ORIGINAL ARTICLE   Open access

Journal of Neurosurgical Sciences 2023 May 09

DOI: 10.23736/S0390-5616.23.06010-1

Copyright © 2023 THE AUTHORS

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language: English

Family-base rare variant association analysis in Saudi Arabian hydrocephalus subjects using whole exome sequencing

Ahmed AMMAR ¹, Dalal K. BUBSHAIT ², Abdulrazaq AL OJAN ¹, Shuroq A. ALSHARI ¹, Cyril CYRUS ³, Rawan ALANAZI ¹, Mohammed A. AL GHAMDI ², Brendan J. KEATING ⁴, Abdulrahman AL-ANAZI ¹, Noorah H. AL QAHTANI ⁵, Amein K. AL-ALI ³ ✉

¹ Department of Neurosurgery, King Fahd Hospital of the University, Alkhobar College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; ² Department of Pediatric, Generic Unit, King Fahd Hospital of the University, Alkhobar College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; ³ Department of Clinical Biochemistry, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; ⁴ Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; ⁵ Department of Obstetrics and Gynecology, King Fahd Hospital of the University, Alkhobar College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

BACKGROUND: Hydrocephalus is a highly heterogeneous multifactorial disease that arises from genetic and environmental factors. Familial genetic studies of hydrocephalus have elucidated four robustly associated hydrocephalus associated loci. This study aims to identify potential genetic causation in cases of hydrocephalus, with or without spina bifida and Dandy Walker Syndrome (DWS), using family-based rare variant association analysis of whole exome sequencing.
METHODS: We performed whole exome sequencing in 143 individuals across 48 families where at least one offspring was affected with hydrocephalus (N.=27), with hydrocephalus with spina bifida (N.=21) and with DWS (N.=3), using Illumina HiSeq 2500 instrument.
RESULTS: No pathogenic or putative pathogenic single-nucleotide variants were evident in the four known hydrocephalus loci in our subjects. However, after examining 73 known hydrocephalus genes previously identified from literature, we identified three potentially impactful variants from the cohort. Using a gene panel comprising variants in known neural tube defects loci, we identified a total of 1024 potentially deleterious variants, of which 797 were missense variants and 191 were frameshift variants, 36 were stop gain/loss variants. A small portion of our family pedigree analyses yielded putative genetic signals which may be responsible for hydrocephaly elated phenotypes, however the low diagnostic yield may be due to lack of capture of genetic variants in the exonic regions i.e. structural variants may only be evident from whole genome sequencing.
CONCLUSIONS: We identified three potentially impactful variants from our cohort in 73 known hydrocephalus genes previously identified in literature.

KEY WORDS: Hydrocephalus; Spinal dysraphism, Saudi Arabia