso Marti, Lorenzo Pinelli, F. McKay, Maria Amorini, Joseph G. Gleeson, F. Benedicenti, Bruria Ben-Zeev, Carla Uggetti, R. Romoli, Richard J. Leventer, Francesco Emma, T. E. Gallager, P. De Lonlay, Marco Seri, Bernard L. Maria, M.A. Donati, Bosanka Jocic-Jakubi, IANNICELLI M, BRANCATI F, MOUGOU-ZERELLI S, MAZZOTTA A, THOMAS S, ELKHARTOUFI N, TRAVAGLINI L, GOMES C, ARDISSINO GL, BERTINI E, BOLTSHAUSER E, CASTORINA P, D'ARRIGO S, FISCHETTO R, LEROY B, LOGET P, BONNIÈRE M, STARCK L, TANTAU J, GENTILIN B, MAJORE S, SWISTUN D, FLORI E, LALATTA F, PANTALEONI C, PENZIEN J, GRAMMATICO P, INTERNATIONAL JSRD STUDY GROUP, DALLAPICCOLA B, GLEESON JG, ATTIE-BITACH T, VALENTE EM. COLLABORATORS: ALI PACHA L, TAZIR M, ZANKL A, LEVENTER R, GRATTAN-SMITH P, JANECKE A, D'HOOGHE M, SZNAJER Y, VAN COSTER R, DEMERLEIR L, DIAS K, MOCO C, MOREIRA A, AE KIM C, MAEGAWA G, LONCAREVIC D, MEJASKI-BOSNJAK V, PETKOVIC D, ABDEL-SALAM GM, ABDEL-ALEEM A, ZAKI MS, MARTI I, QUIJANO-ROY S, SIGAUDY S, DE LONLAY P, ROMANO S, VERLOES A, TOURAINE R, KOENIG M, LAGIER-TOURENNE C, MESSER J, COLLIGNON P, WOLF N, PHILIPPI H, LEMKE J, DACOU-VOUTETAKIS C, KITSIOU TZELI S, PONS R, SZTRIHA L, HALLDORSSON S, JOHANNSDOTTIR J, LUDVIGSSON P, PHADKE SR, UDANI V, STUART B, MAGEE A, LEV D, MICHELSON M, BEN-ZEEV B, DI GIACOMO M, GENTILE M, GUANTI G, D'ADDATO O, PAPADIA F, SPANO M, BERNARDI F, SERI M, BENEDICENTI F, STANZIAL F, BORGATTI R, ACCORSI P, BATTAGLIA S, FAZZI E, GIORDANO L, IZZI C, PINELLI L, BOCCONE L, GUANCIALI P, ROMOLI R, BIGONI S, FERLINI A, ANDREUCCI E, DONATI MA, GENUARDI M, CARIDI G, DIVIZIA MT, FARAVELLI F, GHIGGERI G, PESSAGNO, AMORINI M, BRIGUGLIO M, BRIUGLIA S, RIGOLI L, SALPIETRO C, TORTORELLA G, ADAMI A, MARRA G, RIVA D, SCELSA B, SPACCINI L, UZIEL G, COPPOLA G, DEL GIUDICE E, VITIELLO G, LAVERDA AM, LUDWIG K, PERMUNIAN A, SUPPIEJ A, MACALUSO C, SIGNORINI S, UGGETTI C, BATTINI R, PRIOLO M, CILIO MR, D'AMICO A, DI SABATO ML, EMMA F, LEUZZI V, PARISI P, STRINGINI G, ZANNI G, POLLAZZON M, RENIERI A, VASCOTTO M, SILENGO M, DE VESCOVI R, GRECO D, ROMANO C, CAZZAGON M, SIMONATI A, AL-TAWARI AA, BASTAKI L, MÉGARBANÉ A, MATULEVICIENE