Background: To screen variants in pre-mRNA Splicing genes in 95 Chinese
autosomal dominant retinitis pigmentosa (adRP) families.
Methods: Clinical examination and pedigree analysis were performed. Targeted exome
sequencing (TES) and / or Sanger sequencing were performed to detect the variants in
genes of Splicing factors and conduct intra-familiar segregation analysis with DNA
available. In silico analysis was performed to predict pathogenicity of variants in protein
level and in vitro splicing assays were performed to compare splicing variants with their
corresponding wildtype about their splicing effect.
Results: In this study, total nine different variants were identified in PRPF31,
SNRNP200, and PRPF8 respectively, including six PRPF31 variants [five novel variants
322+1G>A, c.527+2T>G, c.590T>C(p.Leu197Pro), c.1035_1036insGC (p.Pro346Argfs
X18), and c.1224dupG (p.Gln409AlafsX66) plus one reported variant c.1060C>T
(p.Arg354X)], a recurrent PRPF8 variant c.6930G>T (p.Arg2310Ser), two SNRNP200
variants [one heterozygous and homozygous SNRNP200 recurrent variant c.3260G>A
(p.Ser1087Leu), and a reported heterozygous c.2042G>A(p.Arg681His)]. In family
20009, incomplete penetrance was observed. A novel PRPF31 missense variant
c.590T>C (p.Leu197Pro) was predicted to be pathogenic in protein level via in silico
analysis and in vitro splicing assay demonstrated that two novel splicing PRPF31
variants c.322+1G>A and c.527+2T>G affect splicing compared with the wildtype.
Conclusions: In our studies, RP-causing variants of pre-mRNA Splicing genes
(PRPF31, PRPF8 and SNRNP200) were identified in nine of the ninety-five adRP
families respectively, which extend the spectra of RP variant and phenotype. And we
provide the first example that SNRNP200-related RP can be caused by both
heterozygous and homozygous variants of this gene.