Abstract
Thirty percent of all inherited retinal disease (IRD) is accounted for by conditions with extra-ocular features. This study aimed to establish the genetic diagnostic pick-up rate for IRD patients with one or more extra-ocular features undergoing panel-based screening in a clinical setting. One hundred and six participants, tested on a gene panel which contained both isolated and syndromic IRD genes, were retrospectively ascertained from the Manchester Genomic Diagnostics Laboratory database spanning 6 years (2012–2017). Phenotypic features were extracted from the clinical notes and classified according to Human Phenotype Ontology; all identified genetic variants were interpreted in accordance to the American College of Medical Genetics and Genomics guidelines. Overall, 49% (n = 52) of patients received a probable genetic diagnosis. A further 6% (n = 6) had a single disease-associated variant in an autosomal recessive disease-relevant gene. Fifty-two percent (n = 55) of patients had a clinical diagnosis at the time of testing. Of these, 71% (n = 39) received a probable genetic diagnosis. By contrast, for those without a provisional clinical diagnosis (n = 51), only 25% (n = 13) received a probable genetic diagnosis. The clinical diagnosis of Usher (n = 33) and Bardet–Biedl syndrome (n = 10) was confirmed in 67% (n = 22) and 80% (n = 8), respectively. The testing diagnostic rate in patients with clinically diagnosed multisystemic IRD conditions was significantly higher than those without one (71% versus 25%; p value < 0.001). The lower pick-up rate in patients without a clinical diagnosis suggests that panel-based approaches are unlikely to be the most effective means of achieving a molecular diagnosis for this group. Here, we suggest that genome-wide approaches (whole exome or genome) are more appropriate.
Highlights
Inherited retinal disease (IRD) refers to a group of clinically and genetically heterogeneous conditions affecting the retina [1]
For the purpose of this study, an individual is considered to have a syndromic IRD if they have ophthalmic signs and symptoms suggestive of retinal disease and at least one feature identified by a clinical geneticist to be potentially an associated manifestation of a multisystem disorder
There was a wide range of extra-ocular phenotypes; the most common included hearing impairment, developmental delay (DD)/intellectual disability (ID), polydactyly, microcephaly, obesity, abnormal facial shape and kidney/ renal abnormalities; a list of HPO terms generated from the clinical notes of the study population can be found in Supplementary Table S4
Summary
Inherited retinal disease (IRD) refers to a group of clinically and genetically heterogeneous conditions affecting the retina [1]. IRD is usually confined to the eye but up to 30% of affected individuals are considered syndromic as they. Have one or more associated extra-ocular features [2], some of which require health surveillance or specific clinical management measures to be put in place. More than 260 genes have been associated with IRD; over 100 of these have been linked to conditions of IRD with extra-ocular features. These disorders are associated with autosomal dominant (AD), autosomal recessive (AR) and X-linked inheritance (RetNet, http://www.sph.uth.tmc.edu/RetNet/)
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