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1. Contribution of retrotransposition to developmental disorders

Author: Eugene J. Gardner, Elena Prigmore, Giuseppe Gallone, Petr Danecek, Kaitlin E. Samocha, Juliet Handsaker, Sebastian S. Gerety, Holly Ironfield, Patrick J. Short, Alejandro Sifrim, Tarjinder Singh, Kate E. Chandler, Emma Clement, Katherine L. Lachlan, Katrina Prescott, Elisabeth Rosser, David R. FitzPatrick, Helen V. Firth, and Matthew E. Hurles
Subjects: Science
Abstract: Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.
Published: 2019
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2. Valuation of Lost Productivity in Caregivers: A Validation Study

Author: Aaron Gelfand, Julie Sou, Rick Sawatzky, Katrina Prescott, Alison Pearce, Aslam H. Anis, Christine Lee, and Wei Zhang
Subjects: caregiver, Valuation of Lost Productivity questionnaire, absenteeism, presenteeism, productivity loss, validity, Psychology, BF1-990
Abstract: ObjectiveThis study aimed to: (a) adapt the previously validated Valuation of Lost Productivity (VOLP) questionnaire for people with health problems, to a caregiver version to measure productivity losses associated with caregiving responsibilities, and (b) evaluate measurement feasibility and validity of an online version of the caregiver VOLP questionnaire.MethodsA mixed methods design was utilized. Qualitative methods, such as reviewing existing questionnaires that measured caregiver work productivity losses and performing one-on-one interviews with caregivers, were used for VOLP adaptation and online conversion. Quantitative methods were used to evaluate feasibility and validity of the online VOLP. The Work Productivity and Activity Impairment (WPAI) questionnaire for caregivers was included to compare its absenteeism and presenteeism outcomes and their correlations with VOLP outcomes.ResultsWhen adapting the VOLP for caregivers, our qualitative analysis showed the importance of adding three major components: caregiving time, work productivity loss related to volunteer activities and caregivers’ lost job opportunities. A total of 383 caregivers who completed online survey were included in our final quantitative analysis. We found small Spearman rank correlations between VOLP and WPAI, observing a larger correlation between their absenteeism [r = 0.49 (95% confidence interval: 0.37–0.60)] than their presenteeism [r = 0.36 (0.24–0.47)]. Correlations between VOLP outcomes and total caregiving hours were larger for absenteeism [r = 0.38 (0.27–0.47)] than presenteeism [r = 0.22 (0.10–0.34)]. Correlations between WPAI outcomes and total caregiving hours were smaller for absenteeism [r = 0.27 (0.15–0.38)] than presenteeism [r = 0.35 (0.23–0.46)].ConclusionThe study provides evidence of the feasibility and preliminary validity evidence of the adapted VOLP caregiver questionnaire in measuring productivity losses due to caregiving responsibilities, when compared with the results for WPAI and the results from the previous patient-VOLP validation study.
Published: 2021
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3. Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome.

Author: Tomoo Ogi, Sarah Walker, Tom Stiff, Emma Hobson, Siripan Limsirichaikul, Gillian Carpenter, Katrina Prescott, Mohnish Suri, Philip J Byrd, Michiko Matsuse, Norisato Mitsutake, Yuka Nakazawa, Pradeep Vasudevan, Margaret Barrow, Grant S Stewart, A Malcolm R Taylor, Mark O'Driscoll, and Penny A Jeggo
Subjects: Genetics, QH426-470
Abstract: A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be defined.
Published: 2012
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4. Working From Home During the COVID-19 Pandemic

Author: Wei, Zhang, Huiying, Sun, Aaron, Gelfand, Richard, Sawatzky, Alison, Pearce, Aslam H, Anis, Katrina, Prescott, and Christine, Lee
Subjects: Cross-Sectional Studies, Caregivers, Surveys and Questionnaires, Absenteeism, Public Health, Environmental and Occupational Health, Humans, COVID-19, Efficiency, Presenteeism, Pandemics
Abstract: The aim of this study was to measure the association of working from home (WFH) with work productivity loss due to caregiving responsibilities or health problems during the COVID-19 pandemic.We conducted an online survey of family/friend caregivers (n = 150 WFH/75 non-WFH) and patients (n = 95/91) who worked during the past 7 days in May and July 2020, respectively. Absenteeism and presenteeism were measured using the Valuation of Lost Productivity questionnaire.Working from home was associated with higher odds of absenteeism (odds ratio, 2.53; 95% confidence interval, 1.11 to 5.77) and presenteeism (2.79; 1.26 to 6.18) among caregivers and higher odds of presenteeism among patients (2.78; 1.13 to 6.84). However, among caregivers with absenteeism more than 0 days, WFH was significantly associated with fewer absent workdays.Working from home was not associated with overall absenteeism and presenteeism in caregivers or patients. Working from home allows a more flexible and inclusive workplace without impacting productivity, although further research is needed.
Published: 2022

5. The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase

Author: Ida Signe Bohse Larsen, Lorenzo Povolo, Luping Zhou, Weihua Tian, Kasper Johansen Mygind, John Hintze, Chen Jiang, Verity Hartill, Katrina Prescott, Colin A. Johnson, Sureni V. Mullegama, Allyn McConkie-Rosell, Marie McDonald, Lars Hansen, Sergey Y. Vakhrushev, Katrine T. Schjoldager, Henrik Clausen, Thomas Worzfeld, Hiren J. Joshi, and Adnan Halim
Subjects: Multidisciplinary, glycosylation, glycoproteomics, plexin, O-mannosylation, congenital disorders of glycosylation
Abstract: Mutations in the TMEM260 gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 knockout in cells results in receptor maturation defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morphogenesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.
Published: 2023

6. Further delineation of the clinical spectrum of White–Sutton syndrome: 12 new individuals and a review of the literature

Author: Siren Berland, Andreas Benneche, Andrew E. Fry, Kate Chandler, Julie Paulsen, Marie Falkenberg Smeland, Nicola Foulds, Neeti Ghali, Katrina Prescott, Jenny Carmichael, Vani Jain, Kay Metcalfe, Oliver Murch, and Emma Hobson
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Developmental Disabilities, Mutation, Missense, Transposases, Article, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, Genetics, Humans, Medicine, Missense mutation, Abnormalities, Multiple, Child, Genetics (clinical), business.industry, Infant, Dystrophy, Congenital diaphragmatic hernia, Syndrome, medicine.disease, Phenotype, Pedigree, White (mutation), Child, Preschool, Female, Sensorineural hearing loss, business
Abstract: White–Sutton syndrome (WHSUS) is a neurodevelopmental disorder caused by heterozygous loss-of-function variants in POGZ. Through the Deciphering Developmental Disorders study and clinical testing, we identified 12 individuals from 10 families with pathogenic or likely pathogenic variants in POGZ (eight de novo and two inherited). Most individuals had delayed development and/or intellectual disability. We analyzed the clinical findings in our series and combined it with data from 89 previously reported individuals. The results demonstrate WHSUS is associated with variable developmental delay or intellectual disability, increased risk of obesity, visual defects, craniofacial dysmorphism, sensorineural hearing loss, feeding problems, seizures, and structural brain malformations. Our series includes further individuals with rod-cone dystrophy, cleft lip and palate, congenital diaphragmatic hernia, and duplicated renal drainage system, suggesting these are rare complications of WHSUS. In addition, we describe an individual with a novel, de novo missense variant in POGZ and features of WHSUS. Our work further delineates the phenotypic spectrum of WHSUS highlighting the variable severity of this disorder and the observation of familial pathogenic POGZ variants.
Published: 2021

7. Whole genome sequencing of ‘mutation-negative’ individuals with Cornelia de Lange Syndrome

Author: Morad Ansari, Mihail Halachev, David Parry, Jose L. Campos, Elston N. D’Souza, Christopher Barnett, Andrew O. M. Wilkie, Angela Barnicoat, Chirag V. Patel, Elena Sukarova-Angelovska, Katta M. Girisha, Helen V. Firth, Katrina Prescott, Louise C. Wilson, Meriel McEntagart, Rosemarie Davidson, Sally Ann Lynch, Shelagh Joss, Simon T. Holden, Wayne K. Lam, Sanjay M. Sisodiya, Andrew J. Green, Gemma Poke, Nicola Whiffin, David R. FitzPatrick, and Alison Meynert
Abstract: AimsThis study assesses the diagnostic utility of whole genome sequence analysis in a well-characterised research cohort of individuals referred with a clinical suspicion of Cornelia de Lange syndrome (CdLS) in whom prior genetic testing had not identified a causative variant.MethodsShort read, whole genome sequencing was performed in 195 individuals from 105 families, 108 of whom were affected. 100/108 of the affected individuals had prior relevant genetic testing with no pathogenic variant being identified. The study group comprised 42 trios (affected individuals with both unaffected parents), 61 singletons (unrelated affected individuals) and two families with more than one affected individual.Results32/105 (30.5%) unrelated probands had likely causative coding region disrupting variants. 4 loci were identified in >1 proband; NIPBL (10), ANKRD11 (6), EP300 (3), EHMT1 (2). Single alleles were detected in the remaining genes (EBF3, KMT2A, MED13L, NLGN3, NR2F1, PHIP, PUF60, SET, SETD5, SMC1A, TBL1XR1). Possibly causative variants in non-coding regions of NIPBL were identified in four individuals. Single de novo variants were identified in five genes not previously reported to be associated with any developmental disorder: ARID3A, PIK3C3, MCM7, MIS18BP1 and WDR18.ConclusionsClustering of de novo non-coding variants implicate a single uORF and a small region in intron 21 in NIPBL regulation. Causative variants in genes encoding chromatin-associated proteins, with no defined influence on cohesin function, appear to result in CdLS-like clinical features.
Published: 2022

8. Monoallelic Loss of Function BMP2 Variants Result in BMP2-Related Skeletal Dysplasia Spectrum

Author: Jessica R.C. Priestley, Ashish R. Deshwar, Harsha Murthy, Maria Daniela D’Agostino, Lucie Dupuis, Balram Gangaram, Christopher Gray, Rebekah Jobling, Emanuela Pannia, Konrad Platzer, Katrina Prescott, Melody Redman, Alyssa L. Rippert, Jill A. Rosenfeld, Daryl A. Scott, Yi Wen Wang, Zelia Schmederer, Ashwin Dalal, Asodu Sandeep Sarma, Cara Skraban, James.J. Dowling, Roberto Mendoza-Londono, Anne Slavotinek, and Elizabeth J. Bhoj
Subjects: Genetics (clinical)
Published: 2023

