A family with a spectrum of Miyake’s disease possibly caused by a novel RP1L1 mutation (S1207F)

Abstract

Purpose : Mutations of RP1L1 gene was previously reported to be causative of hereditary occult macular dystrophy (OMD; also known as Miyake’s disease) and cone dystrophy. However, it was also reported that while small number of specific variants located at hot spots of RP1L1 gene were pathogenic, huge number of other variants were not pathogenic. Therefore, to determine the pathogenic variants of RP1L1 gene by the segregation analysis of human family is important. This study tested the hypothesis that a spectrum of Miyake’s disease in a Japanese family was caused by a novel and rare RP1L1 variant located at a hot spot.

Methods : A family including two affected subjects (daughter II-1; 9 y.o. and son II-2; 7 y.o.) and two unaffected members (I-1 and I-2; Parents of II-1 and II-2) without evidence of consanguinity underwent detailed ophthalmic evaluations including high-resolution imaging by adaptive optics (AO) fundus photography. Whole exome sequencing, direct sequencing, and in silico molecular analysis were performed for the detection of pathogenic variants.

Results : OCT images showed blurring of photoreceptor ellipsoid zone (EZ) and absence of interdigitation zone (IZ) in affected subjects (II-1 and II-2). Father (I-1) showed normal EZ and IZ. Mother (I-2) showed drusen-like RPE abnormality. An affected subject (II-1) had a mildly reduced amplitude of cone and flicker full-field electroretinograms. AO analysis revealed severely reduced cone density in an affected subject (II-1). Exome sequencing revealed a heterozygous RP1L1 mutation (c.3620C>T, p.S1207F) in two affected subjects (II-1 and II-2) and their father (I-1). The variant was very rare in Japanese and other populations with allele frequency of 0 in both HGMD (Japanese specific) and ExAC database. The variant was predicted to be damaging by both PolyPhen-2 (HDIV) and SIFT. The variant was located at downstream of the doublecortin domain known as a hot spot of pathogenic RP1L1 variants.

Conclusions : Although the RP1L1 variant S1207F was not perfectly co-segregated with phenotype in the family, in silico molecular genetic evaluations and phenotype in affected members simulating Miyake’s disease may indicate the pathogenicity of the variant. Since there are some previous reports of individuals who possess pathogenic RP1L1 variant (R45W) without any abnormality in the retina, incomplete penetrance may play a role for the inheritance of RP1L1.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.