18-Years of single-centre DNA testing in over 7000 index cases with inherited retinal dystrophies and optic neuropathies

Abstract

Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are characterized by distinct genetic causes and molecular mechanisms that can lead to varying degrees of visual impairment. The discovery of pathogenic variants in numerous genes associated with these conditions has deepened our understanding of the molecular pathways that influence both vision and disease manifestation and may ultimately lead to novel therapeutic approaches. Over the past 18 years, our DNA diagnostics unit has been performing genetic testing on patients suspected of having IRD or ION, using state-of-the-art mutation detection technologies that are continuously updated. This report presents a retrospective analysis of genetic data from 6237 IRD and 780 ION patients. Out of these, 3054 IRD patients (49.0%) and 211 ION patients (27.1%) received a definitive molecular diagnosis, with disease-causing variants identified in 139 different genes. The genes most implicated in disease pathologies are ABCA4, accounting for 23.8% of all IRD/ION index cases, followed by BEST1 (7.8%), USH2A (6.2%), PRPH2 (5.7%), RPGR (5.6%), RS1 (5.5%), OPA1 (4.3%), and RHO (3.1%). Our study has compiled the most extensive dataset in combined IRD/ION diagnostics to date and offers valuable insights into the frequencies of mutant alleles and the efficiency of mutation detection in various inherited retinal conditions.

Keywords: DNA testing; Diagnostic yield; Genetic variants; IRD; Inherited retinal disease; Next-generation sequencing.

Fig. 1

Diagnostic yield per indication group. Shown are the proportions of solved vs unsolved index cases in the different indication groups. A patient was classified as solved case if one (likely) pathogenic variant with dominant, X-linked or mitochondrial inheritance was detected or alternatively when two (likely) pathogenic alleles or one (likely) pathogenic allele and one hypomorphic allele were present in recessive conditions. ACHM, Achromatopsia, XLRS, X-linked retinoschisis, CHM, Choroideremia, RP, Retinitis pigmentosa, LCA, Leber congenital amaurosis, MD, Macular dystrophy, CD, Cone dystrophy, CRD, Cone rod dystrophy, USH, Usher syndrome, FEVR, familiar exudative vitreoretinopathy, CSNB, Congenital stationary night blindness, BBS, Bardet-Biedl syndrome, ION, inherited optic neuropathies, Misc. , Miscellaneous.

Fig. 2

Causative genes identified in solved patients by indication group. Shown are the causative genes identified in 3265 solved patients. In 5 patients more than one potential causative gene was identified, respectively in four patients with RP and one patient with CD/CRD. In these cases, both potential causative genes were considered. Only indication groups with more than one potential causative gene are shown, the indication groups X-linked retinoschisis and choroideremia are expected to be solved by each one gene, namely RS1 and CHM, and are therefore not displayed. Total numbers how often a gene was identified to be causative in the overall cohort and in each indication group are given in Supplementary Table 4. N = number of solved patients in each group.