Open access
A Homozygous Frameshift Variant in KHDC4 Is Associated With a Syndromic Inherited Retinal Disease in Humans.
Asodu Sandeep Sarma
Neta Barnoy
P. Gopalakrishnan
Keren Dichter
Rotem Mizrachi
Manar Salameh
E. Banin
D. Sharon
Adi Inbal
Samer Khateb
Medicine
Abstract
Inherited retinal diseases (IRDs) are genetically heterogeneous and often remain unsolved despite advanced sequencing. This study investigated two siblings from a consanguineous Arab-Christian family presenting with a syndromic IRD. Exome sequencing revealed a homozygous frameshift variant (c.1535_1538del:(p.Lys512Argfs*8) in the KHDC4 gene, which segregated with disease in an autosomal recessive pattern. In vitro overexpression of the mutant protein showed aberrant sub-cellular localization, and an in vivo zebrafish knockout model exhibited mild retinal dysfunction. These findings establish KHDC4 as a novel candidate gene for syndromic IRDs in humans, expanding the genetic landscape of the IRDs.