9. De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities of eye movement

Author: Shenzhao Lu, Mengqi Ma, Xiao Mao, Carlos A. Bacino, Joseph Jankovic, V. Reid Sutton, James A. Bartley, Xueying Wang, Jill A. Rosenfeld, Ana Beleza-Meireles, Jaynee Chauhan, Xueyang Pan, Megan Li, Pengfei Liu, Katrina Prescott, Sam Amin, George Davies, Michael F. Wangler, Yuwei Dai, and Hugo J. Bellen
Subjects: DNA, Complementary, Eye Movements, Developmental Disabilities, Tumor Suppressor Proteins, Membrane Proteins, Phosphatidylinositols, Seizures, Intellectual Disability, Report, Genetics, Animals, Humans, Ataxia, Genetics (clinical)
Abstract: Proteins containing the FERM (four-point-one, ezrin, radixin, and moesin) domain link the plasma membrane with cytoskeletal structures at specific cellular locations and have been implicated in the localization of cell-membrane-associated proteins and/or phosphoinositides. FERM domain-containing protein 5 (FRMD5) localizes at cell adherens junctions and stabilizes cell-cell contacts. To date, variants in FRMD5 have not been associated with a Mendelian disease in OMIM. Here, we describe eight probands with rare heterozygous missense variants in FRMD5 who present with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement. The variants are de novo in all for whom parental testing was available (six out of eight probands), and human genetic datasets suggest that FRMD5 is intolerant to loss of function (LoF). We found that the fly ortholog of FRMD5, CG5022 (dFrmd), is expressed in the larval and adult central nervous systems where it is present in neurons but not in glia. dFrmd LoF mutant flies are viable but are extremely sensitive to heat shock, which induces severe seizures. The mutants also exhibit defective responses to light. The human FRMD5 reference (Ref) cDNA rescues the fly dFrmd LoF phenotypes. In contrast, all the FRMD5 variants tested in this study (c.340T>C, c.1051A>G, c.1053C>G, c.1054T>C, c.1045A>C, and c.1637A>G) behave as partial LoF variants. In addition, our results indicate that two variants that were tested have dominant-negative effects. In summary, the evidence supports that the observed variants in FRMD5 cause neurological symptoms in humans.
Published: 2022

10. Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus

Author: Mary R. Sy, Jaynee Chauhan, Katrina Prescott, Aliza Imam, Alison Kraus, Ana Beleza, Lee Salkeld, Saraswati Hosdurga, Michael Parker, Pradeep Vasudevan, Lily Islam, Himanshu Goel, Nicole Bain, Soo‐Mi Park, Shehla Mohammed, Klaus Dieterich, Charles Coutton, Véronique Satre, Gaëlle Vieville, Alan Donaldson, Claire Beneteau, Jamal Ghoumid, Kris Van Den Bogaert, Anneleen Boogaerts, Elise Boudry, Clémence Vanlerberghe, Florence Petit, Laura Bernardini, Barbara Torres, Teresa Mattina, Diana Carli, Giorgia Mandrile, Michele Pinelli, Nicola Brunetti‐Pierri, Katherine Neas, Rachel Beddow, Pernille M. Tørring, Flavio Faletra, Beatrice Spedicati, Paolo Gasparini, Alessandro Mussa, Giovanni Battista Ferrero, Anne Lampe, Wayne Lam, Weimin Bi, Carlos A. Bacino, Akela Kuwahara, Jeffrey O. Bush, Xiaonan Zhao, Pamela N. Luna, Chad A. Shaw, Jill A. Rosenfeld, Daryl A. Scott, Sy, Mary R, Chauhan, Jaynee, Prescott, Katrina, Imam, Aliza, Kraus, Alison, Beleza, Ana, Salkeld, Lee, Hosdurga, Saraswati, Parker, Michael, Vasudevan, Pradeep, Islam, Lily, Goel, Himanshu, Bain, Nicole, Park, Soo-Mi, Mohammed, Shehla, Dieterich, Klau, Coutton, Charle, Satre, Véronique, Vieville, Gaëlle, Donaldson, Alan, Beneteau, Claire, Ghoumid, Jamal, Van Den Bogaert, Kri, Boogaerts, Anneleen, Boudry, Elise, Vanlerberghe, Clémence, Petit, Florence, Bernardini, Laura, Torres, Barbara, Mattina, Teresa, Carli, Diana, Mandrile, Giorgia, Pinelli, Michele, Brunetti-Pierri, Nicola, Neas, Katherine, Beddow, Rachel, Tørring, Pernille M, Faletra, Flavio, Spedicati, Beatrice, Gasparini, Paolo, Mussa, Alessandro, Ferrero, Giovanni Battista, Lampe, Anne, Lam, Wayne, Bi, Weimin, Bacino, Carlos A, Kuwahara, Akela, Bush, Jeffrey O, Zhao, Xiaonan, Luna, Pamela N, Shaw, Chad A, Rosenfeld, Jill A, and Scott, Daryl A
Subjects: tracheoesophageal fistula, NRXN1, Fanconi anemia, Genetics, Humans, TCF4, esophageal atresia, exome sequencing, Exome, Genetics (clinical)
Abstract: Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.
Published: 2022

11. Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome

Author: Jamie M Ellingford, Huw B. Thomas, Raymond T. O'Keefe, Glenda M. Beaman, Sofia Douzgou, William G. Newman, Katrina Prescott, Katherine A. Wood, and Emma Hobson
Subjects: Heart Defects, Congenital, Spliceosome, Genotype, RNA Splicing, Biology, Deafness, Choanal Atresia, Exon, splicing, Rare Disease, Genetics, Humans, Genetic Predisposition to Disease, Promoter Regions, Genetic, Transcription factor, Genetics (clinical), Alleles, Genetic Association Studies, Ribonucleoprotein, U5 Small Nuclear, Binding Sites, burn mckeown syndrome, TNXL4A, Facies, Promoter, Pedigree, DNA binding site, Phenotype, RNA splicing, Mutation, Female, Trans-acting, Minigene, Protein Binding, Transcription Factors
Abstract: The developmental disorder Burn-McKeown Syndrome (BMKS) is characterised by choanal atresia and specific craniofacial features. BMKS is caused by biallelic variants in the pre-messenger RNA splicing factor TXNL4A. Most patients have a loss-of-function variant in trans with a 34-base pair (bp) deletion (type 1 Δ34) in the promoter region. Here, we identified two patients with BMKS. One individual has a TXNL4A c.93_94delCC, p.His32Argfs*21 variant combined with a type 1 Δ34 promoter deletion. The other has an intronic TXNL4A splice site variant (c.258-3C>G) and a type 1 Δ34 promoter deletion. We show the c.258-3C>G variant, and a previously reported c.258-2A>G variant, cause skipping of the final exon of TXNL4A in a minigene splicing assay. Furthermore, we identify putative transcription factor binding sites within the 56bp of the TXNL4A promoter affected by the type 1 and type 2 Δ34 and use dual luciferase assays to identify a 22bp repeated motif essential for TXNL4A expression within this promoter region. We propose that additional variants affecting critical transcription factor binding nucleotides within the 22bp repeated motif could be relevant to BMKS etiology. Finally, our data emphasizes the need to analyse the non-coding sequence in individuals where a single likely pathogenic coding variant is identified in an autosomal recessive disorder consistent with the clinical presentation.
Published: 2021

12. Mosaicism in ASXL3-related syndrome: Description of five patients from three families

Author: Katrina Prescott, Anna Platt, Sumit Punj, Meena Balasubramanian, Deciphering Developmental Disorders Study, Schaida Schirwani, Sahar Mansour, Natalie Hauser, and Natalie Canham
Subjects: 0301 basic medicine, Male, Developmental Disabilities, Germline mosaicism, Disease, 030105 genetics & heredity, Saliva sample, Biology, Germline, 03 medical and health sciences, Neurodevelopmental disorder, Genetics, medicine, Humans, Child, Gene, Genetics (clinical), Mechanism (biology), Mosaicism, General Medicine, medicine.disease, Pedigree, genomic DNA, 030104 developmental biology, Child, Preschool, Mutation, Female, Transcription Factors
Abstract: De novo pathogenic variants in the additional sex combs-like 3 (ASXL3) gene cause a rare multi-systemic neurodevelopmental disorder. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. There is one previous report of ASXL3-related syndrome caused by de novo pathogenic variants in two siblings suggesting gonadal mosaicism. In this report, we present five patients with ASXL3-related syndrome, describing two families comprising two non-twin siblings harbouring apparent de novo pathogenic variants in ASXL3. Parents were clinically unaffected and there was no evidence of mosaicism from genomic DNA on exome-trio data, suggesting germline mosaicism in one of the parents. We also describe clinical details of a patient with typical features of ASXL3-related syndrome and mosaic de novo pathogenic variant in ASXL3 in 30-35% of both blood and saliva sample on trio-exome sequencing. We expand the known genetic basis of ASXL3-related syndromes and discuss mosaicism as a disease mechanism in five patients from three unrelated families. The findings of this report highlight the importance of taking gonadal mosaicism into consideration when counselling families regarding recurrence risk. We also discuss postzygotic mosaicism as a cause of fully penetrant ASXL3-related syndrome.
Published: 2020