A, SABOLIC AVRAMOVSKA V, SAID E, DE JONG MM, PRESCOTT T, STROMME P, VON DER LIPPE C, KOUL R, RAJAB A, AZAM M, BARBOT C, JOCIC-JAKUBI B, GENER QUEROL B, MARTORELL SAMPOL L, RODRIGUEZ B, PASCUAL-CASTROVIEJO I, STROZZI S, FLUSS J, TEBER S, TOPCU M, ANLAR B, COMU S, KARACA E, KAYSERILI H, YÜKSEL A, AKGUL M, AKCAKUS M, AL GAZALI L, NICHOLL D, WOODS CG, BENNETT C, HURST J, SHERIDAN E, BARNICOAT A, CARR L, HENNEKAM R, LEES M, MCKAY F, YATES L, BLAIR E, BERNES S, SANCHEZ H, CLARK AE, DEMARCO E, DONAHUE C, SHERR E, HAHN J, SANGER TD, GALLAGER TE, DOBYNS WB, DAUGHERTY C, KRISHNAMOORTHY KS, SARCO D, WALSH CA, MCKANNA T, MILISA J, CJUNG WK, DE VIVO DC, RAYNES H, SCHUBERT R, SEWARD A, BROOKS DG, GOLDSTEIN A, CALDWELL J, FINSECKE E, MARIA BL, HOLDEN K, CRUSE RP, SWOBODA KJ, VISKOCHIL D., Pediatric surgery, NCA - Childhood White Matter Diseases, Iannicelli, M, Brancati, F, Mougou Zerelli, S, Mazzotta, A, Thomas, S, Elkhartoufi, N, Travaglini, L, Gomes, C, Ardissino, Gl, Bertini, E, Boltshauser, E, Castorina, P, D'Arrigo, S, Fischetto, R, Leroy, B, Loget, P, Bonnière, M, Starck, L, Tantau, J, Gentilin, B, Majore, S, Swistun, D, Flori, E, Lalatta, F, Pantaleoni, C, Penzien, J, Grammatico, P, Dallapiccola, B, Gleeson, Jg, Attie Bitach, T, Valente, Em, International JSRD Study, Group, DEL GIUDICE, Ennio, University of Zurich, and Attie-Bitach, T
- Subjects
Liver Cirrhosis ,2716 Genetics (clinical) ,meckelin ,Ciliopathies ,Joubert syndrome ,Genotype ,congenital hepatic fibrosis ,coach syndrome ,mks3 ,meckel syndrome ,joubert syndrome ,tmem67 ,TMEM67 ,Meckel syndrome ,DNA Mutational Analysis ,610 Medicine & health ,Biology ,medicine.disease_cause ,MKS3 ,COACH syndrome ,Article ,NO ,1311 Genetics ,Nephronophthisis ,Pregnancy ,Prenatal Diagnosis ,Genetics ,medicine ,COACH syndrome, Congenital hepatic fibrosis, Joubert syndrome, Meckel syndrome, MKS3, TMEM67 ,Missense mutation ,Humans ,Abnormalities, Multiple ,Genetics (clinical) ,Mutation ,Cilium ,Membrane Proteins ,Kidney Diseases, Cystic ,medicine.disease ,Phenotype ,10036 Medical Clinic ,Female - Abstract
Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.
