Identification of Four Novel Variants and Determination of Genotype-Phenotype Correlations for ABCA4 Variants Associated With Inherited Retinal Degenerations.

Qing Zhu,Xun-Lun Sheng,Xue Rui,Bo Lei,Ya Li,Ya You

doi:10.3389/fcell.2021.634843

Abstract

PurposeThe purpose of the study is to describe the genetic and clinical features of 17 patients with ABCA4-related inherited retinal degenerations (IRDs) and define the phenotype–genotype correlations.MethodsIn this multicenter retrospective study, 17 patients from 16 families were enrolled, and ABCA4 gene variants were detected using targeted next-generation sequencing using a custom designed panel for IRDs. Sanger sequencing and co-segregation analysis of the suspected pathogenic variants were performed with the family members. The pathogenicities of variants were evaluated according to the American College of Medical Genetics and Genomics guidelines (ACMG). Protein structure modifications mediated by the variants were studied using bioinformatic analyses.ResultsThe probands were diagnosed with Stargardt disease 1 (7), cone-rod dystrophy type 3 (8), cone dystrophy (1), and retinitis pigmentosa 19 (1). Onset of symptoms occurred between 5 and 27 years of age (median age = 12.4 years). A total of 30 unique ABCA4 suspicious pathogenic variations were observed, including 18 missense mutations, seven frameshift mutations, two nonsense mutations, one canonical splice site mutation, one small in-frame deletion, and one insertion. Four novel ABCA4 variants were identified. Two novel frameshift variants, c.1290dupC (p.W431fs), and c.2967dupT (G990fs), were determined to be pathogenic. A novel missense variant c.G5761T (p.V1921L) was likely pathogenic, and another novel missense c.C170G (p.P57R) variant was of undetermined significance. All ABCA4 variants tested in this study inordinately changed the physico-chemical parameters and structure of protein based on in silico analysis.ConclusionABCA4-related IRD is genetically and clinically highly heterogeneous. Four novel ABCA4 variants were identified. This study will expand the spectrum of disease-causing variants in ABCA4, which will further facilitate genetic counseling.

Highlights

Inherited retinal degenerations (IRDs) are a group of blinding diseases that cause severe impairments of visual functions such as visual acuity and visual field
Different ABCA4 mutations lead to a broad range of IRD phenotypes (Rozet et al, 1998; van Driel et al, 1998; Xu et al, 2014; Garces et al, 2018)
We identified four novel variants of the ABCA4 gene (Figure 4)

Summary

Introduction

Inherited retinal degenerations (IRDs) are a group of blinding diseases that cause severe impairments of visual functions such as visual acuity and visual field. ABCA4 gene encodes a transmembrane protein that is exclusively expressed in photoreceptors and retina pigment epithelial cells (Lenis et al, 2018). The misfolding and loss of functional activity of the transporter, caused by gene mutations, lead to accumulation of toxic substances such as all-trans-retinal and 11-cis-retinal in the outer segment of photoreceptor cells. Following diurnal phagocytosis of the distal outer segment of photoreceptors, excessive deposition of secondary toxic products, such as bisretinoid, eventually leads to the death of retinal pigment epithelium (Young and Bok, 1969; Weng et al, 1999; Quazi and Molday, 2014; Lenis et al, 2018). Phenotype severity mainly depends on the degree of influence of variations on protein functions (Fujinami et al, 2015)

Objectives

Methods

Results

Conclusion