A founder <i>RDH5</i> splice site mutation leads to retinitis punctata albescens in two inbred Pakistani kindreds

<b>Background</b>: Retinitis punctate albescens (RPA) is a rare form of retinal dystrophy characterized by congenital stationary night blindness and a characteristic fundus appearance. Missense or nonsense mutations in <i>RDH5</i> in homozygous or heterozygous state have been implicated in <b>RPA</b>. <b>Material and methods</b>: Two consanguineous Pakistani kindreds with the highly variable manifestation of RPA were studied. Whole-exome sequencing was applied to the index subjects in both families. Sanger sequencing of the candidate <i>RDH5</i> variant was carried out. Pathogenicity of the detected variant was assessed through bioinformatics tools. <b>Results</b>: The ophthalmic examination through full-field electroretinogram of affected patients in both families was consistent with RPA. A novel splice donor variant at the first exon/intron boundary of <i>RDH5</i> (NM_002905.3: c.-33 + 2dup) segregated in recessive fashion with the clinical phenotype in both families. One of the heterozygous variant carriers was also observed to have a milder expression of retinal flecks. Haplotype analysis surrounding the splice variant and pattern of runs of homozygosity were suggestive of common ancestry in these families. <b>Conclusion</b>: This is the first report of any pathogenic splice variant at first exon/intron boundary implicated in RPA and suggests another mechanism through which <i>RDH5</i> variants could be associated with eye phenotype. This study also highlights the importance of a thorough phenotypic evaluation of heterozygous mutation carriers who may exhibit milder symptoms.