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- 2010
46. Additional clinical and molecular analyses ofTFAP2Ain patients with the branchio-oculo-facial syndrome
- Author
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Dietmar Müller, Walter Just, Judith J. Reiber, Yves Sznajer, Stanislas Lyonnet, Clarisse Baumann, and Elena Guillén Posteguillo
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Adult ,Male ,Adolescent ,Molecular Sequence Data ,Single-nucleotide polymorphism ,Biology ,medicine.disease_cause ,DNA sequencing ,Conserved sequence ,Young Adult ,Exon ,Pregnancy ,Genetics ,medicine ,Humans ,Missense mutation ,Amino Acid Sequence ,Gene ,Conserved Sequence ,Genetics (clinical) ,Mutation ,Infant, Newborn ,Infant ,Exons ,medicine.disease ,Transcription Factor AP-2 ,Child, Preschool ,Female ,Branchio-oculo-facial syndrome ,Branchio-Oto-Renal Syndrome - Abstract
The branchio-oculo-facial syndrome (BOFS) is a rare disorder with approximately 50 sporadic and familial cases in the literature. We report on the clinical and molecular analyses of five additional patients with BOFS (two familial and three sporadic). DNA analysis of the TFAP2A gene associated with BOFS using DNA sequencing detected a mutation [c.763A>G (p.Arg255Gly)] in two unrelated patients. This mutation had been reported in another patient and indicates a probable mutational hotspot in the TFAP2A gene. We also detected three new mutations which are restricted to exons 4-6. These gene regions are almost free of any single nucleotide polymorphisms. An evolutionary sequence comparison showed a high degree of sequence conservation from humans to the honey bee (Apis mellifera) in exon 6 showing that this part of the protein is probably essential. Our study represents the second group of BOFS patients with molecular confirmation, expanding the phenotype and spectrum of mutations and limiting it to a restricted part of the gene.
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- 2010
47. LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma
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Marc Abramowicz, Françoise Meire, Yves Sznajer, Marc Schrooyen, Françoise Roulez, Fanny Depasse, and Julie Désir
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Marfan syndrome ,Male ,Genetic Linkage ,DNA Mutational Analysis ,Molecular Sequence Data ,Genes, Recessive ,Biology ,Article ,Megalocornea ,Microspherophakia ,Marfan ,Genetics ,medicine ,Humans ,Eye Abnormalities ,RNA, Messenger ,Ectopia lentis ,Child ,Genetics (clinical) ,Base Sequence ,Infant ,Glaucoma ,Syndrome ,Sciences bio-médicales et agricoles ,medicine.disease ,Disease gene identification ,Null allele ,Exon skipping ,Pedigree ,Latent TGF-beta Binding Proteins ,Child, Preschool ,Mutation ,microspherophakia ,Female ,Candidate Gene Analysis ,megalocornea - Abstract
The latent TGFbeta-binding proteins (LTBPs) and fibrillins are a superfamily of large, multidomain proteins with structural and TGFbeta-signalling roles in the extracellular matrix. Their importance is underscored by fibrillin-1 mutations responsible for Marfan syndrome, but their respective roles are still incompletely understood. We report here on two families where children from healthy, consanguineous parents, presented with megalocornea and impaired vision associated with small, round, dislocated lenses (microspherophakia and ectopia lentis) and myopia, as well as a high-arched palate, and, in older children, tall stature with an abnormally large arm span over body height ratio, that is, associated features of Marfan syndrome. Glaucoma was not present at birth, but was diagnosed in older children. Whole genome homozygosity mapping followed by candidate gene analysis identified homozygous truncating mutations of LTBP2 gene in patients from both families. Fibroblast mRNA analysis was consistent with nonsense-mediated mRNA decay, with no evidence of mutated exon skipping. We conclude that biallelic null LTBP2 mutations cause the ocular phenotype in both families and could lead to Marfan-like features in older children. We suggest that intraocular pressures should be followed-up in young children with an ocular phenotype consisting of megalocornea, spherophakia and/or lens dislocation, and recommend LTBP2 gene analysis in these patients.European Journal of Human Genetics advance online publication, 24 February 2010; doi:10.1038/ejhg.2010.11., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2010
48. IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign
- Author
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L. Van Maldergem, Bénédicte Bayet, Valérie Drouin-Garraud, Nicole Revencu, David Geneviève, Geneviève François, Catheline Vilain, Alice Goldenberg, Romain Vanwijck, Christine Verellen-Dumoulin, Kathleen Claes, A. Gozu, Geneviève Pierquin, P. Makrythanasis, Odile Boute, Joke B. G. M. Verheij, Laurence Desmyter, Miikka Vikkula, Fiona Connell, Muriel Holder-Espinasse, M. Bouma, Sylvie Manouvrier-Hanu, Anne Dieux-Coeslier, Melissa Lees, Marie-Claude Addor, Catherine Vincent-Delorme, Sylvie Odent, U. Mcentagart, Hervé Benateau, A. Sanchez, Michèle Mathieu, Koenraad Devriendt, Yves Sznajer, Geert Mortier, Sascha Vermeer, Michella Ghassibé, Anne Moncla, and Yves Gillerot
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Orthodontics ,0303 health sciences ,medicine.medical_specialty ,business.industry ,030305 genetics & heredity ,Lower lip ,medicine.disease ,Dermatology ,Revised diagnosis ,stomatognathic diseases ,03 medical and health sciences ,Mutation (genetic algorithm) ,Genetics ,Mutation screening ,Medicine ,IRF6 ,Van der Woude syndrome ,Family history ,business ,Genetics (clinical) ,Non syndromic ,030304 developmental biology - Abstract
Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.
