Whole genome sequencing requested directly from a multi-ethnic london adult retinal clinic

Abstract

Aims/Purpose: Physicians in the UK can now request whole genome sequencing (WGS) for suspected inherited retinal disease (IRD), funded by a National Genomic Medicine Service. Achieving genetic diagnoses can be more challenging for ethnicities with lower representation in reference genomes. We report initial results from a specialist adult retinal service, with no prior experience of direct genetic testing from clinic.

Methods: WGS was undertaken with screening of a virtual panel of known IRD-associated genes. Exceptions to WGS included suspected albinism and pseudoxanthoma elasticum, where targeted sequencing was undertaken of albinism-associated genes or ABCC6 respectively.

Results: To date, results for 28 patients (mean (SD) age, 51 (17) years; 17 females) from 27 families have been received. Ethnicities were white European (13), African (9), South Asian (3), and mixed (3). Reports were positive in 15 cases (variants in ABCA4, BEST1, USH2A, TYR, COL18A1, RHO, ABCC6, PRPF8, CRB1, EFEMP1, NR2E3, CNGB3, CERKL) and were consistent with the clinical phenotype. Ten reports were negative and 3 were inconclusive. In 2 of the latter, the phenotype was sufficiently specific (Bietti crystalline dystrophy and Oguchi disease) to allow attribution of disease to variants found in CYP4V2 and GRK1 respectively. Of 17 patients achieving a genetic diagnosis, 9 were white European, 6 were of African origin, 1 South Asian, and 1 of mixed ethnicity). Mean (SD) time between patient consent and report availability was 9.0 (2.5) months.

Conclusions: In this analysis of tests performed so far from a clinic serving a multi-ethnic patient population, a molecular diagnosis was achieved in 61% of patients. The phenotype continues to be important for correctly interpreting genetic data. Achieving genetic diagnosis allows confirmation of genetic aetiology, more informed counselling relating to risk to children, and determines eligibility for the increasing number of gene-directed experimental therapies.