13. The broad phenotypic spectrum of PPP2R1A -related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Author: Amy McTague, Siddharth Srivastava, Tamison Jewett, Ali Al-Beshri, Constance Smith-Hicks, Shelagh Joss, Jennifer A. Sullivan, Sarju G. Mehta, Koenraad Devriendt, Pascal Joset, Laurence Faivre, Emma Kivuva, William G. Wilson, Gunnar Houge, Naama Orenstein, Yana Hoorne, Vickie L. Hannig, Malou Heijligers, Bart Loeys, Vandana Shashi, Katrina Prescott, Iris Verbinnen, Annick Toutain, Lauren M. Baldwin, Stephen P. Fulton, Katharina Steindl, Anne Marie Childs, Anna Chassevent, Shelley Towner, Cornelia Daumer-Haas, Oded Wechsberg, Alison Male, Hannah F. Johnson, Wendy K. Chung, Anita Rauch, Anna Ruiz, Isabelle Maystadt, Sara Reynhout, Sébastien Moutton, Yvette van Ierland, Veerle Janssens, Frédéric Laumonnier, Martina Baethmann, Lisa Lenaerts, Vani Jain, Vinod Varghese, Suzanne M. Koudijs, Elisabeth Gabau, Frédérique Bonnet-Brilhault, Rizwan Hamid, Susan E. Holder, Barbara Plecko, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Queen Elizabeth University Hospital (Glasgow), Kennedy Krieger Institute [Baltimore], University of Antwerp (UA), Universität Zürich [Zürich] = University of Zurich (UZH), Addenbrooke’s Hospital [Cambridge, UK], Columbia University Medical Center (CUMC), Columbia University [New York], North West Thames Regional Genetics Service [London, UK] (Harrow), North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow-Northwick Park Hospital [Harrow, UK] (NPH), Wake Forest University, University of Virginia [Charlottesville], Boston Children's Hospital, Prenatal Medicine Munich [Munich, Germany] (PMM), Klinikum Dritter Orden [Munich], Universitat Autònoma de Barcelona (UAB), University Hospital of Wales [Cardiff, UK], University of Alabama at Birmingham [ Birmingham] (UAB), Le Bonheur Children's Hospital [Memphis, TN, USA] (LBCH), Schneider Children’s Medical Center of Israel [Petah Tikva], Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Leeds Teaching Hospitals NHS Trust, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Maison de Santé Protestante de Bordeaux-Bagatelle (MSPB), Duke University Medical Center, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Royal Devon and Exeter NHS Foundation Trust [UK], Great Ormond Street Institute of Child Health [London, UK] (UCL), University College of London [London] (UCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Medical University Graz, Institut de Pathologie et Génétique [Gosselies] (I.P.G.), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Haukeland University Hospital, University of Bergen (UiB), Leuven Brain Institute [Leuven, Belgium] (LBI), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Clinical Genetics, University of Virginia, University Hospital of Wales (UHW), Tel Aviv University (TAU), Great Ormond Street Institute of Child Health (UCL), and Laumonnier, Frédéric
Subjects: 0301 basic medicine, Microcephaly, [SDV]Life Sciences [q-bio], Intellectual disability, 030105 genetics & heredity, Bioinformatics, Epilepsy, Neurodevelopmental disorder, CORE, Protein Phosphatase 2, SPECIFICITY, Genetics (clinical), PROTEIN PHOSPHATASE 2A, Phenotype, Hypotonia, FAMILY, 3. Good health, PP2A, [SDV] Life Sciences [q-bio], PPP2R1A, PPP2R5D, INSIGHTS, intellectual disability, Muscle Hypotonia, medicine.symptom, Language delay, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, business.industry, Macrocephaly, DEPHOSPHORYLATION, medicine.disease, neurodevelopmental disorder, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, SUBUNIT, epilepsy, Human medicine, TAU, business, Transcription Factors
Abstract: PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported. ispartof: Genetics In Medicine vol:23 issue:2 ispartof: location:United States status: Published online
Published: 2020

14. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author: Enrico D.H. Konrad, Niels Nardini, Almuth Caliebe, Inga Nagel, Dana Young, Gabriella Horvath, Stephanie L. Santoro, Christine Shuss, Alban Ziegler, Dominique Bonneau, Marlies Kempers, Rolph Pfundt, Eric Legius, Arjan Bouman, Kyra E. Stuurman, Katrin Õunap, Sander Pajusalu, Monica H. Wojcik, Georgia Vasileiou, Gwenaël Le Guyader, Hege M. Schnelle, Siren Berland, Evelien Zonneveld-Huijssoon, Simone Kersten, Aditi Gupta, Patrick R. Blackburn, Marissa S. Ellingson, Matthew J. Ferber, Radhika Dhamija, Eric W. Klee, Meriel McEntagart, Klaske D. Lichtenbelt, Amy Kenney, Samantha A. Vergano, Rami Abou Jamra, Konrad Platzer, Mary Ella Pierpont, Divya Khattar, Robert J. Hopkin, Richard J. Martin, Marjolijn C.J. Jongmans, Vivian Y. Chang, Julian A. Martinez-Agosto, Outi Kuismin, Mitja I. Kurki, Olli Pietiläinen, Aarno Palotie, Timothy J. Maarup, Diana S. Johnson, Katja Venborg Pedersen, Lone W. Laulund, Sally A. Lynch, Moira Blyth, Katrina Prescott, Natalie Canham, Rita Ibitoye, Eva H. Brilstra, Marwan Shinawi, Emily Fassi, Heinrich Sticht, Anne Gregor, Hilde Van Esch, Christiane Zweier, Graduate School, Clinical Genetics, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Center for Population, Health and Society, Centre of Excellence in Complex Disease Genetics, and Aarno Palotie / Principal Investigator
Subjects: Male, CCCTC-Binding Factor, Developmental Disabilities, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Transcriptome, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Drosophila Proteins, Missense mutation, TOOL, Genetics(clinical), Child, Genetics (clinical), Genetics & Heredity, Genetics, 0303 health sciences, biology, GENE ONTOLOGY, neurodevelopmental disorders, 1184 Genetics, developmental biology, physiology, HUMANS, Chromatin, 3. Good health, DROSOPHILA, Drosophila melanogaster, intellectual disability, LIBRARY, Female, INACTIVATION, Life Sciences & Biomedicine, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], EXPRESSION, DATABASE, Mutation, Missense, Article, Young Adult, 03 medical and health sciences, Exome Sequencing, medicine, Animals, Gene, 030304 developmental biology, Science & Technology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Gene Expression Profiling, biology.organism_classification, medicine.disease, CTCF, Gene Expression Regulation, DE-NOVO MUTATIONS, Mutation, 030217 neurology & neurosurgery, Transcription Factors, chromatin organization
Abstract: PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila. ispartof: GENETICS IN MEDICINE vol:21 issue:12 pages:2723-2733 ispartof: location:United States status: published
Published: 2019

15. Contribution of retrotransposition to developmental disorders

Author: Katherine Lachlan, Elena Prigmore, Emma Clement, Patrick J. Short, Katrina Prescott, David R. FitzPatrick, Petr Danecek, Kate Chandler, Holly Ironfield, Alejandro Sifrim, Helen V. Firth, Giuseppe Gallone, Matthew E. Hurles, Tarjinder Singh, Eugene J. Gardner, Sebastian S. Gerety, Kaitlin E. Samocha, Juliet Handsaker, Elisabeth Rosser, Gardner, Eugene J [0000-0001-9671-1533], Gerety, Sebastian S [0000-0002-6126-5040], Short, Patrick J [0000-0002-7626-6177], Singh, Tarjinder [0000-0003-0601-6815], and Apollo - University of Cambridge Repository
Subjects: Proband, 0301 basic medicine, Mutation rate, BROWSER, Retroelements, DATABASE, Science, Developmental Disabilities, Mutagenesis (molecular biology technique), General Physics and Astronomy, Retrotransposon, VARIANTS, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Germline, 03 medical and health sciences, Negative selection, 0302 clinical medicine, Mutation Rate, Genetic variation, ELEMENTS, Humans, lcsh:Science, Exome, Gene, 030304 developmental biology, Genetics, 0303 health sciences, Science & Technology, Multidisciplinary, Neurodevelopmental disorders, Genetic Variation, General Chemistry, FRAMEWORK, Multidisciplinary Sciences, GENOME, 030104 developmental biology, DE-NOVO MUTATIONS, Mutation, PATTERNS, Science & Technology - Other Topics, lcsh:Q, Structural variation, Mobile genetic elements, Medical genomics, 030217 neurology & neurosurgery
Abstract: Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies., Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.
Published: 2019

16. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study

Author: Jenny, Lord, Dominic J, McMullan, Ruth Y, Eberhardt, Gabriele, Rinck, Susan J, Hamilton, Elizabeth, Quinlan-Jones, Elena, Prigmore, Rebecca, Keelagher, Sunayna K, Best, Georgina K, Carey, Rhiannon, Mellis, Sarah, Robart, Ian R, Berry, Kate E, Chandler, Deirdre, Cilliers, Lara, Cresswell, Sandra L, Edwards, Carol, Gardiner, Alex, Henderson, Simon T, Holden, Tessa, Homfray, Tracy, Lester, Rebecca A, Lewis, Ruth, Newbury-Ecob, Katrina, Prescott, Oliver W, Quarrell, Simon C, Ramsden, Eileen, Roberts, Dagmar, Tapon, Madeleine J, Tooley, Pradeep C, Vasudevan, Astrid P, Weber, Diana G, Wellesley, Paul, Westwood, Helen, White, Michael, Parker, Denise, Williams, Lucy, Jenkins, Richard H, Scott, Mark D, Kilby, Lyn S, Chitty, Matthew E, Hurles, Eamonn R, Maher, and Elizabeth, Wilson
Subjects: Male, Parents, medicine.medical_specialty, DNA Copy Number Variations, Perinatal Death, Abnormal Karyotype, Aneuploidy, Article, Congenital Abnormalities, Fetal Development, 03 medical and health sciences, Fetus, 0302 clinical medicine, Pregnancy, Prenatal Diagnosis, Exome Sequencing, Correspondence, medicine, Humans, Prospective Studies, Copy-number variation, Prospective cohort study, Increased nuchal translucency, Allele frequency, Exome sequencing, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, business.industry, Obstetrics, Patient Selection, Infant, Newborn, Obstetrics and Gynecology, General Medicine, Stillbirth, medicine.disease, 3. Good health, Abortion, Spontaneous, Developmental disorder, Phenotype, Female, Ultrasonography, Nuchal Translucency Measurement, business, Live Birth, Abortion, Eugenic, Cohort study
Abstract: Background Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). Methods In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. Findings The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4–11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). Interpretation WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. Funding UK Department of Health and Social Care and The Wellcome Trust.
Published: 2019

17. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author: Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], 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), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, 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), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)
Subjects: 0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
Published: 2019

18. Correction: Arterial tortuosity syndrome: 40 new families and literature review

Author: Damien Bonnet, Paul Coucke, David R. Deyle, Mohammed Z. Haider, Fahrettin Uysal, Eudice E. Fontenot, Inge De Wandele, Margot A. Cousin, Waheed Al-Manea, Sehime Gulsun Temel, Massimiliano Rossi, Fabienne Giuliano, Sofie De Schepper, Joshua S. Hardin, Mazen Al-Essa, Ergun Cil, N Canham, Majed Dasouki, Harry C. Dietz, Juliette Albuisson, Pamela Moceri, Sophie Dupuis-Girod, Koenraad Devriendt, David Warner, Bart Loeys, Özlem M. Bostan, Andrea Taylor, Neus Baena, Elise Schaefer, Sheela Nampoothiri, Eric W. Klee, Karin Pichler, Elaine C. Davis, Andy Willaert, Odile Boute, Tiffany Busa, Björn Fischer-Zirnsak, Alper Gezdirici, Jamal Ghoumid, Manuel F. Landecho, Shehla Mohammed, Yuri A. Zarate, Maria Ramos-Arroyo, Tom R. Collins, Aude Beyens, Stanislas Lyonnet, Laura Muiño-Mosquera, Uwe Kornak, Marine Vanhomwegen, Helen Michael, Anna Rajeb, Mohammed Zain Seidahmed, Anne De Paepe, Deepthi De Silva, Bert Callewaert, Elisabeth Steichen-Gersdorf, Lut Van Laer, Annekatrien Boel, Anne Legrand, Xavier Jeunemaitre, Lionel Van Maldergem, Katrina Prescott, Mustafa A. Salih, and Julie De Backer
Subjects: medicine.medical_specialty, Arterial tortuosity syndrome, business.industry, Published Erratum, MEDLINE, medicine.disease, Human genetics, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, medicine, Intensive care medicine, business, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract: In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper.
Published: 2019
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19. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author: Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
Subjects: 0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: © 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
Published: 2018

