RELN biallelic variant as a candidate risk factor in a consanguineous Pakistani family with bipolar disorder and clinical heterogeneity

BACKGROUND: Bipolar disorder (BD) is highly heritable, polygenic, multifactorial, and has complex genetic heterogeneity. This study aimed to identify rare variants contributing to the aetiology of BD in a consanguineous family from Pakistan. METHODS: Genome-wide SNP microarray and whole exome sequencing (WES) were used for variant identification in a large BD-affected consanguineous Pakistani family. RESULTS: In family BF04, we identified three main regions of homozygosity-by-descent (HBD) over 1 Mb in length, by far the largest being a 43.6 Mb segment on chromosome 7, and, through WES analysis, found one promising novel homozygous variant in RELN (NM_005045; c.2090G>A; p.(Gly697Asp)), within this HBD region segregating in all the BD-affected members. CONCLUSION: Based on the clinical and genetic data, the present familial study revealed the plausible contribution of a novel variant of RELN in association with BD in the affected family. The present study's findings are valuable in understanding the genetic basis of the multifactorial phenotype BD and pave a better path for future functional studies.