Ranad Shaheen1, Mohammed Adeeb Sebai1, Nisha Patel1, Nour Ewida1, Wesam Kurdi2, Ikhlass Altweijri3, Sameera Sogaty4, Elham Almardawi2, Mohammed Zain Seidahmed5, Abdulrahman Alnemri6, Sateesh Madirevula1, Niema Ibrahim1, Firdous Abdulwahab1, Mais Hashem1, Tarfa Al-Sheddi1, Rana Alomar1, Eman Alobeid1, Bahauddin Sallout7, Badi AlBaqawi7, Wajeih AlAali7,8, Nouf Ajaji7, Harry Lesmana9, Robert J Hopkin9, Lucie Dupuis10, Roberto Mendoza-Londono10, Hadeel Al Rukban10, Grace Yoon10,11, Eissa Faqeih12, Fowzan S Alkuraya1,13,14. 1. Departments of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 2. Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 3. Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 4. Department of Medical Genetics, King Fahad General Hospital, Jeddah, Saudi Arabia. 5. Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia. 6. Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 7. Maternal Fetal Medicine Department, Women's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia. 8. Bnoon Medical Center, Riyadh, Saudi Arabia. 9. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. 10. Division of Clinical and Metabolic Genetics and, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 11. Neurology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 12. Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia. 13. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 14. Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
Abstract
OBJECTIVE: Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, 2 X-linked (L1CAM and AP1S2) and 2 autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease. METHODS: Exome sequencing combined, where applicable, with positional mapping. RESULTS: We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X-linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles. INTERPRETATION: Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. Ann Neurol 2017;81:890-897.
OBJECTIVE:Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, 2 X-linked (L1CAM and AP1S2) and 2 autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease. METHODS: Exome sequencing combined, where applicable, with positional mapping. RESULTS: We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X-linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles. INTERPRETATION: Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. Ann Neurol 2017;81:890-897.
Authors: Sheng Chih Jin; Weilai Dong; Adam J Kundishora; Shreyas Panchagnula; Andres Moreno-De-Luca; Charuta G Furey; August A Allocco; Rebecca L Walker; Carol Nelson-Williams; Hannah Smith; Ashley Dunbar; Sierra Conine; Qiongshi Lu; Xue Zeng; Michael C Sierant; James R Knight; William Sullivan; Phan Q Duy; Tyrone DeSpenza; Benjamin C Reeves; Jason K Karimy; Arnaud Marlier; Christopher Castaldi; Irina R Tikhonova; Boyang Li; Helena Perez Peña; James R Broach; Edith M Kabachelor; Peter Ssenyonga; Christine Hehnly; Li Ge; Boris Keren; Andrew T Timberlake; June Goto; Francesco T Mangano; James M Johnston; William E Butler; Benjamin C Warf; Edward R Smith; Steven J Schiff; David D Limbrick; Gregory Heuer; Eric M Jackson; Bermans J Iskandar; Shrikant Mane; Shozeb Haider; Bulent Guclu; Yasar Bayri; Yener Sahin; Charles C Duncan; Michael L J Apuzzo; Michael L DiLuna; Ellen J Hoffman; Nenad Sestan; Laura R Ment; Seth L Alper; Kaya Bilguvar; Daniel H Geschwind; Murat Günel; Richard P Lifton; Kristopher T Kahle Journal: Nat Med Date: 2020-10-19 Impact factor: 53.440
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Authors: Wei Wang; Tana S Pottorf; Henry H Wang; Ruochen Dong; Matthew A Kavanaugh; Joseph T Cornelius; Katie L Dennis; Udayan Apte; Michele T Pritchard; Madhulika Sharma; Pamela V Tran Journal: J Pathol Date: 2021-05-21 Impact factor: 7.996
Authors: Mohamed S Abdel-Hamid; Sahar Sabry; Sherif F Abdel-Ghafar; Sara H El-Dessouky; Ghada M H Abdel-Salam Journal: Neurogenetics Date: 2021-08-02 Impact factor: 2.660