20. Whole Exon Deletion in the GFAP Gene Is a Novel Molecular Mechanism Causing Alexander Disease

Author: Eamonn Sheridan, Anne Marie Childs, Dan Warren, Helen McCullagh, Ian R. Berry, Katrina Prescott, Lydia Green, Nick Camm, Marjo S. van der Knaap, Ian Craven, John H. Livingston, Sandhya Jose, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Pediatric surgery, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Male, Tomography Scanners, X-Ray Computed, Mutant, DNA Mutational Analysis, macromolecular substances, medicine.disease_cause, 03 medical and health sciences, Exon, 0302 clinical medicine, Glial Fibrillary Acidic Protein, medicine, Missense mutation, Humans, Child, Exome sequencing, Mutation, Glial fibrillary acidic protein, biology, business.industry, Leukodystrophy, Brain, General Medicine, Exons, medicine.disease, Molecular biology, Magnetic Resonance Imaging, Alexander disease, 030104 developmental biology, nervous system, Child, Preschool, Pediatrics, Perinatology and Child Health, biology.protein, Neurology (clinical), Alexander Disease, business, 030217 neurology & neurosurgery, Gene Deletion, Follow-Up Studies
Abstract: Alexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the GFAP gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no GFAP mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white–gray junction. Initial mutation screening of the GFAP gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the GFAP gene. Mutations in the GFAP gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in GFAP. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease.
Published: 2018

21. Arterial tortuosity syndrome: 40 new families and literature review

Author: Uwe Kornak, Fabienne Giuliano, Aude Beyens, Mustafa A. Salih, Massimiliano Rossi, Marine Vanhomwegen, Lut Van Laer, Fahrettin Uysal, Koenraad Devriendt, David R. Deyle, Mohammed Z. Haider, Elise Schaefer, Tom R. Collins, Annekatrien Boel, Mazen Al-Essa, Elaine C. Davis, Elisabeth Steichen-Gersdorf, Ergun Cil, Eudice E. Fontenot, Andy Willaert, Bart Loeys, Eric W. Klee, Björn Fischer-Zirnsak, Joshua S. Hardin, Sophie Dupuis-Girod, N Canham, Majed Dasouki, Harry C. Dietz, Laura Muiño-Mosquera, Yuri A. Zarate, Karin Pichler, Xavier Jeunemaitre, Neus Baena Diez, Maria Ramos-Arroyo, Damien Bonnet, Paul Coucke, Waheed Al-Manea, Anne De Paepe, Tiffany Busa, Anna Rajeb, Shehla Mohammed, Odile Boute, Sofie De Schepper, Mohammed Zain Seidahmed, Juliette Albuisson, Andrea Taylor, Deepthi De Silva, Inge De Wandele, Helen Michael, Margot A. Cousin, Sehime Gulsun Temel, Pamela Moceri, Julie De Backer, Lionel Van Maldergem, Stanislas Lyonnet, Özlem M. Bostan, Katrina Prescott, Bert Callewaert, Anne Legrand, David Warner, Sheela Nampoothiri, Alper Gezdirici, Jamal Ghoumid, and Manuel F. Landecho
Subjects: 0301 basic medicine, Marfan syndrome, Adult, Joint Instability, Male, Connective Tissue Disorder, Pathology, medicine.medical_specialty, Arterial tortuosity syndrome, Adolescent, Vascular Malformations, Biopsy, Perforation (oil well), Glucose Transport Proteins, Facilitative, Smad2 Protein, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Aneurysm, Transforming Growth Factor beta, medicine, Humans, Diaphragmatic hernia, Child, Genetics (clinical), Vascular tissue, Aorta, Skin, Hernia, Diaphragmatic, Respiratory Distress Syndrome, Newborn, biology, business.industry, Connective Tissue Growth Factor, Infant, Skin Diseases, Genetic, Arteries, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, Child, Preschool, Mutation, biology.protein, Female, Human medicine, business, Elastin
Abstract: PurposeWe delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.MethodsWe retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF.ResultsStenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling.ConclusionOur findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.GENETICS in MEDICINE advance online publication, 11 January 2018; doi:10.1038/gim.2017.253. ispartof: Genetics in Medicine vol:20 issue:10 pages:1236-1245 ispartof: location:United States status: published
Published: 2018
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22. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

Author: Víctor Faundes, William G. Newman, Laura Bernardini, Natalie Canham, Jill Clayton-Smith, Bruno Dallapiccola, Sally J. Davies, Michelle K. Demos, Amy Goldman, Harinder Gill, Rachel Horton, Bronwyn Kerr, Dhavendra Kumar, Anna Lehman, Shane McKee, Jenny Morton, Michael J. Parker, Julia Rankin, Lisa Robertson, I. Karen Temple, Siddharth Banka, Shelin Adam, Christèle du Souich, Alison M. Elliott, Jill Mwenifumbo, Tanya N. Nelson, Clara van Karnebeek, Jan M. Friedman, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, V.K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, and Matthew E. . Hurles
Subjects: 0301 basic medicine, ASH1L, Male, Methyltransferase, Adolescent, Histone lysine methylation, KMT5B, Developmental Disabilities, Haploinsufficiency, Biology, Compound heterozygosity, histone lysine methyltransferase, Chromatin remodeling, chromatin remodeling, 03 medical and health sciences, histone lysine demethylase, Report, Genetics, Humans, Child, Genetics (clinical), Regulation of gene expression, Histone Demethylases, Developmental disorders, KMT2C, KMT2B, Histone-Lysine N-Methyltransferase, 030104 developmental biology, Histone, Overgrowth syndrome, Child, Preschool, Mutation, biology.protein, KDM5B, Female
Abstract: Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.
Published: 2017

23. Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome

Author: Sheila Clarke, Emilia K. Bijlsma, Richard C. Trembath, Laura Southgate, Anna Lehman, Lut Van Laer, Sander J A Beekmans, Anna-Barbara Stittrich, Appolonia Helderman-Van Den Enden, Claudia A. L. Ruivenkamp, Bart Loeys, Bert B.A. de Vries, Josephina A.N. Meester, Wim Wuyts, Gustavo Glusman, Martin Zenker, Nicolette S. den Hollander, Maja Sukalo, Hanka Venselaar, Peter Itin, Jared C. Roach, Millan S. Patel, Katrina Prescott, Joke B. G. M. Verheij, Klinische Genetica, RS: CARIM - R2 - Cardiac function and failure, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Genetica & Celbiologie, RS: CARIM School for Cardiovascular Diseases, Plastic, Reconstructive and Hand Surgery, and Other Research
Subjects: ANOMALIES, Heterozygote, Molecular Sequence Data, Notch signaling pathway, Limb Deformities, Congenital, Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0], Context (language use), Biology, medicine.disease_cause, Ectodermal Dysplasia, Genetics, medicine, Missense mutation, Humans, Genetics(clinical), Amino Acid Sequence, Gene, Genetics (clinical), Loss function, Adaptor Proteins, Signal Transducing, Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, Receptors, Notch, RBPJ, Calcium-Binding Proteins, DEFECTS, Sequence Analysis, DNA, DOCK6, medicine.disease, Pedigree, Scalp Dermatoses, APLASIA-CUTIS-CONGENITA, cardiovascular system, Intercellular Signaling Peptides and Proteins, Human medicine, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], VASCULAR DEVELOPMENT, Adams–Oliver syndrome, Signal Transduction
Abstract: Contains fulltext : 152973.pdf (Publisher’s version ) (Closed access) Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because RBPJ, NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pathogenesis. Using a candidate-gene-based approach, we prioritized DLL4, a critical NOTCH ligand, due to its essential role in vascular development in the context of cardiovascular features in AOS-affected individuals. Targeted resequencing of the DLL4 gene with a custom enrichment panel in 89 independent families resulted in the identification of seven mutations. A defect in DLL4 was also detected in two families via whole-exome or genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants, the latter encompassing four mutations that replace or create cysteine residues, which are most likely critical for maintaining structural integrity of the protein. Affected individuals with DLL4 mutations present with variable clinical expression with no emerging genotype-phenotype correlations. Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder.
Published: 2015

24. Comprehensive Clinical and Molecular Analysis of 12 Families with Type 1 Recessive Cutis Laxa

Author: Sofie Symoens, Bert Callewaert, Jean-Luc Bresson, Sahar Mansour, Chi-Ting Su, Meghan K. Mac Neal, Elaine C. Davis, Joseph G. H. Lee, Ketil Heimdal, Gérald Pierard, Katrina Prescott, Salome De Almeida, Paul Coucke, Anne De Paepe, Tim Van Damme, Bianca Schulz, Zsolt Urban, Uwe Kornak, Aicha Salhi, Lionel Van Maldergem, Olivier Vanakker, Sheila Unger, Philip Vlummens, Fransiska Malfait, Maria E. Gosendi, Harald Gaspar, Frank C. Sciurba, and Suneeta Madan-Khetarpal
Subjects: Male, Adolescent, Blotting, Western, Gene Expression, Consanguinity, Biology, medicine.disease_cause, Cutis Laxa, Article, Young Adult, Mutant protein, Genetics, medicine, Humans, Missense mutation, Child, Genetics (clinical), Skin, Family Health, Extracellular Matrix Proteins, Mutation, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Infant, Sequence Analysis, DNA, medicine.disease, Molecular biology, Phenotype, Pedigree, Microscopy, Electron, Latent TGF-beta Binding Proteins, Pulmonary Emphysema, Child, Preschool, FBLN5, Female, Fibrillin, Cutis laxa
Abstract: Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFβ) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.
Published: 2012

25. Whole-Exome Sequencing Identifies Mutations in GPR179 Leading to Autosomal-Recessive Complete Congenital Stationary Night Blindness

