Table_3_Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions.xlsx

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.

RP1截短变异体（RP1 truncation variants），包括移码突变、无义突变及剪接位点变异，是视网膜色素变性（retinitis pigmentosa, RP）的常见致病原因。RP1是一类特殊基因，其截短变异可分别导致常染色体显性遗传性视网膜色素变性（autosomal dominant RP, adRP）或常染色体隐性遗传性视网膜色素变性（autosomal recessive RP, arRP），具体类型取决于变异的所在位置。本研究旨在通过对本实验室7092名个体的外显子组测序（exome-sequencing）数据中筛选出的165个RP1变异进行系统分析，并结合对已发表文献中185个RP1变异的全面梳理，阐明RP1截短变异导致adRP与arRP的分界阈值。在本研究队列中，共在16个家系中检出潜在致病变异，其中11个为新发现家系，5个为既往已报道家系。16个家系中，7个adRP家系的患者携带位于基因中段的杂合性截短变异；而9个分别表现为arRP（8个）或黄斑变性的家系，则在基因N端与C端携带双等位基因变异，涉及10个已知变异与7个新发现变异。经文献检索，已报道147个RP1截短变异分别与arRP（85个）、adRP（58个）或同时关联两种表型（4个）相关。对RP1致病变异的整体分析显示，该基因可划分为三个独立区域：即从c.1（p.1）至c.1837（p.613）的N端区域、从c.1981（p.661）至c.2749（p.917）的中段区域，以及从c.2816（p.939）至c.6471（p.2157）的C端区域。其中，基因中段的截短变异与adRP相关，而N端与C端的截短变异则与arRP相关。仅携带N端或C端截短变异的杂合子个体，其致病风险极低。但有13个变异存在表型关联的反向报道，提示RP1变异的致病机制较为复杂，有待进一步阐释。此外，针对c.5797位点及之后区域的纯合性截短变异、错义变异，以及位于上述两个区域间隙的截短变异的致病性，仍有待进一步明确。本研究不仅验证并细化了RP1截短变异导致显性与隐性RP的分界阈值，还发现了若干有待后续研究解答的科学问题。本研究结果提示，在临床基因检测中解读RP1变异结果时需格外谨慎；且类似的基因变异表型依赖位点的现象，可能也存在于其他部分基因中。