Diagnostic yield of panel-based genetic testing in syndromic inherited retinal disease

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 pickup 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 pickup 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.

NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases

“…The overall characterization rate achieved in our study was 52% using mainly targeted gene panel testing but also WES analysis; this rate is similar to that observed in other cohorts (Manara et al 2019 ; Jiman et al 2020 ), ranging between 55% and 60% (Supplementary Table S9). However, a diagnostic rate of 85% was reported in a cohort formed exclusively by consanguineous families with ciliopathies (Shaheen et al 2016 ).…”

“…SRDs are a highly heterogeneous group of ocular diseases characterized by a challenging molecular characterization and clinical management (Shaheen et al 2016 ; Tatour and Ben-Yosef 2020 ). In the literature, it is rather frequent to find studies focused on specific syndromes (Knopp et al 2015 ; Vilboux et al 2017 ) or single panel-based studies (Shaheen et al 2016 ; Jiman et al 2020 ), which provide a biased landscape of SRDs. We present the study of a cohort comprising naïve and previously studied cases of well-known syndromes and unspecific SRD patients from a single center, focusing on the challenges derived from diagnosis and molecular characterization.…”

Molecular diagnostic challenges for non‐retinal developmental eye disorders in the United Kingdom

“…Over 250 disease‐causing genes have been identified, mainly over the past two decades, and this had led to the first approved retinal gene therapy, voretigene neparovec, for autosomal recessive biallelic RPE65 ‐retinopathy, with a multitude of gene/mutation‐based clinical trials underway (Maguire et al, 2019 ; Miraldi Utz, Coussa, Antaki, & Traboulsi, 2018 ; Russell et al, 2017 ). Genetic diagnostic rates in IRDs vary according to the population being tested, but range between 50 and 70% (Audo et al, 2012 ; Bernardis et al, 2016 ; Consugar et al, 2015 ; Ellingford et al, 2016 ; Jiman et al, 2020 ; Tayebi et al, 2019 ). The progress seen in the IRD field is likely due to the consistent scientific investment made internationally.…”

Novel biallelic USH2A variants in a patient with usher syndrome type IIA- a case report

“…Genomic DNA was isolated from peripheral blood. Next generation sequencing using an inherited retinal disease gene panel covering 175 genes was performed as previously described [ 9 ], with assessment of identified genetic variants performed by NHS Clinical scientists within the Genomic Diagnostics Laboratory. Segregation analysis was performed using a DNA sample from an unaffected child of the proband.…”

“…Initial interpretation of genetic variants was performed by UK National Healthcare Service (NHS) clinical scientists within the Genomic Diagnostics Laboratory at MCGM as previously described [ 9 ]. Briefly, this included assessment of the proband’s clinical referral, evaluation of scientific literature including Human Gene Mutation Database (HGMD; www.biobase-international.com/hgmd ) and Genome Aggregation Database (gnomAD; https://gnomad.broadinstitute.org ), and in silico prediction of pathogenicity using the Variant Effect Predictors (VEP) SIFT, PolyPhen2, MutationTaster and AlignGVGD embedded in Alamut Visual Version 2.6 (Interactive Biosoftware, Rouen, France).…”