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

Maria Iqbal; Reza Maroofian; Büşranur Çavdarlı; Florence Riccardi; Michael Field; Siddharth Banka; Dalal K Bubshait; Yun Li; Jozef Hertecant; Shahid Mahmood Baig; David Dyment; Stephanie Efthymiou; Uzma Abdullah; Ehtisham Ul Haq Makhdoom; Zafar Ali; Tobias Scherf de Almeida; Florence Molinari; Cécile Mignon-Ravix; Brigitte Chabrol; Jayne Antony; Lesley Ades; Alistair T Pagnamenta; Adam Jackson; Sofia Douzgou; Christian Beetz; Vasiliki Karageorgou; Barbara Vona; Aboulfazl Rad; Jamshaid Mahmood Baig; Tipu Sultan; Javeria Raza Alvi; Shazia Maqbool; Fatima Rahman; Mehran Beiraghi Toosi; Farah Ashrafzadeh; Shima Imannezhad; Ehsan Ghayoor Karimiani; Yasra Sarwar; Sheraz Khan; Muhammad Jameel; Angelika A Noegel; Birgit Budde; Janine Altmüller; Susanne Motameny; Wolfgang Höhne; Henry Houlden; Peter Nürnberg; Bernd Wollnik; Laurent Villard; Fowzan Sami Alkuraya; Matthew Osmond; Muhammad Sajid Hussain; Gökhan Yigit; Genomics England Research Consortium

doi:10.1038/s41436-021-01260-4

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

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

Maria Iqbal, Reza Maroofian, Büşranur Çavdarlı, Florence Riccardi, Michael Field, Siddharth Banka, Dalal K Bubshait, Yun Li, Jozef Hertecant, Shahid Mahmood Baig, …

Genetics in medicine, Vol.23(11), pp.2138-2149

01/11/2021

DOI: https://doi.org/10.1038/s41436-021-01260-4

PMID: 34244665

Abstract

Cadherin Related Proteins

Cadherins - genetics

Humans

Intellectual Disability - genetics

Microcephaly - genetics

Neurodevelopmental Disorders - genetics

Pedigree

Phenotype

Seizures - genetics

We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. 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. 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 -binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4. 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.

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Title: Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies
Creators - without role: Maria Iqbal - University Hospital Cologne
Reza Maroofian - Department of Neuromuscular Disorders, UCL Institute of Neurology, London, UK
Büşranur Çavdarlı - Bilkent University
Florence Riccardi - Hôpital de la Timone
Michael Field - Hunter Genetics
Siddharth Banka - Manchester University NHS Foundation Trust
Dalal K Bubshait - Imam Abdulrahman Bin Faisal University
Yun Li - Universitätsmedizin Göttingen
Jozef Hertecant - Tawam Hospital
Shahid Mahmood Baig - Pakistan Institute of Engineering and Applied Sciences
David Dyment - University of Ottawa
Stephanie Efthymiou - Department of Neuromuscular Disorders, UCL Institute of Neurology, London, UK
Uzma Abdullah - Pir Mehr Ali Shah Arid Agriculture University
Ehtisham Ul Haq Makhdoom - University of Cologne
Zafar Ali - University of Swat
Tobias Scherf de Almeida - Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
Florence Molinari - Inserm
Cécile Mignon-Ravix - Inserm
Brigitte Chabrol - Marseille Public University Hospital System
Jayne Antony - Children's Hospital at Westmead
Lesley Ades - University of Sydney
Alistair T Pagnamenta - University of Oxford
Adam Jackson - Manchester University NHS Foundation Trust
Sofia Douzgou - Manchester University NHS Foundation Trust
Christian Beetz - Centogene
Vasiliki Karageorgou - Centogene
Barbara Vona - University of Tübingen
Aboulfazl Rad - University of Tübingen
Jamshaid Mahmood Baig - International Islamic University, Islamabad
Tipu Sultan - Department of Pediatric Neurology, Children’s Hospital and Institute of Child Health, Lahore, Pakistan
Javeria Raza Alvi - Department of Pediatric Neurology, Children’s Hospital and Institute of Child Health, Lahore, Pakistan
Shazia Maqbool - Development and Behavioural Pediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan
Fatima Rahman - Development and Behavioural Pediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan
Mehran Beiraghi Toosi - Mashhad University of Medical Sciences
Farah Ashrafzadeh - Mashhad University of Medical Sciences
Shima Imannezhad - Mashhad University of Medical Sciences
Ehsan Ghayoor Karimiani - St George's, University of London
Yasra Sarwar - National Institute for Biotechnology and Genetic Engineering
Sheraz Khan - National Institute for Biotechnology and Genetic Engineering
Muhammad Jameel - National Institute for Biotechnology and Genetic Engineering
Angelika A Noegel - University of Cologne
Birgit Budde - University Hospital Cologne
Janine Altmüller - University Hospital Cologne
Susanne Motameny - University of Cologne
Wolfgang Höhne - University Hospital Cologne
Henry Houlden - Department of Neuromuscular Disorders, UCL Institute of Neurology, London, UK
Peter Nürnberg - University of Cologne
Bernd Wollnik - University of Göttingen
Laurent Villard - Assistance Publique-Hôpitaux de Marseille, Hôpital La Timone Enfants, Département de Génétique Médicale, Marseille, France
Fowzan Sami Alkuraya - Alfaisal University
Matthew Osmond - University of Ottawa
Muhammad Sajid Hussain - University Hospital Cologne
Gökhan Yigit - Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany. goekhan.yigit@med.uni-goettingen.de
Genomics England Research Consortium
Publication Details: Genetics in medicine, Vol.23(11), pp.2138-2149
Grant note: G0601943 / Medical Research Council Wellcome Trust MR/S005021/1 / Medical Research Council MR/S01165X/1 / Medical Research Council
Identifiers: 9914549908331
Academic Unit: Imam Abdulrahman Bin Faisal University; King Khalid University; King Faisal University; King Saud University; Alfaisal University
Language: English
Resource Type: Journal article