Genetic and clinical findings of panel-based targeted exome sequencing in a northeast Chinese cohort with retinitis pigmentosa

Abstract

Background: Panel-based targeted exome sequencing was used to analyze the genetic and clinical findings of targeted genes in a cohort of northeast Chinese with retinitis pigmentosa.

Methods: A total of 87 subjects, comprising 23 probands and their family members (total patients: 32) with confirmed retinitis pigmentosa were recruited in the study. Panel-based targeted exome sequencing was used to sequence the patients and family members, all subjects with retinitis pigmentosa underwent a complete ophthalmologic examination.

Results: Of the 23 probands, the clinical manifestations include night blindness, narrowing of vision, secondary cataracts, choroidal atrophy, color blindness, and high myopia, the average age of onset of night blindness is 12.9 ± 14 (range, 0-65; median, 8). Posterior subcapsular opacities is the most common forms of secondary cataracts (nine cases, 39.1%), and peripheral choroidal atrophy is the most common form of secondary choroidal atrophy (12 cases, 52.2%). Of these probands with complication peripheral choroidal atrophy, there were eight probands (66.7%, 8/12) caused by the pathogenic variation in USH2A gene. A total of 17 genes and 45 variants were detected in 23 probands. Among these genes, the commonest genes were USH2A (40%; 18/45), RP1 (15.6%; 7/45), and EYS (8.9%; 4/45), and the top three genes account for 56.5% (13/23) of diagnostic probands. Among these variants, comprising 22 (48.9%) pathogenic variants, 14 (31%) likely pathogenic variants, and nine (20%) uncertain clinical significance variants, and 22 variants was discovered first time. Most of the mutations associated with RP were missense (53.3%, 24/45), and the remaining mutation types include frameshift (35.6%, 16/45), nonsense (6.7%, 3/45), and spliceSite (4.4%, 2/45). Among the probands with mutations detected, compound heterozygous forms was detected in 13 (56.5%, 13/23) probands, and digenic inheritance (DI) forms was detected in five (21.7%, 5/23) probands.

Conclusion: Panel-based targeted exome sequencing revealed 23 novel mutations, recognized different combinations forms of variants, and extended the mutational spectrum of retinitis pigmentosa and depicted common variants in northeast China.

Keywords: compound heterozygous; digenic inheritance; panel-based targeted exome sequencing; retinitis pigmentosa.

Figure 1

Basic information of clinical presentation and genetic finding of the target exome sequencing in the patients. (a) The age distribution of the total Patients, including age ≤10 years (n = 15), 10–20 years (n = 4), 20–30 years (n = 2), 30–40 years (n = 1), and >40 years (n = 1); (b), Distribution of retinitis pigmentosa (RP)‐causative genes in the 32 patients. Mutations were identified in 17 genes, with 65% of the mutations found in the top three genes (USH2A, RP1, EYS). (c) Forty‐five pathogenic/likely pathogenic/uncertain clinical significance variants were identified, including missense (n = 24), frameshift (n = 16), nonsense (n = 3), and splicing (n = 2) variants. (d) Forty‐five pathogenic/likely pathogenic/uncertain clinical significance variants were identified, including pathogenic (n = 22), likely pathogenic (n = 14), and uncertain clinical significance (n = 9) variants. Of these variants, 23 of them were described for the first time