A variant in the RP1L1 gene in a family with occult macular dystrophy in a predicted intrinsically disordered region.

Significance The responsible genetic variants for occult macular dystrophy (OMD) were found at the predicted intrinsically disordered region (IDR) of theRP1L1gene. Purpose We examined the phenotypes and genotypes of family members from OMD. In addition, the genetic characteristics of theRP1L1gene in OMD were investigated. Methods Whole-exome sequencing was applied on two affected family members, and Sanger sequencing was performed on three members. The structural property of RP1L1 and pathogenic variants was analyzed using predictor of natural disordered regions (PONDR). Results Two affected members showed moderate visual impairment and relative central scotoma. The spectral domain optical coherence tomography (SD-OCT) images showed an absence of the interdigitation zone (IZ) and ellipsoid zone (EZ) in one case, and an obscure EZ line in the other case. ARP1L1variant (c.3593 C > T, p.Ser1198Phe) was identified in two affected members but not in the unaffected member. The PONDR analysis showed that the region from p.1189 to p.1248 could be predicted to be an IDR in the RP1L1 molecule. And the p. Ser1198Phe variant showed significant reduction of PONDR score. Conclusions Although, the major pathogenic variant of OMD is p.Arg45Trp, multiple reports indicate that the region between p.1194 and p.1201 is another hot spot of OMD. The PONDR analysis predicted that the RP1L1 molecule is one of the intrinsically disordered proteins. It is speculated that the region around p.1200 is essential for the normal function of the RP1L1 molecule, and the missense variants of that area cause the development of OMD.