Genetic spectrum of retinal dystrophies in Tunisia

Imen Habibi,Ahmed Chebil,Asma Hassairi,Ahmed Turki,Khaled El Matri,Yosra Falfoul,Daniel F Schorderet,Leila El Matri

doi:10.1038/s41598-020-67792-y

Abstract

We report the molecular basis of the largest Tunisian cohort with inherited retinal dystrophies (IRD) reported to date, identify disease-causing pathogenic variants and describe genotype–phenotype correlations. A subset of 26 families from a cohort of 73 families with clinical diagnosis of autosomal recessive IRD (AR-IRD) excluding Usher syndrome was analyzed by whole exome sequencing and autozygosity mapping. Causative pathogenic variants were identified in 50 families (68.4%), 42% of which were novel.The most prevalent pathogenic variants were observed in ABCA4 (14%) and RPE65, CRB1 and CERKL (8% each). 26 variants (8 novel and 18 known) in 19 genes were identified in 26 families (14 missense substitutions, 5 deletions, 4 nonsense pathogenic variants and 3 splice site variants), with further allelic heterogeneity arising from different pathogenic variants in the same gene. The most common phenotype in our cohort is retinitis pigmentosa (23%) and cone rod dystrophy (23%) followed by Leber congenital amaurosis (19.2%). We report the association of new disease phenotypes. This research was carried out in Tunisian patients with IRD in order to delineate the genetic population architecture.

Highlights

We report the molecular basis of the largest Tunisian cohort with inherited retinal dystrophies (IRD) reported to date, identify disease-causing pathogenic variants and describe genotype–phenotype correlations
Clinical diagnosis and pathogenic and likely pathogenic (P/LP) variants identified. 50 affected and 48 unaffected relatives belonging to 26 families with suspected recessive inheritance were included
A total of 26 causative P/LP variants in 19 genes were identified in 26 families, including 14 missense substitutions (53.9%), 5 deletions (19.2%), 4 nonsense P/LP variants (15.4%) and 3 splice site pathogenic variants (11.5%). 8 (30.8%) P/LP variants were novel, while the remaining 18 (69.2%) were reported previously. 96.2% of all P/LP variants were homozygous, only one family carried a heterozygous patho

Summary

Introduction

We report the molecular basis of the largest Tunisian cohort with inherited retinal dystrophies (IRD) reported to date, identify disease-causing pathogenic variants and describe genotype–phenotype correlations. Molecular genetics is essential for gene-based treatment, clarify diagnoses and to direct appropriate counseling. It is currently unknown how many genes are involved in IRDs, and even by using the latest generation sequencing (NGS) techniques, pathogenic and likely pathogenic variants are identified only in 50% to 75% of p atients[4]. To identify causative pathogenic variants in a large cohort of families diagnosed with nonsyndromic (24/26) or syndromic (2/26) AR-IRD, homozygosity mapping of known IRD loci was carried out. We believe it is essential to combine molecular and clinical data to diagnose IRD patients, especially with the emergence of therapeutic options

Methods

Results

Conclusion