Comprehensive geno- and phenotyping in a complex pedigree including four different inherited retinal dystrophies

Abstract

Purpose : Inherited retinal dystrophies (IRDs) are characterized by a high clinical and genetic heterogeneity. A precise disease characterization is desirable for diagnosis and has broad impact on prognosis and patient counseling. With the development of innovative therapeutic approaches - in particular gene therapy – a precise phenotypic characterization as well as the detection of the disease-causing gene is also becoming increasingly important. Here, we demonstrate the effectiveness of the combination of in-depth retinal phenotyping and molecular genetic testing in complex pedigrees with different IRDs.

Methods : Four Caucasian patients (48, 45, 13, 11 years of age) from one family were characterized. Clinical assessment included standardized clinical examination, best corrected visual acuity testing and full-field electroretinography. Retinal imaging included spectral domain optical coherence tomography, autofluorescence imaging, and fundus photography. Genetic testing was performed by targeted next-generation sequencing. The identified variants were verified by intrafamilial co-segregation analysis, bioinformatic annotations and in silico analysis.

Results : A considerable intrafamilial phenotypic and genotypic heterogeneity was identified. The parents presented with rod-cone dystrophy (father) and ABCA4-related retinopathy (mother) while the two sons revealed phenotypic characteristics in the spectrum of incomplete congenital stationary night blindness and ocular albinism, respectively. Molecular testing revealed previously described variants in the RHO (c.644C>T), ABCA4 (c.740A>T, c.4594G>A), and MITF (c.710+1G>A) genes as well as a novel variant in the CACNA1F (c.1079C>T) gene, indicating different disease causes for every family member. The hemizygous CACNA1F missense variant resulted in an amino acid exchange at an evolutionarily highly conserved position (p.(Ser360Phe)) in the α_1F subunit of the Ca_v1.4 calcium channel.

Conclusions : The coexistence of four independent IRDs caused by distinct mutations and inheritance modes in one family is demonstrated. The findings highlight the complexity of IRDs and underscore the need for the combination of extensive molecular genetic testing and clinical characterization. In addition, a novel variant in the CACNA1F gene is reported associated with incomplete congenital stationary night blindness.

This is a 2020 ARVO Annual Meeting abstract.