In silico functional analysis of genetic variants in chromosome 19 to identify disease-causing gene in a large Greek family with autosomal dominant macular dystrophy

Abstract

Purpose : Autosomal dominant macular dystrophy is a heterogeneous group of disorders characterized by central visual loss typically in the first two decades of life and macular atrophy. A number of genes causing autosomal dominant macular dystrophies have been identified including ELOVL4, PROML1, VMD2, Peripherin/RDS, EFEMP1 and TIMP3. A genomewide linkage scan previously performed in a large Greek family identified a novel locus on 19q13 associated with the disease. However, prior Sanger sequencing of several candidate genes within the linkage region failed to identify disease-causing mutation in the family. This study aims to identify potential causal genes in chromosome (chr) 19 that may eventually contribute to new knowledge on the pathogenesis of this condition.

Methods : Annotation of whole genome sequencing data of 6 affected and 3 unaffected family members of a large Greek family with autosomal dominant macular dystrophy was carried out using wANNOVAR. Only the functional variants were selected for further analysis. In silico analyses of their functional effects was conducted using SIFT, Polyphen2, Mutation Taster, Mutation Assessor and FATHMM. Deleterious variants that scored 3 out of 5 prediction algorithms or designated as pathogenic in ClinVar were then analyzed individually for association with the disease.

Results : Analysis of previously studied genes (GNG8, SIX5, ZNF224, XTP7, GPR4, FKRP, ZNF45, ZNF342, PLAUR, CCDC8, RTN2) at the locus 19q13 was executed first, to be certain that no mutations were missed. Our initial findings concurred with the previous report of no disease-causing mutation in these variants. Further analysis of other genetic variants found in the linkage region of chr 19 is currently being undertaken to seek potential genes responsible for the disease.

Conclusions : Numerous studies have identified genes potentially causing a disease using sequence-based and structure-based prediction tools. We anticipate that the identification of genes responsible for autosomal dominant macular dystrophy using in silico prediction approach will reveal the molecular mechanisms of the disease and pave the way to better treatment options in the future.

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