Suzanne de Bruijn

79 Homozygous KIAA1549 variants are associated with retinitis pigmentosa INTRODUCTION Retinitis pigmentosa (RP) encompasses a clinical and genetic heterogeneous group of progressive inherited retinal diseases (IRD). RP is characterized by the primary degeneration of rod photoreceptor cells, followed by the loss of cone photoreceptor cells and retinal pigment epithelium (RPE). With a prevalence of approximately 1 in 4,000 persons, it is considered themost common formof IRD. 1 RP typically displays night blindness in early adulthood or adolescence, followed by the progressive loss of the peripheral visual field. The visual acuity can be relatively preserved until the advanced disease stages, but RP leads to severe visual impairment or blindness in a large number of patients. 2 Besides clinical heterogeneity, RP is also characterized by its broad range of genetic heterogeneity. A large number of genes has been implicated in the pathogenesis of RP, and pathogenic variants can be inherited in a recessive, dominant or X-linked manner (RetNet). 3 Recently, it has been estimated that in only 60-80% of RP cases the genetic explanation can be found using whole exome sequencing (WES), which is currently the most widely appliedmethod for disease gene identification. 4,5 A better understanding of the underlying disease mechanisms, the role of variants in the pathogenesis of disease in currently known RP genes, and genotype-phenotype correlations are required to provide further insights towards developing therapeutic approaches. Recently, KIAA1549 (GenBank: NM_001164665) has been proposed as a candidate RP gene; however, supporting evidence is limited. In an autosomal recessive RP (arRP) family a homozygous frameshift variant in KIAA1549 was described to be the only variant remaining after applying filtering criteria on WES data. 5 In this study, we report on homozygous variants in KIAA1549 in two families with arRP. In addition, protein localization studies have been performed to provide insight in the involvement of KIAA1549 in photoreceptor function, supporting its role as an RP gene. MATERIALS AND METHODS Subjects and clinical examinations Two families with individuals with genetically unexplained RP were included in this study; one consanguineous Iranian family with two affected siblings, and one case