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).

Unraveling the genetic complexities of combined retinal dystrophy and hearing impairment

“…Heimler syndrome is a peroxisome disorder caused by biallelic variants in PEX1, PEX6, and PEX26. Proband 46 and several published cases with suspected USH presented biallelic mutations in PEX1 and PEX26 (Neuhaus et al 2017;Diñeiro et al 2020). The typical tooth (enamel) and nail abnormalities of Heimler syndrome were overlooked before molecular diagnosis.…”

The utility of genomic testing in the ophthalmology clinic: A review

“…Similarly, Wang et al found greater coverage in a custom designed hereditary eye disease panel than in WES for a cohort of Chinese IRD patients, resulting in a 41% diagnostic yield for their panel, compared to 33% for WES for a similar cohort 28 . Adjustments to the panel to include intronic variants, 27 or extra probes at difficult to sequence target regions 15,20 are commonly reported during panel development. This ability to customise targeted panels (compared to “off‐the‐shelf” exome capture products) means that panels can have greater flexibility and provide higher quality data than WES, particularly for genes that are challenging to sequence with massively parallel sequencing (e.g., FOXC1 for anterior segment dysgenesis 20 or RPGR ORF15 for retinitis pigmentosa 15 ).…”

“…Gene‐based therapies are fast becoming a reality, with the first drug of this class recently approved for the treatment of Leber's congenital amaurosis or retinitis pigmentosa caused by variants in the RPE65 gene. Numerous trials are underway for therapies targeting other inherited retinal dystrophies (IRDs) (reviewed in Talib and Boon 14 ) and identifying patients with the genotypes required for these trials, or for treatment following drug approvals, is a recognised benefit of genomic testing 13,15 …”

“…Adjustments to the panel to include intronic variants, 27 or extra probes at difficult to sequence target regions 15,20 are commonly reported during panel development. This ability to customise targeted panels (compared to “off‐the‐shelf” exome capture products) means that panels can have greater flexibility and provide higher quality data than WES, particularly for genes that are challenging to sequence with massively parallel sequencing (e.g., FOXC1 for anterior segment dysgenesis 20 or RPGR ORF15 for retinitis pigmentosa 15 ). They can also detect pathogenic intronic variants that are not present in the exome (e.g., intronic variants in ABCA4 , CEP290 and USH2A for various IRDs and associated syndromes 20,27 ).…”

“…The American College of Medical Genetics recommends WES (or WGS) when phenotype or family history are strongly suggestive of a genetic disorder but are non‐specific, where there is substantial genetic heterogeneity or where prior specific tests have failed 29 . In contrast, and more recently, several studies show that for IRDs, which are highly heterogeneous, a well‐curated panel provides greater sensitivity and diagnostic yield than WES, 27,28 and multiple studies demonstrate that panels are able to detect pathogenic variants for some patients in genes not primarily associated with the phenotype 15,27,28 . However, the diagnostic rate varies greatly with phenotypes and is in the range 25%–64% for most studies of varied phenotypes 13,20,24–28,30 .…”