Identification of Putative Pathogenic Variants in Genes Responsible for Intellectual disability

Abstract

Intellectual disability (ID) is a neurodevelopmental disorder that seriously affects cognition, adaptive and intellectual functions of the individuals. It is a heterogeneous disorder with prevalence rate of 1-3%. There are ~700 known ID genes but the underlying genes are unknown in large number of ID patients. For this study two families (A & B) were recruited from the remote areas of Sindh and Punjab, provinces of Pakistan. Both families exhibit non-syndromic ID. Whole genome single nucleotide polymorphism (SNP) genotyping was performed on both families which results in the identification of multiple homozygous regions in family B only. For family A, the genotype data was manually accessed to find the presence of genomic deletion, which identified a probable deletion on chromosome 2. This region was flanked by rs6706472 and rs12713108 and spans a genomic region of ~559kb (chr2:50,228,332-50,786,770), but PCR based assays did not confirm the presence of deletion in the affected members of this family. In case of family B, Homozygosity Mapper identified 4 homozygous regions. Exome sequencing of IV-4 individual of this family could not identify the ID causing variant. As a consequence, BAM file of this individual was evaluated to check the coverage of genes present in the HBD regions. For chromosome 1: 38401933-64109264 HBD region two genes POMGNT1 (exon-23) and SZT2 (exon-5-15) were partially uncovered while on chromosome 14:56307478-75947712 homozygous by descent (HBD) region KIAA0586 (exon-6 & 33) gene was uncovered. Sanger sequencing of these uncovered regions, could not identify any pathogenic variant. Only one polymorphism was found in exon-6 of KIAA0586 gene which was present in the intronic region, but has no impact on splicing. Though no pathogenic variant was identified in these families by using exome sequencing, the disease causing mutations can be identified by using genome sequencing