North-Carolina Macular dystrophy like phenotype in a three generation pedigree wit autosomal dominant inheritance and exclusion of MCRD1

Abstract

Purpose : To report the clinical and molecular genetic findings in a three-generation family with 4 patients presenting with a North Carolina macular dystrophy (NCMD) phenotype and molecular genetic exclusion of MCRD1.

Methods : NCMD was diagnosis in 4/8 members of one German family based on clinical findings and detailed retinal imaging. The DNase1 hypersensitivity site (DHS) between PRDM13and CCNCwas analyzed by Sanger sequencing. Linkage analysis was done using the HumanCoreExome-12 v1.1 genotyping chip. Exome sequencing was performed using an Illumina Genome Analyzer IIx platform.

Results : Four of the eight family members (three generations, age range 2 – 64 years) presented with bilateral macular lesions typical for NCMD, relative preserved visual function since childhood without progression. In the affected patients, visual acuity ranged from 20/60 to 20/40 in the better eye. Male-to-male transmission indicated autosomal dominant inheritance.SNVs V1-V3 at the MCDR1 locus were excluded as causative in the family. Linkage analysis revealed five regions which reached the theoretical maximum LOD score of 1.8 including a 25 Mbp region harbouring the MCDR3 locus at 5p15-p13. Exome sequencing identified 17 candidate coding sequence variants of which a missense mutation in the DOCK7 gene segregated with the disease in this family.

Conclusions : The present family further emphasizes the heterogeneity of the autosomal dominant NCMD-like phenotype.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.