Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies.
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Iqbal Maria, Maroofian Reza, Çavdarlı Büşranur, Riccardi Florence, Field Michael, Banka Siddharth, Bubshait Dalal K, Li Yun, Hertecant Jozef, Baig Shahid Mahmood, Dyment David, Efthymiou Stephanie, Abdullah Uzma, Makhdoom Ehtisham Ul Haq, Ali Zafar, Scherf de Almeida Tobias, Molinari Florence, Mignon-Ravix Cécile, Chabrol Brigitte, Antony Jayne, Ades Lesley, Pagnamenta Alistair T, Jackson Adam, Douzgou Sofia, Genomics England Research Consortium, Beetz Christian, Karageorgou Vasiliki, Vona Barbara, Rad Aboulfazl, Baig Jamshaid Mahmood, Sultan Tipu, Alvi Javeria Raza, Maqbool Shazia, Rahman Fatima, Toosi Mehran Beiraghi, Ashrafzadeh Farah, Imannezhad Shima, Karimiani Ehsan Ghayoor, Sarwar Yasra, Khan Sheraz, Jameel Muhammad, Noegel Angelika A, Budde Birgit, Altmüller Janine, Motameny Susanne, Höhne Wolfgang, Houlden Henry, Nürnberg Peter, Wollnik Bernd, Villard Laurent, Alkuraya Fowzan Sami, Osmond Matthew, Hussain Muhammad Sajid, Yigit Gökhan
Аннотация
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.