Exome sequencing identifies a homozygous splice site variant in as the underlying cause of autosomal recessive retinitis pigmentosa in a Pakistani family.

Background: Mutations in gene are the third leading cause of inherited retinal dystrophies (IRDs) in Pakistani families.

Patients: A two-generation consanguineous Pakistani family underwent both clinical and genetic analyses. Clinical examinations included visual acuity test, visual field, fundoscopy, and ocular coherence tomography (OCT). Whole exome sequencing (WES) was performed on the proband's DNA, and Sanger sequencing was performed to validate the WES findings. Splicing prediction tools such as Human Splicing Finder (HSF), NNSplice predictor, SpliceAI, MaxENTScan, and SpliceRover were used.

Results: A nuclear family of seven children, comprising five affected individuals (four males and one female) and two healthy siblings, was recruited from northwestern Pakistan. The proband was a 49-years old male who was presented with complaints of decreased visual acuity and night blindness since early childhood. Upon clinical evaluation, the proband appeared to have severely reduced visual acuity of hand movement (HM), bilateral visual field constriction, a waxy pale disc with vascular attenuation, pigmentary bone spicules at the periphery associated with chorioretinal degeneration, diffuse macular atrophy, and horizontal nystagmus in both of his eyes. Exome sequencing (ES) in the proband identified a homozygous splice site variant (NM_006269.2: c.615 + 1G > A) in gene. analysis, genotype-phenotype co-segregation study, and literature survey strongly supported the causality of the detected variant.

Conclusions: We report a previously known pathogenic splice site variant of as the underlying cause of early-onset autosomal recessive retinitis pigmentosa (arRP) in a Pakistani family. We contemplate that the detected allele might constitute a mutational hotspot in .