Abstract
RP1 truncation variants, including frameshift, nonsense, and splicing, are a common cause of retinitis pigmentosa (RP). RP1 is a unique gene where truncations cause either autosomal dominant RP (adRP) or autosomal recessive RP (arRP) depending on the location of the variants. This study aims to clarify the boundaries between adRP and arRP caused by RP1 truncation variants based on a systemic analysis of 165 RP1 variants from our in-house exome-sequencing data of 7,092 individuals as well as a thorough review of 185 RP1 variants from published literature. In our cohort, potential pathogenic variants were detected in 16 families, including 11 new and five previously described families. Of the 16, seven families with adRP had heterozygous truncations in the middle portion, while nine families with either arRP (eight) or macular degeneration had biallelic variants in the N- and C-terminals, involving 10 known and seven novel variants. In the literature, 147 truncations in RP1 were reported to be responsible for either arRP (85) or adRP (58) or both (four). An overall evaluation of RP1 causative variants suggested three separate regions, i.e., the N-terminal from c.1 (p.1) to c.1837 (p.613), the middle portion from c.1981 (p.661) to c.2749 (p.917), and the C-terminal from c.2816 (p.939) to c.6471 (p.2157), where truncations in the middle portion were associated with adRP, while those in the N- and C-terminals were responsible for arRP. Heterozygous truncations alone in the N- and C- terminals were unlikely pathogenic. However, conflict reports with reverse situation were present for 13 variants, suggesting a complicated pathogenicity awaiting to be further elucidated. In addition, pathogenicity for homozygous truncations around c.5797 and thereafter might also need to be further clarified, so as for missense variants and for truncations located in the two gaps. Our data not only confirmed and refined the boundaries between dominant and recessive RP1 truncations but also revealed unsolved questions valuable for further investigation. These findings remind us that great care is needed in interpreting the results of RP1 variants in clinical gene testing as well as similar features may also be present in some other genes.
Highlights
RP1 (OMIM 603937), mapped to chromosome 8q11.2–12.1, is an axonemal microtubule-associated gene with four exons, where the protein-coding region is in the last three (Blanton et al, 1991; Pierce et al, 1999; Méndez-Vidal et al, 2014)
Results from a systemic analysis of RP1 variants from our in-house data as well as those from published literature demonstrate some common features of pathogenic variants in this gene, including: (1) about 80% of pathogenic variants are truncation variants; (2) truncation variants in the middle portion (c.1981 to c.2749) are associated with autosomal dominant retinitis pigmentosa (adRP), while those in the N-terminal (c.1 to c.1837) and C-terminal (c.2816 to c.6471) are responsible for autosomal recessive retinitis pigmentosa (arRP), supported by 91.9% of truncations; and (3) heterozygous truncation variants alone in the N- and Cterminals are unlikely pathogenic
Several questions remain to be clarified in future studies regarding the pathogenicity of the following RP1 variants: (1) truncation variants located in the two gaps between the N-terminal and middle portion as well as between the middle portion and C-terminal; (2) homozygous truncation variants around the c.5797 and thereafter; (3) missense variants, especially those with adRP; (4) the mechanism for the common features of RP1 truncation variants; and (5) the possible reasons for 8.1% of truncation variants with phenotypes contrary to the common feature
Summary
RP1 (OMIM 603937), mapped to chromosome 8q11.2–12.1, is an axonemal microtubule-associated gene with four exons, where the protein-coding region is in the last three (Blanton et al, 1991; Pierce et al, 1999; Méndez-Vidal et al, 2014). It encodes a 2,156-amino acid protein that is expressed in photoreceptor connecting cilia (Liu et al, 2002, 2003), participating in protein transport between the inner and outer segments of the photoreceptors via two domains: the doublecortin (DCX) domain and the bifocal (BIF) domain (Pierce et al, 1999; Liu et al, 2002; Siemiatkowska et al, 2012; Méndez-Vidal et al, 2014). It is expected to confirm and refine the boundaries as well as the genotype–phenotype correlation of RP1 variants based on a large dataset, especially at the era of widespread application of clinical genetic testing
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