Japan Occult Macular Dystrophy Project: Association of Genotype and Photoreceptor Architecture

Abstract

Purpose : To determine the clinical and molecular genetic characteristics of Japanese cohort with occult macular dystrophy (OMD) in a multi-central study.

Methods : Twenty-three patients from 21 families with the clinical diagnosis with OMD were recruited from ten institutes over Japan. Full medical history and clinical examinations including spectral-domain optic coherence tomography (SD-OCT) were undertaken. Patients were classified into one of the two groups based on the SD-OCT findings; classical group showing both blurring of photoreceptor ellipsoid zone and absence of interdigitation zone; and non-classical group lacking at least one of these two features. Primal exome sequencing with targeted analysis and in silico pathogenicity evaluation were performed for mutation detection. Statistical association between architectural phenotype classification and genotype classification (presence of pathogenic RP1L1 variants) was investigated.

Results : There were 12 families with the classical SD-OCT findings and 9 with non-classical findings. Nine pathogenic RP1L1 missense variants were identified in 12 families (57%) including three previously reported variants (p.R45W, p.S1199C, p.G1200A) and six novel variants (p.G221R, p.T1194M, p.T1196I, p.G1200D, p.G1200V, p.V1201G). A novel homozygous frameshift variant with premature termination (c.6063delC, p.D2021EfsX3) was found in a patient. Statistically significant association between architectural phenotype and genotype was revealed.

Conclusions : The spectrum of morphologic phenotype and pathogenic RP1L1 variants was documented in a nation-wide Japanese cohort with OMD. Association of the architectural phenotype and genotype indicates two types of pathophysiology underlying the clinical presentation of OMD; “hereditary” OMD including RP1L1-retinopathy with the classical phenotype and OMD-like syndrome (progressive occult maculopathy).

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.