Author: Aurore Germain, Veselina Moskova-Doumanova, Guylène Le Meur, Francis L. Munier, Christina Zeitz, Kim T. Nguyen-Ba-Charvet, Jean-Paul Saraiva, Bernd Wissinger, Hoan Nguyen, Eberhart Zrenner, Elise Orhan, Samuel G. Jacobson, Aline Antonio, Daniel F. Schorderet, Agnes B. Renner, Susanne Kohl, Wolfgang Berger, Sabine Defoort-Dhellemmes, Christian P. Hamel, Dror Sharon, Françoise Meire, Katrina Prescott, Bart P. Leroy, Dominique Bonneau, Ian Simmons, Ulrich Kellner, Hélène Dollfus, Thierry Léveillard, Xavier Zanlonghi, Christelle Michiels, Olivier Poch, Odile Lecompte, Robert K. Koenekoop, Isabelle Drumare, Marie-Elise Lancelot, Thomy de Ravel, Birgit Lorenz, Vernon Long, Christoph Friedburg, Markus N. Preising, Tien D. Luu, Mélanie Letexier, Eyal Banin, Elfride De Baere, Kinga M. Bujakowska, José-Alain Sahel, Charlotte M. Poloschek, Isabelle Audo, Claire Audier, Shomi S. Bhattacharya, Ingele Casteels, Saddek Mohand-Said, Institut des Maladies Rares (France), Retina France, Fondation Voir et Entendre, Agence Nationale de la Recherche (France), Foundation Fighting Blindness, Région Ile-de-France, Association Française contre les Myopathies, National Institutes of Health (US), University of Zurich, Zeitz, Christina, Clinical sciences, and Medical Genetics
Subjects: Gamma-Subunit, Male, Electroretinography/methods, Genotyping Techniques, Phenotypic Impact, Receptors, Metabotropic Glutamate, Receptors, G-Protein-Coupled, 11124 Institute of Medical Molecular Genetics, 0302 clinical medicine, Cone dystrophy, Night Blindness, Myopia, Missense mutation, Genetics(clinical), Cone Dystrophy, Exome, Genetics (clinical), Exome sequencing, Sanger sequencing, Congenital stationary night blindness, Genetics, 0303 health sciences, Muscular-Dystrophy, Channel Subunit, Bipolar Cells, Homozygote, Genotyping Techniques/methods, Receptors, Metabotropic Glutamate/genetics, Eye Diseases, Hereditary, Genetic Diseases, X-Linked, 3. Good health, Phenotype, Mouse Retina, symbols, Proteoglycans, Female, Erratum, Myopia/genetics, Heterozygote, 2716 Genetics (clinical), mice, TRPM Cation Channels, 610 Medicine & health, Biology, Night Blindness/genetics, Polymorphism, Single Nucleotide, Retina, Frameshift mutation, Genetic Heterogeneity, 03 medical and health sciences, symbols.namesake, 1311 Genetics, Report, Electroretinography, medicine, Animals, Humans, Alleles, TRPM1, 030304 developmental biology, Retina/abnormalities, Protein, medicine.disease, Protein Structure, Tertiary, Proteoglycans/genetics, Cgmp-Phosphodiesterase, Complete Form, TRPM Cation Channels/genetics, 030221 ophthalmology & optometry, 570 Life sciences, biology, sense organs, mutation, Receptors, G-Protein-Coupled/genetics, exome, 030217 neurology & neurosurgery
Abstract: Audo, Isabelle, et al., Congenital stationary night blindness (CSNB) is a heterogeneous retinal disorder characterized by visual impairment under low light conditions. This disorder is due to a signal transmission defect from rod photoreceptors to adjacent bipolar cells in the retina. Two forms can be distinguished clinically, complete CSNB (cCSNB) or incomplete CSNB; the two forms are distinguished on the basis of the affected signaling pathway. Mutations in NYX, GRM6, and TRPM1, expressed in the outer plexiform layer (OPL) lead to disruption of the ON-bipolar cell response and have been seen in patients with cCSNB. Whole-exome sequencing in cCSNB patients lacking mutations in the known genes led to the identification of a homozygous missense mutation (c.1807C>T [p.His603Tyr]) in one consanguineous autosomal-recessive cCSNB family and a homozygous frameshift mutation in GPR179 (c.278delC [p.Pro93Glnfs57]) in a simplex male cCSNB patient. Additional screening with Sanger sequencing of 40 patients identified three other cCSNB patients harboring additional allelic mutations in GPR179. Although, immunhistological studies revealed Gpr179 in the OPL in wild-type mouse retina, Gpr179 did not colocalize with specific ON-bipolar markers. Interestingly, Gpr179 was highly concentrated in horizontal cells and Müller cell endfeet. The involvement of these cells in cCSNB and the specific function of GPR179 remain to be elucidated., The project was supported by GIS-maladies rares (C.Z.), Retina France ([part of the 100-Exome Project] I.A., C.P.H., J.-A.S., H.D. and C.Z.), Foundation Voir et Entendre (C.Z.), Agence National de la Recherche (S.S.B), Foundation Fighting Blindness (FFB) grant CD-CL-0808-0466-CHNO (I.A. and the CIC503, recognized as an FFB center), FFB grant C-CMM-0907-0428-INSERM04, Ville de Paris and Région Ille de France, the French Association against Myopathy (AFM) grant KBM-14390 (O.P.), and National Institutes of Health grant 1R01EY020902-01A1 (K.B.).
Published: 2012

26. Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects

Author: Giovanna Bosshard, Steven J Moss, Christine Bole-Feysot, Jean-Marc Fritschy, Karine Siquier-Pernet, Patrick Nitschké, Olivier Alibeu, Ann-Kristina Fritz, Dennis Mircsof, David P. Wolfer, Florence Crestani, Markus Rudin, Steven A. Brown, Nathalie Boddaert, Rochelle M. Hines, Arnold Munnich, Jeanne Amiel, Petra Seebeck, Matej Žnidarič, Christina Koester, Nicolas Cagnard, Ludmila Gaspar, Maéva Langouët, Shiva K. Tyagarajan, Laurence Colleaux, Aileen Schröter, Marlène Rio, Sébastien Moutton, Katrina Prescott, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Bioinformatique [SFR Necker] (BIP-D), Institute of Anatomy, Universität Zürich [Zürich] = University of Zurich (UZH), Service de radiologie pédiatrique [CHU Necker], Department of Clnical Genetics, Chapel Allerton Hospital, Institute of Pharmacology and Toxicology [Zurich], University of Zurich, Brown, Steven A, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), University of Zürich [Zürich] (UZH), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: Male, Protein family, Adolescent, 10050 Institute of Pharmacology and Toxicology, RNA-binding protein, 610 Medicine & health, Mice, Transgenic, Biology, Inhibitory postsynaptic potential, Article, Mice, Nuclear Matrix-Associated Proteins, Cellular neuroscience, Intellectual Disability, Intellectual disability, medicine, Transcriptional regulation, Animals, Humans, 10237 Institute of Biomedical Engineering, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Genetics, Gephyrin, General Neuroscience, 2800 General Neuroscience, Brain, RNA-Binding Proteins, Neural Inhibition, medicine.disease, Pedigree, DNA-Binding Proteins, Mice, Inbred C57BL, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Synapses, biology.protein, GABAergic, 570 Life sciences, biology, Octamer Transcription Factors, Neuroscience
Abstract: The NONO protein has been characterized as an important transcriptional regulator in diverse cellular contexts. Here we show that loss of NONO function is a likely cause of human intellectual disability and that NONO-deficient mice have cognitive and affective deficits. Correspondingly, we find specific defects at inhibitory synapses, where NONO regulates synaptic transcription and gephyrin scaffold structure. Our data identify NONO as a possible neurodevelopmental disease gene and highlight the key role of the DBHS protein family in functional organization of GABAergic synapses.
Published: 2015

27. PORCNmutations in focal dermal hypoplasia: coping with lethality

Author: Kaatje Heinelt, Juliane Strien, Annalisa Patrizi, María del Carmen Boente, Karl-Heinz Grzeschik, Yasemin Alanay, Nicolas Chassaing, Ben C.J. Hamel, Ingo Lohrisch, Marie Eleanore O. Nicolas, G. Eda Utine, Ian O. Ellis, Carlo Marcelis, Jeffrey A. Ascherman, Katrina Prescott, Bart Loeys, Arne König, Mauro Paradisi, Christina Raissa I. Francisco, Wolfgang Kastrup, Frank Oeffner, Patricia Silvia Della Giovanna, Paul J. Benke, Dorothea Bornholdt, Maria Piccione, Yasmin Mehraein, Cristina Has, Andreas R. Janecke, Ineke van der Burgt, Bettina Prager, Dana Pagliarini, Hildegunde Piza-Katzer, Marc S. Zeller, and Rudolf Happle
Subjects: Genetics, Mutation, Genetic counseling, Nonsense mutation, Biology, medicine.disease_cause, medicine.disease, Focal dermal hypoplasia, PORCN, medicine, Missense mutation, Skewed X-inactivation, Genetics (clinical), Loss function
Abstract: The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi-Hunermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.
Published: 2009

28. Genetic aspects of birth defects: new understandings of old problems

Author: Katrina Prescott and Andrew O.M. Wilkie
Subjects: Chromosome Aberrations, Pathology, medicine.medical_specialty, Mosaicism, business.industry, Cancer predisposition, Infant, Newborn, Obstetrics and Gynecology, Diagnostic accuracy, Syndrome, Review, General Medicine, Infant newborn, Congenital Abnormalities, Developmental psychology, Genomic Imprinting, Neoplasms, Mutation, Pediatrics, Perinatology and Child Health, Humans, Medicine, Abnormalities, Multiple, Genetic Predisposition to Disease, business, Genome architecture
Abstract: Over the past two decades, combined advances in genetics, developmental biology and biochemistry have transformed the study of human birth defects. This review describes the importance of genome architecture, parent of origin effects (imprinting), molecular pathophysiology, developmental pathways, mosaicism and cancer predisposition syndromes in the understanding of birth defects. This knowledge can be applied to improve diagnostic accuracy, prognostic information, counselling and sometimes even treatment of these conditions.
Published: 2007

29. Investigation into the Importance of genes encoding ciliary proteins in congenital heart disease using whole exome sequencing

Author: K Ashcroft, Katrina Prescott, Verity L. Hartill, S Barwick, Colin A. Johnson, Christopher P. Bennett, David A. Parry, K English, Clare V. Logan, A Dobbie, Katarzyna Szymanska, Eamonn Sheridan, and J Goodship
Subjects: Genetics, Heart disease, Cilium, Cell Biology, Biology, medicine.disease, Ciliopathies, Human genetics, Pathogenesis, Poster Presentation, medicine, Gene, Exome sequencing, Primary ciliary dyskinesia
Abstract: Congenital Heart Disease (CHD) is the most common congenital defect. Many families with left-right laterality defects and complex CHD have an unknown genetic aetiology. Many ciliopathies, including Primary Ciliary Dyskinesia (PCD), are associated with intracardiac defects. The role of primary cilia in cardiac morphogenesis remains unknown, although cardiac cilia have roles that are distinct from the definition of laterality at the embryonic node. We hypothesise that defects in genes important in the assembly and function of cilia are responsible for some inherited forms of CHD. This research project aims to recruit families with a recurrence of CHD and to perform Whole Exome Sequencing (WES) to identify putative pathogenic variants and to delineate novel genetic causes of CHD. Twelve families have now been recruited and WES has been carried out in seven of these families using paired-end sequencing. Data analysis follows a standardised pipeline to call and then filter variants in order to assess their pathogenic potential. Variants are prioritized on the basis of known or suspected function of the encoded protein, and publicly-available RNA expression data. Variant filtering has allowed the identification of a limited number of candidate variants in recruited families. Of particular interest, a likely causative homozygous variant within a PCD gene has been identified in two siblings affected with heterotaxy, thus confirming a link between ciliopathies and CHD. The function and interactions of identified genes will be assessed, using cellular techniques and animal models, to provide insights into the pathogenesis of CHD.
Published: 2015

