Long-read sequencing uncovers two independent pathogenic variants co-segregating in a consanguineous Pakistani family

A bioRxiv preprint describes the investigation of a consanguineous Pakistani family in which three affected siblings — including dizygotic twins — present with a combination of neurodevelopmental disorder and hearing loss. Using long-read whole-genome sequencing, bulk transcriptomics, and protein profiling, the authors identified two independently segregating variants: a novel variant in EPS8, a gene associated with autosomal recessive hearing loss, and a variant in HPDL, associated with autosomal recessive neurodevelopmental disorder.

Consanguinity increases the probability of homozygosity at multiple disease-associated loci simultaneously, and this family illustrates how two pathogenic variants can co-segregate in a way that produces a clinically complex and overlapping phenotype. The use of long-read whole-genome sequencing was central to phasing the variants and establishing their independent segregation — an area where short-read approaches can be less informative in highly homozygous backgrounds.

The case adds to a growing body of literature on multilocus pathogenic variation (sometimes described in the literature as dual or blended phenotypes), and the authors document their clinical evaluation and molecular workup in detail. Genetic counsellors and researchers working on rare disease diagnosis may find the methodology and family structure of practical interest, particularly the approach to distinguishing two co-occurring diagnoses from a single unifying genetic cause.

As a preprint, the findings have not yet been peer-reviewed.