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

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.

Genome-wide SNP microarray and whole exome sequencing (WES) were used for variant identification in a large BD-affected consanguineous Pakistani family.

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.

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.