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 Bubshait, Yun Li, Jozef Hertecant, Shahid Mahmood Baig, David A. Dyment, Stéphanie Efthymiou, Uzma Abdullah, Ehtisham Ul Haq Makhdoom, Zafar Ali, Tobias Scherf de Almeida, Florence Molinari, Cécile Mignon‐Ravix, B. Chabrol, Jayne Antony, Lesley C. Adès, Alistair T. Pagnamenta, Adam Jackson, Sofia Douzgou, John C. Ambrose, Prabhu Arumugam, Marta Bleda, F. Boardman-Pretty, C. R. Boustred, Helen Brittain, Mark J. Caulfield, G. C. Chan, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim Hubbard, R. Jackson, J. Louise Jones, Dalia Kasperavičiūtė, Melis Kayikci, Athanasios Kousathanas, L. Lahnstein, S. E. A. Leigh, I. U. S. Leong, Fabrice Lopez, F. Maleady-Crowe, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Christopher A. Odhams, Christine Patch, D. Perez-Gil, Mariana Buongermino Pereira, J. Pullinger, T. Rahim, Augusto Rendon, T. Rogers, K. Savage, K. Sawant, Richard H. Scott, Afshan Siddiq, A. Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, M. Tanguy, Ellen Thomas, Simon R. Thompson, Arianna Tucci, Elizabeth T. Walsh, M. J. Welland, Eric O. Williams, Katarzyna Witkowska, S. M. Wood, Christian Beetz, Vasiliki Karageorgou, Barbara Vona, Abolfazl 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
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: -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.