30. Focal segmental glomerulosclerosis in a female patient with Donnai–Barrow syndrome

Author: Mauro Longoni, Shelagh Joss, Katrina Prescott, Ihab Sakr Shaheen, Meaghan K. Russell, and Eric Finlay
Subjects: Pathology, medicine.medical_specialty, Hernia, Craniofacial abnormality, Hearing loss, Pathology and Forensic Medicine, Craniofacial Abnormalities, Focal segmental glomerulosclerosis, Female patient, medicine, Humans, Eye Abnormalities, Child, Hearing Loss, Genetics (clinical), Proteinuria, Glomerulosclerosis, Focal Segmental, business.industry, Syndrome, General Medicine, Donnai–Barrow syndrome, medicine.disease, Eye abnormality, Low Density Lipoprotein Receptor-Related Protein-2, Phenotype, Karyotyping, Pediatrics, Perinatology and Child Health, Female, Agenesis of Corpus Callosum, Anatomy, medicine.symptom, business
Published: 2010

31. Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa

Author: Hussain Jafri, Samuel G. Jacobson, Katrina Prescott, Manir Ali, Sorcha Finnegan, Paul Hocking, Mike Shires, Douglas H. Lester, James A. Poulter, David A. Mackey, William J. Curry, Jonathan B Ruddle, Martin McKibbin, Chris F. Inglehearn, Adam Booth, David W. Burt, Yasmin Raashid, and Carmel Toomes
Subjects: Retinal degeneration, Male, Candidate gene, Genotype, Blotting, Western, Leber Congenital Amaurosis, Locus (genetics), Biology, Retinitis pigmentosa, medicine, Missense mutation, Animals, Humans, Allele, Fluorescent Antibody Technique, Indirect, Alleles, Genetics, Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, Retinal Degeneration, Membrane Proteins, Sequence Analysis, DNA, medicine.disease, Null allele, Disease Models, Animal, Mutation, Retinal dysplasia, Female, sense organs, Carrier Proteins, Chickens, Retinitis Pigmentosa
Abstract: Purpose. To identify the defective gene in the sex-linked, recessively inherited retinal dysplasia and degeneration (rdd) chicken and to search for the human equivalent disease. Methods. Microsatellites from chicken chromosome Z were genotyped in 77 progeny of a carrier male (rdd/+) and an affected female (rdd/W), and candidate genes were sequenced. Retinal cross-sections from rdd and wild-type birds were analyzed by immunohistology. The human orthologous gene was screened in a panel of archival DNAs from 276 patients with retinitis pigmentosa (RP) or Leber congenital amaurosis (LCA) using melting curve analysis and DNA sequencing. Results. The rdd locus was refined to an approximately 3-Mb region on chromosome Z. Sequence analysis identified a C→T change in the mpdz gene that created a premature stop codon (c.1372C→T, p.R458X), which segregated with the disease phenotype. As expected, the full-length mpdz protein was absent in rdd retinas, but in wild-type birds, it localized to the retinal outer limiting membrane, where it may have a role in the interactions between photoreceptors and Muller glia cells. The screen to identify the human equivalent disease found 10 heterozygous variants in the orthologous gene in patients with RP (three missense and two null alleles) and LCA (four missense and one null allele). Conclusions. These findings reveal that MPDZ is essential for normal development of the retina and may have a role in maintaining photoreceptor integrity. The identification of human mutations suggests that MPDZ plays a role in human retinal disease, but the precise nature of this role remains to be determined.
Published: 2011

32. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome

Author: Ingrid Slade, Bruce Morland, Derek J. King, Charles A. Stiller, Kathryn Pritchard-Jones, Clare Turnbull, Lucy Side, Sucheta Vaidya, Anne Murray, Helen Davies, Katrina Prescott, Barry Pizer, Paul Ward, Heidi Traunecker, Rita Barfoot, Anand Saggar, Richard S. Houlston, Helen Jenkinson, Sandra Hanks, Michael R. Stratton, Gordan M. Vujanic, Andrew G. Nicholson, Julia C. Chisholm, Nazneen Rahman, P. Andrew Futreal, Martin Hewitt, Amos Burke, Fatemeh Abbaszadeh, Jenny Douglas, John R. Priest, Neil J. Sebire, and Chiara Bacchelli
Subjects: Ribonuclease III, endocrine system, Molecular Sequence Data, Pleuropulmonary blastoma, Haploinsufficiency, Biology, medicine.disease_cause, DEAD-box RNA Helicases, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Neoplasms, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genetics (clinical), Germ-Line Mutation, 030304 developmental biology, DICER1 Syndrome, Medulloblastoma, 0303 health sciences, Mutation, Cystic nephroma, Cancer, Sequence Analysis, DNA, Syndrome, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Cancer research
Abstract: BACKGROUND: Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB). AIM: To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer. METHODS AND RESULTS: The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional DICER1 mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli-Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli-Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. DICER1 mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli-Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from DICER1 mutation-positive patients showed universal retention of the wild-type allele. DICER1 truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations. CONCLUSION: Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli-Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which DICER1 mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition 'DICER1 syndrome'. ACCESSION NUMBERS: The cDNA Genbank accession number for the DICER1 sequence reported in this paper is NM_030621.2.
Published: 2011

33. The face of Ulnar Mammary syndrome?

Author: Katrina Prescott, Stefan Mundlos, Ruth Newbury-Ecob, John Tolmie, Richard Fisher, Shelagh Joss, and Usha Kini
Subjects: Delayed puberty, Proband, Adult, Male, Ulna, Biology, Short stature, Fingers, Breast Diseases, Young Adult, Ulnar–mammary syndrome, Genetics, medicine, Humans, Abnormalities, Multiple, Child, Genetics (clinical), Family Health, Polydactyly, Infant, General Medicine, Anatomy, Syndrome, Middle Aged, medicine.disease, Pedigree, Breast Hypoplasia, medicine.anatomical_structure, Child, Preschool, Face, Mutation, Female, medicine.symptom, Haploinsufficiency, T-Box Domain Proteins
Abstract: Ulnar Mammary syndrome (UMS) is an autosomal disorder caused by haploinsufficiency of the TBX3 gene. There is marked intrafamilial variation in expression of the syndrome. We present one three generation family in which the proband has absence of the right ulna and third, fourth and fifth rays in her right hand. Her mother and maternal grandmother have more subtle anomalies while all have a similar facial appearance with a broad nasal tip, a broad jaw, a prominent chin and a tongue frenulum. They have a single base pair insertion (c. 992dup) in TBX3. We compare faces from the handful of published UMS patients which include photographs, this family and four other cases with TBX3 mutations. All have similarities in appearance which we suggest could alert clinicians to the possibility of a TBX3 mutation if individuals present with more subtle features of UMS such as postaxial polydactyly, isolated 5th finger anomalies, delayed puberty in males, breast hypoplasia or short stature with or without growth hormone deficiency.
Published: 2010

34. Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in mice

Author: Georg Steffes, Karen P. Steel, Karen McCue, Angela N. Barrett, Vanessa Kyriakopoulou, Victoria Randall, Subreena Simrick, Erika A. Bosman, Francesca Vitelli, M. Albert Basson, Elizabeth Illingworth, Catherine Roberts, Charles Shaw-Smith, Sarah Beddow, Koenraad Devriendt, Katrina Prescott, and Peter J. Scambler
Subjects: TBX1, Aorta, Thoracic, Choanal atresia, Biology, Mice, 03 medical and health sciences, CHARGE syndrome, 0302 clinical medicine, 22q11 Deletion Syndrome, Ectoderm, medicine, Animals, Humans, Alleles, 030304 developmental biology, Mice, Knockout, Comparative Genomic Hybridization, 0303 health sciences, Coloboma, Gene Expression Regulation, Developmental, General Medicine, Anatomy, Aplasia, medicine.disease, DNA-Binding Proteins, Mice, Inbred C57BL, Ear morphogenesis, embryonic structures, T-Box Domain Proteins, Haploinsufficiency, 030217 neurology & neurosurgery, Research Article
Abstract: Aortic arch artery patterning defects account for approximately 20% of congenital cardiovascular malformations and are observed frequently in velocardiofacial syndrome (VCFS). In the current study, we screened for chromosome rearrangements in patients suspected of VCFS, but who lacked a 22q11 deletion or TBX1 mutation. One individual displayed hemizygous CHD7, which encodes a chromodomain protein. CHD7 haploinsufficiency is the major cause of coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, and ear anomalies/deafness (CHARGE) syndrome, but this patient lacked the major diagnostic features of coloboma and choanal atresia. Because a subset of CHARGE cases also display 22q11 deletions, we explored the embryological relationship between CHARGE and VCSF using mouse models. The hallmark of Tbx1 haploinsufficiency is hypo/aplasia of the fourth pharyngeal arch artery (PAA) at E10.5. Identical malformations were observed in Chd7 heterozygotes, with resulting aortic arch interruption at later stages. Other than Tbx1, Chd7 is the only gene reported to affect fourth PAA development by haploinsufficiency. Moreover, Tbx1+/–;Chd7+/– double heterozygotes demonstrated a synergistic interaction during fourth PAA, thymus, and ear morphogenesis. We could not rescue PAA morphogenesis by restoring neural crest Chd7 expression. Rather, biallelic expression of Chd7 and Tbx1 in the pharyngeal ectoderm was required for normal PAA development.
Published: 2009

35. 06-P038 Great vessel development requires dizygous expression of Chd7 and Tbx1 in pharyngeal ectoderm

Author: M. Albert Basson, Karen McCue, Victoria Randall, Charles Shaw-Smith, Peter J. Scambler, Francesca Vitelli, Catherine Roberts, Vanessa Kyriakopoulou, Elizabeth Illingworth, Koenraad Devriendt, Katrina Prescott, and Subreena Simrick
Subjects: TBX1, Embryology, medicine.anatomical_structure, Expression (architecture), Great vessels, medicine, Ectoderm, Biology, Cell biology, Developmental Biology
Published: 2009
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36. Reduced TFAP2A function causes variable optic fissure closure and retinal defects and sensitizes eye development to mutations in other morphogenetic regulators

