TY - JOUR
T1 - Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies
AU - Genomics England Research Consortium
AU - Iqbal, Maria
AU - Maroofian, Reza
AU - Çavdarlı, Büşranur
AU - Riccardi, Florence
AU - Field, Michael
AU - Banka, Siddharth
AU - Bubshait, Dalal K.
AU - Li, Yun
AU - Hertecant, Jozef
AU - Baig, Shahid Mahmood
AU - Dyment, David
AU - Efthymiou, Stephanie
AU - Abdullah, Uzma
AU - Makhdoom, Ehtisham Ul Haq
AU - Ali, Zafar
AU - Scherf de Almeida, Tobias
AU - Molinari, Florence
AU - Mignon-Ravix, Cécile
AU - Chabrol, Brigitte
AU - Antony, Jayne
AU - Ades, Lesley
AU - Pagnamenta, Alistair T.
AU - Jackson, Adam
AU - Douzgou, Sofia
AU - Ambrose, J. C.
AU - Arumugam, P.
AU - Bleda, M.
AU - Boardman-Pretty, F.
AU - Boustred, C. R.
AU - Brittain, H.
AU - Caulfield, M. J.
AU - Chan, G. C.
AU - Fowler, T.
AU - Giess, A.
AU - Hamblin, A.
AU - Henderson, S.
AU - Hubbard, T. J.P.
AU - Jackson, R.
AU - Jones, L. J.
AU - Kasperaviciute, D.
AU - Kayikci, M.
AU - Kousathanas, A.
AU - Lahnstein, L.
AU - Leigh, S. E.A.
AU - Leong, I. U.
AU - Lopez, F. J.
AU - Maleady-Crowe, F.
AU - Moutsianas, L.
AU - Mueller, M.
AU - Murugaesu, N.
N1 - Funding Information:
We are grateful to all family members that participated in this study. This work was supported by the Higher Education Commission (HEC) of Pakistan to M.I. and E.U.H. M.; the Center for Molecular Medicine Cologne (CMMC) (Projects 38-RP and C12; 2635/8029/01 and 2635/8326/01) to P.N. and M.S.H.; the Koeln Fortune Program (Faculty of Medicine, University of Cologne; 381/2020) to M.S.H.; Intramural Funding from the Fortune Program (Faculty of Medicine, University of Tübingen; 2545-1-0) and the Ministry of Science, Research and Art Baden-Württemberg to B.V.; the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) under Germany’s Excellence Strategy–EXC 2067/1-390729940 to B.W.; the Medical Research Council (MRC) (MR/S01165X/1, MR/S005021/1, G0601943), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, the Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA) to H.H.; sequencing of family 3 was performed under the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute (OGI-147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Quebec, and Children’s Hospital of Eastern Ontario Foundation. Three of the authors of this publication are members of the European Reference Network for Intellectual Disability, Telehealth and Congenital Anomalies (ERN-ITHACA; Project ID No 739543) (F.Riccardi; S.Banka; S.Douzgou). Family 5 was collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) (WT093205 MA and WT104033AIA) funding and research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Genomic data for family 8 was generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. A.J. is supported by Solve-RD. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/11
Y1 - 2021/11
N2 - Purpose: We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Methods: We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable. Results: In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4. Conclusion: We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.
AB - Purpose: We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Methods: We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable. Results: In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4. Conclusion: We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.
UR - http://www.scopus.com/inward/record.url?scp=85111775332&partnerID=8YFLogxK
U2 - 10.1038/s41436-021-01260-4
DO - 10.1038/s41436-021-01260-4
M3 - Article
C2 - 34244665
AN - SCOPUS:85111775332
SN - 1098-3600
VL - 23
SP - 2138
EP - 2149
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 11
ER -