EXOME SEQUENCING REVEALS CAUSATIVE VARIANTS IN FOUR GENES ASSOCIATED WITH NEURODEVELOPMENTAL DELAY
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Keywords
Neurodevelopmental disorders; Whole-exome sequencing; Autosomal recessive; ASPM; SRD5A3; SNX14; SLC6A8
Abstract
Neurodevelopmental disorders (NDDs) represent a diverse category of diseases that are associated with impaired brain development and functioning, resulting in intellectual disability (ID), developmental delay (DD), autism spectrum disorders ASDs), epilepsy, and diverse other neurological impairments. Consanguinity offers a useful background to detecting the presence of autosomal recessive (AR) mutations that cause these conditions using whole-exome sequencing (WES). This study was designed to find the genetic variants of NDDs in consanguineous families. Four consanguineous Pakistani families with various NDD phenotypes were sequenced using whole-exome sequencing. Causative mutations were identified using variant filtering and segregation analysis, and in silico prediction of pathogenicity. A total of four pathogenic variants were found: a homozygous nonsense mutation (c.3978G>A;p.Trp1326* ASPM in PKND3) leading to a premature stop codon at Trp1326; a nonsense mutation (c.57G>A, p.Trp19* SRD5A3 in PKND5, an upstream splice -site mutation (c.-48+1G>C, p.? SNX14 in PKND6), a hemizygous in-frame deletion c.1222-1224del p.Phe408del in the SLC6A8 gene was identified in the PKND8 family. This study expands the range of mutations associated with known NDD-related genes by proposing SLC6A8 as a possible novel pathogenic variant. The results support the diagnostic value of WES in consanguineous families and contribute to the molecular understanding of autosomal recessive neurodevelopmental defects.
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Shamsul Ghani
Department of Biological Sciences, International Islamic University, Islamabad, 44000.
Muhammad Imran Shabbir
Department of Biological Sciences, International Islamic University, Islamabad, 44000.
