Comprehensive genomic diagnosis of inherited retinal and optical nerve disorders reveals hidden syndromes and personalized therapeutic options

Abstract

Purpose: In the era of precision medicine, genomic characterization of blind patients is critical. Here, we evaluate the effects of comprehensive genetic analysis on the etiologic diagnosis of potentially hereditary vision loss and its impact on clinical management.

Methods: We studied 100 non-syndromic and syndromic Spanish patients with a clinical diagnosis of blindness caused by alterations on the retina, choroid, vitreous and/or optic nerve. We used a next-generation sequencing (NGS) panel (OFTALMOgenics™), developed and validated within this study, including up to 362 genes previously associated with these conditions.

Results: We identified the genetic cause of blindness in 45% of patients (45/100). A total of 28.9% of genetically diagnosed cases (13/45) were syndromic and, of those, in 30.8% (4/13) extraophthalmic features had been overlooked and/or not related to visual impairment before genetic testing, including cases with Mainzer-Saldino, Bardet-Biedl, mucolipidosis and MLCRD syndromes. In two additional cases-syndromic blindness had been proposed before, but not specifically diagnosed, and one patient with Heimler syndrome had been misdiagnosed as an Usher case before testing. 33.3% of the genetically diagnosed patients (15/45) had causative variants in genes targeted by clinical trials exploring the curative potential of gene therapy approaches.

Conclusion: Comprehensive genomic testing provided clinically relevant insights in a large proportion of blind patients, identifying potential therapeutic opportunities or previously undiagnosed syndromes in 42.2% of the genetically diagnosed cases (19/45).

Keywords: genomic diagnostics; hereditary; inherited retinal dystrophies; next-generation sequencing; panel sequencing; precision ophthalmology; vision loss.

Fig. 1

Genes considered responsible for hereditary visual impairment in our cohort and their associated phenotypes. Ellipses represent phenotypes (black characters) involving vision loss caused by alterations in the retina, vitreous, choroid and/or optic nerve and consistently associated to defects in the genes (blue characters) they contain. For genes with causative alterations affecting more than one patient in our cohort, the number of affected patients is shown in brackets below. Phenotype acronyms: CMTX5: Charcot‐Marie‐Tooth disease, X‐linked recessive, 5; MLCRD: microcephaly, lymphoedema, chorioretinal displasia syndrome.

Fig. 2

Modes of inheritance of the genetic conditions considered responsible for hereditary vision loss in our cohort. From outer to inner rings, affected genes, associated phenotypes and modes of inheritance are shown. The area of each sector is proportional to the number of cases represented within it. For genes with causative alterations affecting more than one patient, the number of affected patients is shown in brackets. AD: autosomal dominant; AR: autosomal recessive; X‐linked recessive, 5; LCA: Leber congenital amaurosis; MLCRD: microcephaly, lymphoedema, chorioretinal displasia syndrome; RP: retinitis pigmentosa; SM: Saldino–Mainzer syndrome; XD: X‐linked dominant; XR: X‐linked recessive.