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- 2010
49. Lhermitte-Duclos disease with obstructive hydrocephalus: An illustrative case treated with endoscopic ventriculo-cisternostomy
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Yves Sznajer, Michel Triffaux, Charles-Antoine Sibille, M. Gille, and Kathleen Claes
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medicine.medical_specialty ,Lhermitte–Duclos disease ,medicine.diagnostic_test ,business.industry ,MEDLINE ,Obstructive hydrocephalus ,Magnetic resonance imaging ,medicine.disease ,Surgery ,Remission induction ,Neurology ,medicine ,Neurology (clinical) ,Radiology ,business ,Gangliocytoma - Published
- 2013
50. DYNC2H1 Mutations Cause Asphyxiating Thoracic Dystrophy and Short Rib-Polydactyly Syndrome, Type III
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Elisabeth Flori, Martine Le Merrer, Denise P. Cavalcanti, Anne-Lise Delezoide, Valérie Cormier-Daire, Geneviève Baujat, Yves Sznajer, Sarah F. Smithson, David Geneviève, Céline Huber, Laura Tecco, Nathalie Dagoneau, Valérie Serre, Jelena Martinovic, Arnold Munnich, and Marie Goulet
- Subjects
Cytoplasmic Dyneins ,Models, Molecular ,Pathology ,medicine.medical_specialty ,Short Rib-Polydactyly Syndrome ,Biology ,medicine.disease_cause ,Compound heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,Report ,Cytoplasmic dynein complex ,Genetics ,medicine ,Humans ,Genetics(clinical) ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Mutation ,Short rib – polydactyly syndrome ,Polydactyly ,Chromosomes, Human, Pair 11 ,Dyneins ,Dysostosis ,Dystrophy ,Anatomy ,medicine.disease ,Pedigree ,Ciliopathy ,Carrier Proteins ,Respiratory Insufficiency ,030217 neurology & neurosurgery - Abstract
Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive chondrodysplasia characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof. ATD is closely related to the short rib polydactyly syndrome (SRP) type III, which is a more severe condition characterized by early prenatal expression and lethality and variable malformations. We first excluded IFT80 in a series of 26 fetuses and children belonging to 14 families diagnosed with either ATD or SRP type III. Studying a consanguineous family from Morocco, we mapped an ATD gene to chromosome 11q14.3-q23.1 in a 20.4 Mb region and identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children. Compound heterozygosity for DYNC2H1 mutations was also identified in four additional families. Among the five families, 3/5 were diagnosed with ATD and 2/5 included pregnancies terminated for SRP type III. DYNC2H1 is a component of a cytoplasmic dynein complex and is directly involved in the generation and maintenance of cilia. From this study, we conclude that ATD and SRP type III are variants of a single disorder belonging to the ciliopathy group.
- Published
- 2009
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