Author: Gaia Gestri, David O. Robinson, Susan M. Gribble, Dianne Gerrelli, David J. Bunyan, Katrina Prescott, Nicola K. Ragge, Stephen W. Wilson, Robert Osborne, Alexander W. Wyatt, Tomas W Fitzgerald, Nigel P. Carter, J. Richard O. Collin, Alan Fryer, and Helen Stewart
Subjects: Adult, Male, Biology, medicine.disease_cause, Eye, Retina, Article, Genetics, medicine, Morphogenesis, Animals, Humans, Expressivity (genetics), Eye Abnormalities, Genetics (clinical), Zebrafish, Coloboma, Mutation, Anophthalmia, Infant, Middle Aged, Zebrafish Proteins, medicine.disease, Penetrance, Phenotype, Transcription Factor AP-2, Child, Preschool, Eye development, Female, Branchio-oculo-facial syndrome, Branchio-Oto-Renal Syndrome, Gene Deletion
Abstract: Mutations in the transcription factor encoding TFAP2A gene underlie branchio-oculo-facial syndrome (BOFS), a rare dominant disorder characterized by distinctive craniofacial, ocular, ectodermal and renal anomalies. To elucidate the range of ocular phenotypes caused by mutations in TFAP2A, we took three approaches. First, we screened a cohort of 37 highly selected individuals with severe ocular anomalies plus variable defects associated with BOFS for mutations or deletions in TFAP2A. We identified one individual with a de novo TFAP2A four amino acid deletion, a second individual with two non-synonymous variations in an alternative splice isoform TFAP2A2, and a sibling-pair with a paternally inherited whole gene deletion with variable phenotypic expression. Second, we determined that TFAP2A is expressed in the lens, neural retina, nasal process, and epithelial lining of the oral cavity and palatal shelves of human and mouse embryos--sites consistent with the phenotype observed in patients with BOFS. Third, we used zebrafish to examine how partial abrogation of the fish ortholog of TFAP2A affects the penetrance and expressivity of ocular phenotypes due to mutations in genes encoding bmp4 or tcf7l1a. In both cases, we observed synthetic, enhanced ocular phenotypes including coloboma and anophthalmia when tfap2a is knocked down in embryos with bmp4 or tcf7l1a mutations. These results reveal that mutations in TFAP2A are associated with a wide range of eye phenotypes and that hypomorphic tfap2a mutations can increase the risk of developmental defects arising from mutations at other loci.
Published: 2009

37. Molecular genetics of velo-cardio-facial syndrome

Author: Peter J. Scambler and Katrina Prescott
Subjects: Genetics, Candidate gene, medicine.medical_specialty, 22q11 Deletion Syndrome, Point mutation, DiGeorge syndrome, medicine, Medical genetics, Germline mosaicism, Low copy repeats, Biology, medicine.disease, Haploinsufficiency
Abstract: The occurrence of familial 22q11 deletion syndrome (22q11DS) raises the possibility of prenatal diagnosis for those families at risk, and parents of any new case should be offered deletion screening. Deletion of 22q11 is the most frequent interstitial chromosome deletion observed in man, begging the question as to whether there is any structural predisposition to chromosome rearrangements of this region. The single gene hypothesis predicted that a subset of those velo-cardio-facial syndrome/DiGeorge Syndrome (VCFS/DGS) patients with no apparent deletion of 22q11 would have a small deletion or point mutation inactivating the major gene haploinsufficient in the condition. The frustration at failure to find any loss of function mutations of DGCR genes in patients with no deletion prompted investigators to pursue animal models. Given the cognitive deficits and increased incidence of behavioral difficulty in 22q11DS attempts have been made to identify behavioral correlates in the mouse deletion model.
Published: 2005

38. Discriminating power of localized three-dimensional facial morphology

Author: Peter Hammond, Annette Karmiloff-Smith, Linda E. Campbell, Raoul C.M. Hennekam, Michael A. Patton, I. Karen Temple, Judith Allanson, Jill Clayton-Smith, Dian Donnai, Bernard F. Buxton, May Tassabehji, A F Stevens, Peter J. Scambler, Tim J. Hutton, Kieran C. Murphy, Barbara R. Pober, Kay Metcalfe, A. M. Smith, Katrina Prescott, Adam Shaw, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Paediatric Genetics
Subjects: Adult, Genetic Markers, Male, Models, Anatomic, Chromosomes, Human, Pair 22, Biology, White People, Pattern Recognition, Automated, Correlation, 03 medical and health sciences, Imaging, Three-Dimensional, Bardet–Biedl syndrome, medicine, Genetics, Humans, Genetics(clinical), 10. No inequality, Alleles, In Situ Hybridization, Fluorescence, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Polymorphism, Genetic, business.industry, Noonan Syndrome, 030305 genetics & heredity, Pattern recognition, Articles, medicine.disease, Smith–Magenis syndrome, Visualization, Face, Face (geometry), Pattern recognition (psychology), Linear Models, Noonan syndrome, Gestalt psychology, Female, Artificial intelligence, business, Chromosomes, Human, Pair 7, Gene Deletion, Microsatellite Repeats
Abstract: Many genetic syndromes involve a facial gestalt that suggests a preliminary diagnosis to an experienced clinical geneticist even before a clinical examination and genotyping are undertaken. Previously, using visualization and pattern recognition, we showed that dense surface models (DSMs) of full face shape characterize facial dysmorphology in Noonan and in 22q11 deletion syndromes. In this much larger study of 696 individuals, we extend the use of DSMs of the full face to establish accurate discrimination between controls and individuals with Williams, Smith-Magenis, 22q11 deletion, or Noonan syndromes and between individuals with different syndromes in these groups. However, the full power of the DSM approach is demonstrated by the comparable discriminating abilities of localized facial features, such as periorbital, perinasal, and perioral patches, and the correlation of DSM-based predictions and molecular findings. This study demonstrates the potential of face shape models to assist clinical training through visualization, to support clinical diagnosis of affected individuals through pattern recognition, and to enable the objective comparison of individuals sharing other phenotypic or genotypic properties.
Published: 2005

39. Microarray analysis of the Df1 mouse model of the 22q11 deletion syndrome

Author: Katrina Prescott, Peter J. Scambler, Mike Hubank, Sarah Ivins, Antonio Baldini, Elizabeth A. Lindsay, Prescott, K, Ivins, S, Hubank, M, Lindsay, Ea, Baldini, Antonio, and Scambler, P.
Subjects: TBX1, Male, Chromosomes, Human, Pair 22, Gene Dosage, Biology, Gene dosage, Polymerase Chain Reaction, Mice, 22q11 Deletion Syndrome, DiGeorge syndrome, Genetics, medicine, DiGeorge Syndrome, Animals, Cluster Analysis, Humans, Genetics (clinical), Dosage compensation, Microarray analysis techniques, medicine.disease, Microarray Analysis, Phenotype, Mice, Mutant Strains, Mice, Inbred C57BL, Disease Models, Animal, Female, Chromosome Deletion, Haploinsufficiency, T-Box Domain Proteins
Abstract: The 22q11 deletion syndrome (22q11DS; DiGeorge/velo-cardio-facial syndrome) primarily affects the structures comprising the pharyngeal arches and pouches resulting in arch artery, cardiac, parathyroid, thymus, palatal and craniofacial defects. Tbx1 haploinsufficiency is thought to account for the main structural anomalies observed in the 22q11DS. The Df1 deleted mouse provides a model for 22q11DS, the deletion reflecting Tbx1 haploinsufficiency in the context of the deletion of 21 adjacent genes. We examined the expression of genes in Df1 embryos at embryonic day (E) 10.5, a stage when the arch-artery phenotype is fully penetrant. Our aims were threefold, with our primary aim to identify differentially regulated genes. Second, we asked whether any of the genes hemizygous in Df1 were dosage compensated to wild type levels, and third we investigated whether genes immediately adjacent to the deletion were dysregulated secondary to a position effect. Utilisation of oligonulceotide arrays allowed us to achieve our aims with 9 out of 12 Df1 deleted genes passing the stringent statistical filtering applied. Several genes involved in vasculogenesis and cardiogenesis were validated by real time quantitative PCR (RTQPCR), including Connexin 45, a gene required for normal vascular development, and Dnajb9 a gene implicated in microvascular differentiation. There was no evidence of any dosage compensation of deleted genes, suggesting this phenomenon is rare, and no dysregulation of genes mapping immediately adjacent to the deletion was detected. However Crkl, another gene implicated in the 22q11DS phenotype, was found to be downregulated by microarray and RTQPCR.
Published: 2004

40. A novel 5q11.2 deletion detected by microarray comparative genomic hybridisation in a child referred as a case of suspected 22q11 deletion syndrome

Author: Maurice Super, Paula Stubbs, Katrina Prescott, Nigel P. Carter, Bronwyn Kerr, Rodger Palmer, Peter J. Scambler, and Kathryn Woodfine
Subjects: Genetics, Male, Microarray, Chromosomes, Human, Pair 22, Developmental Disabilities, Chromosome, Infant, Nucleic Acid Hybridization, Karyotype, Biology, medicine.disease, Human genetics, 22q11 Deletion Syndrome, Gene mapping, DiGeorge syndrome, medicine, Microsatellite, Chromosomes, Human, Pair 5, Humans, Chromosome Deletion, Child, Genetics (clinical), Microsatellite Repeats, Oligonucleotide Array Sequence Analysis
Abstract: The 22q11 deletion syndrome (22q11DS) is a developmental syndrome comprising of heart, palate, thymus and parathyroid glands defects. Individuals with 22q11DS usually carry a 1.5- to 3-Mb heterozygous deletion on chromosome 22q11.2. However, there are many patients with features of 22q11DS without a known cause from conventional karyotype and FISH analysis. Six patients with features of 22q11DS, a normal chromosomal and FISH 22q11 analysis, were selected for investigation by microarray genomic comparative hybridisation (array CGH). Array-CGH is a powerful technology enabling detection of submicroscopic chromosome duplications and deletions by comparing a differentially labelled test sample to a control. The samples are co-hybridised to a microarray containing genomic clones and the resulting ratio of fluorescence intensities on each array element is proportional to the DNA copy number difference. No chromosomal changes were detected by hybridisation to a high resolution array representing chromosome 22q. However, one patient was found to have a 6-Mb deletion on 5q11.2 detected by a whole genome 1-Mb array. This deletion was confirmed with fluorescence in-situ hybridisation (FISH) and microsatellite marker analysis. It is the first deletion described in this region. The patient had tetralogy of Fallot, a bifid uvula and velopharyngeal insufficiency, short stature, learning and behavioural difficulties. This case shows the increased sensitivity of array CGH over detailed karyotype analysis for detection of chromosomal changes. It is anticipated that array CGH will improve the clinician's capacity to diagnose congenital syndromes with an unknown aetiology.
Published: 2004

