Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies

2021 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies​
Iqbal, M.; Maroofian, R.; Çavdarlı, B.; Riccardi, F.; Field, M.; Banka, S. & Bubshait, D. K. et al.​ (2021) 
Genetics in Medicine,.​ DOI: https://doi.org/10.1038/s41436-021-01260-4 

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Authors Group
Genomics England Research Consortium
The authors list is uncomplete:
Authors
Iqbal, Maria; Maroofian, Reza; Çavdarlı, Büşranur; Riccardi, Florence; Field, Michael; Banka, Siddharth; Bubshait, Dalal K.; Li, Yun ; Hertecant, Jozef; Yigit, Gökhan 
Abstract
Abstract 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 Ca 2+ -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.
Issue Date
2021
Journal
Genetics in Medicine 
Project
EXC 2067: Multiscale Bioimaging 
Working Group
RG Wollnik 
ISSN
1098-3600
eISSN
1530-0366
Language
English

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