Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort

Abstract

We conducted targeted next-generation sequencing (TGS) and/or whole exome sequencing (WES) to assess the genetic profiles of clinically suspected retinitis pigmentosa (RP) in the Korean population. A cohort of 279 unrelated Korean patients with clinically diagnosed RP and available family members underwent molecular analyses using TGS consisting of 88 RP-causing genes and/or WES with clinical variant interpretation. The combined genetic tests (TGS and/or WES) found a mutation in the 44 RP-causing genes and seven inherited retinal disease (IRD)-causing genes, and the total mutation detection rate was 57%. The mutation detection rate was higher in patients who experienced visual deterioration at a younger age (75.4%, age of symptom onset under 10 years) and who had a family history of RP (70.7%). The most common causative genes were EYS (8.2%), USH2A (6.8%), and PDE6B (4.7%), but mutations were dispersed among the 51 RP/IRD genes generally. Meanwhile, the PDE6B mutation was the most common in patients experiencing initial symptoms in their first decade, EYS in their second to third decades, and USH2A in their fifth decades and older. Of note, WES revealed some unexpected genotypes: ABCC6, CHM, CYP4V2, RS1, TGFBI, VPS13B, and WDR19, which were verified by ophthalmological re-phenotyping.

Keywords: inherited retinal diseases; retinitis pigmentosa; targeted next-generation sequencing; whole exome sequencing.

Figure 1

Flowchart demonstrating the recruitment progress of genetic tests in patients with retinitis pigmentosa.

Figure 2

Mutational spectra of 279 probands with retinitis pigmentosa. (a) Mutational spectrum of total subjects, combining targeted next-generation sequencing (TGS) and whole exome sequencing (WES). (b) Mutational spectrum of patients who underwent TGS. (c) Mutational spectrum of patients who underwent WES due to TGS with inconclusive results. (d) Mutational spectrum of patients who underwent WES only. (e) Mutational spectrum of total patients who underwent WES with inconclusive TGS results and WES only. AD, autosomal dominant; AR, autosomal recessive; XL, x-linked inheritance.

Figure 3

Mutational spectra of 279 probands with retinitis pigmentosa according to age at symptom onset. (a) Mutational spectrum for age at symptom onset under 10 years. (b) Mutational spectrum for age at symptom onset between 11 and 20 years. (c) Mutational spectrum for age at symptom onset between 21 and 40 years. (d) Mutational spectrum for age at symptom onset over 41 years.