41. PORCNmutations in focal dermal hypoplasia: coping with lethality

Author: Paul J. Benke, Yasmin Mehraein, Cristina Has, J Strien, Katrina Prescott, Dorothea Bornholdt, Carlo Marcelis, B Prager, I Lohrisch, Zeller, W Kastrup, Andreas R. Janecke, B.C.J. Hamel, Arne König, Nicolas Chassaing, Rudolf Happle, Maria Piccione, Bart Loeys, GE Utine, P Della Giovanna, K Heinelt, Hildegunde Piza-Katzer, I van der Burgt, D Pagliarini, Boente, Jeffrey A. Ascherman, Karl-Heinz Grzeschik, Ian O. Ellis, Mauro Paradisi, Cri Francisco, Meo Nicolas, Annalisa Patrizi, Yasemin Alanay, and Frank Oeffner
Subjects: Oncology, medicine.medical_specialty, Coping (psychology), Internal medicine, Genetics, medicine, Lethality, Biology, medicine.disease, Genetics (clinical), Focal dermal hypoplasia, PORCN
Published: 2009

42. Identification of the First ATRIP–Deficient Patient and Novel Mutations in ATR Define a Clinical Spectrum for ATR–ATRIP Seckel Syndrome

Author: Mohnish Suri, Mark O'Driscoll, Norisato Mitsutake, Emma Hobson, Pradeep C. Vasudevan, Grant S. Stewart, Gillian Carpenter, Penny A. Jeggo, A. Malcolm R. Taylor, Sarah R. Walker, Tomoo Ogi, Yuka Nakazawa, Katrina Prescott, Margaret Barrow, Michiko Matsuse, Philip J. Byrd, Tom Stiff, and Siripan Limsirichaikul
Subjects: Male, Cancer Research, Microcephaly, Heredity, Gene Identification and Analysis, Dwarfism, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, medicine.disease_cause, Compound heterozygosity, Gene Splicing, Micrognathism, Genetics (clinical), Growth Disorders, Genetics, Mutation, Fetal Growth Retardation, Ear, Patella, DNA-Binding Proteins, Phenotypes, Codon, Nonsense, Female, Research Article, Signal Transduction, Heterozygote, lcsh:QH426-470, RNA Splicing, Biology, Protein Serine-Threonine Kinases, Osteochondrodysplasias, Molecular Genetics, Genetic Mutation, medicine, Humans, Allele, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Adaptor Proteins, Signal Transducing, Congenital Microtia, medicine.disease, lcsh:Genetics, Seckel syndrome, Gene Expression Regulation, Genetics of Disease, Primordial dwarfism
Abstract: A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR–Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR–ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR–ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP–deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR–deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR–ATRIP deficient sub-class of Seckel Syndrome. ATR–ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR–SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR–ATRIP Seckel Syndrome to be defined., Author Summary Seckel Syndrome (SS) is a rare human disorder characterised by small head circumference and delayed growth. Patients can show additional features including abnormal bone development, receding chins, sloping foreheads, and small ears. In 2003, we identified ataxia telangiectasia and Rad3 related (ATR) as a causal genetic defect in two related families displaying SS. However, additional patients with mutations in ATR have not hitherto been identified. Here, we describe two further patients with novel mutations in ATR. Additionally, we identify a patient with mutations in ATRIP, which encodes an interacting partner of ATR, representing a novel genetic defect causing SS. ATR functions to promote the ability of cells to recover from difficulties encountered during replication. We show that patient-derived cells have reduced ATR and ATRIP protein levels and defective ATR/ATRIP function. Our identification of further ATR–ATRIP defective patients and a consideration of their clinical features aids the characterisation and identification of this form of SS and provides insight into the role played by the ATR–ATRIP complex during development.
Published: 2012

43. Cystic fibrosis and Russell-Silver syndrome in a child with maternal isodisomy of chromosome 7.

Author: Samatha Sonnappa, Katrina Prescott, Beryl Adler, Robert Dinwiddie, and Colin Wallis
Published: 2005
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44. Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study

Author: Nicola S. Cooper, S Samant, H Purnell, Claire L. S. Turner, A Vandersteen, Alex Magee, Susan Tomkins, Louise C. Wilson, L Greenhalgh, IK Temple, Irina Colgiu, A Duncan, G Cross, Susan E. Holder, C Wragg, Deirdre E. Donnelly, Nadia Akawi, Linda Sneddon, Eamonn Sheridan, Wendy D Jones, I Ellis, David Bourn, Joanna Poulton, Ingrid Simonic, R Singzon, Lisa Bradley, Matthew E. Hurles, Meena Balasubramanian, Dominic J. McMullan, Trevor Cole, Gillian Roberts, J Thomson, Moira Blyth, G Hollingsworth, Neeti Ghali, Alex Henderson, Zara Skitt, E Roberts, G Woods, David Goudie, J Awada, Caroline Langman, U Anjum, Martin O. Pollard, Usha Kini, Stephen Clayton, J Burn, Daniel M Barrett, Vka Kumar, Angela E. Douglas, Natalie Canham, Ruth Armstrong, Denise Williams, C Shaw-Smith, Lorraine Gaunt, S Ingram, Edward Blair, K Brunstrom, O. W.J. Quarrell, Ben Hutton, Nora Shannon, S Wallwark, Laura E Mason, Sarah F. Smithson, Jeremy F. McRae, Amanda L. Collins, Shane McKee, Katrina Prescott, Lara Cresswell, Sofia Douzgou, L Islam, C Deshpande, J Waters, Anna Middleton, S-M Park, Tarjinder Singh, Liu He, M Tein, T Fendick, B Kaemba, Tara Montgomery, Michael Wright, Jenny Morton, J Roberts, Emma Hobson, Caroline Mackie Ogilvie, Katrina Tatton-Brown, Lucy Jenkins, A Coates, Abhijit Dixit, Deborah J. Shears, Kath Smith, D. Baty, D Lim, D Cilliers, Richard Gibbons, Ruth Newbury-Ecob, M Squires, Nicola K. Ragge, Anneke Seller, E Kivuva, Kay Metcalfe, Fiona Stewart, K Marks, Elisabeth Rosser, R Fisher, Andrew E. Fry, Joan Paterson, Diana Wellesley, Dian Donnai, Christopher P. Bennett, Jonathan Berg, Ganesh J. Swaminathan, Lucy Raymond, Sally Ann Lynch, Pradeep C. Vasudevan, Rosemarie Davidson, Melita Irving, John Dean, Margo Whiteford, Melissa Lees, S Payne, K-R Ong, Emma Gray, M Holder, Dragana Josifova, Claire Kirk, McConnell, Helen Cox, Sarju G. Mehta, Elena Prigmore, Emma Shearing, Anand Saggar, Angela Barnicoat, Alejandro Sifrim, Nicola Foulds, Katherine Martin, Joanna Kaplanis, Sahar Mansour, Kirsty Ambridge, Clowes, A Procter, Z Miedzybrodzka, Katherine Lachlan, S Schweiger, E Maher, Allyson Ross, Simon Brent, C Sequeira, Tabib Dabir, Netravathi Krishnappa, Andrew Smith, B Bernhard, Andrew Green, Sara Widaa, Daniel A. King, Astrid Weber, Harinder Gill, Frances Flinter, Ruth McGowan, Siddharth Banka, Susan E. McNerlan, Elizabeth M. Sweeney, L Nevitt, Michael Parker, Hood Mugalaasi, AP Bevan, L Harrison, Varghese, Lucy Hildyard, Murday, G Kirby, S Clasper, Sutton, Clare Taylor, Andrew Jackson, A Selby, E Wilkinson, Miranda Splitt, Stuart Aitken, Shelagh Joss, Fiona Connell, Julie Vogt, Jill Clayton-Smith, Alan Fryer, N Pratt, Parthiban Vijayarangakannan, Shehla Mohammed, Susan Price, Wayne Lam, Peter D. Turnpenny, C Tysoe, Raheleh Rahbari, Marc Tischkowitz, N Williams, Tessa Homfray, Maria Bitner-Glindzicz, Helen Murphy, Meriel M. McEntagart, Sian Ellard, M Ahmed, R O'Shea, Andrew R. Norman, Daniel Perrett, Harrison, Philip Greene, David Moore, R Hawkins, DT Pilz, FitzPatrick, P Batstone, Esther Kinning, Caroline F. Wright, Yanick J. Crow, Kate Chandler, C Donnelly, Leema Robert, Straub, Susan M. Gribble, Philip Jones, D de Vries, K Evans, Simon J. Davies, Diana Baralle, E Miles, Jeffrey C. Barrett, A Lampe, Joshua C. Randall, Bruce Castle, K McKay, D Rice, Becky Treacy, Richard H Scott, Rosemary Kelsell, Angela F. Brady, Julian R. Sampson, J Jarvis, Laura Yates, R Sandford, Hayley Archer, M Yau, Mohnish Suri, Caroline Pottinger, Dhavendra Kumar, R. Taylor, Alison Kraus, L Bourdon, Alan Donaldson, S Everest, S Kazembe, Sian Morgan, C Longman, Ingrid Scurr, Alison Male, Ajoy Sarkar, Helen Kingston, Emma McCann, Julie M. Phipps, Andrea H. Németh, A Pridham, D Bohanna, C Gardiner, Diana Johnson, Tomas W Fitzgerald, Eleni A. Chatzimichali, A Dobbie, Diana Rajan, Frances Elmslie, Mohsan Alvi, Pendaran Roberts, Bronwyn Kerr, M D'Alessandro, Elizabeth A. Jones, Simon Holden, U Maye, Helen V. Firth, J Rankin, H. Stewart, S Naik, Adrian Tivey, Chirag N. Patel, Tanya Bayzetinova, G Lowther, G Devlin, A Torokwa, DJ Bunyan, Judith A. Goodship, Sarah Hewitt, Emma Wakeling, Christoffer Nellåker, S Wilcox, Saba Sharif, MN Collinson, C Brewer, Jacqueline Eason, C McWilliam, Jane A. Hurst, Angus John Clarke, Mervyn Humphreys, and Stephen W. Hellens
Subjects: Genetics, 0303 health sciences, education.field_of_study, Genetic heterogeneity, Population, Biology, Phenotype, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, education, Indel, Gene, Exome, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 × 10−7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age.AbbreviationsPTVProtein-Truncating VariantDNMDe Novo MutationDDDevelopmental DisorderDDDDeciphering Developmental Disorders study

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