Putative digenic inheritance of heterozygous <i>RP1L1</i> and <i>C2orf71</i> null mutations in syndromic retinal dystrophy

<i>Background</i>: Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype. <i>Materials and methods</i>: In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy, whole exome sequencing was performed. The candidate pathogenic variants were tested by developing an <i>in vivo</i> zebrafish model and assaying for retinal and cerebellar integrity. <i>Results</i>: Exome sequencing revealed a complex heterozygous protein-truncating mutation in <i>RP1L1</i>, p.[(Lys111Glnfs*27; Gln2373*)], and a heterozygous nonsense mutation in <i>C2orf71</i>, p.(Ser512*). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression of <i>rp1l1</i> and <i>c2orf71l</i> induced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum. <i>Conclusions</i>: We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology.背景：视网膜色素变性（Retinitis pigmentosa, RP）是最常见的遗传性视网膜退行性疾病，可分为非综合征型与综合征型两类。综合征型RP常伴随智力障碍、听力损失或先天性畸形等其他症状。已知两种疾病类型均存在复杂的遗传相互作用，可调控表型的外显率与表现度。 材料与方法：针对1例表现为非典型RP、听力损失、共济失调及小脑萎缩的患者，本研究实施了全外显子组测序。通过构建体内（in vivo）斑马鱼模型并检测视网膜与小脑的完整性，对候选致病变异进行功能验证。 结果：外显子组测序在*RP1L1*基因中检出一处复杂的杂合性蛋白截短突变，即p.[(Lys111Glnfs*27; Gln2373*)]，同时在*C2orf71*基因中检出一处杂合无义突变p.(Ser512*)。既往研究显示，上述两个基因的突变均与常染色体隐性遗传非综合征型RP相关，提示该家系可能存在双基因遗传模式。通过斑马鱼模型对患者的两种关键表型开展功能验证后发现，联合抑制*rp1l1*与*c2orf71l*基因可引发特征性病理改变：眼球体积缩小、光感受器视紫红质表达缺失，同时伴随小脑结构紊乱。 结论：本研究提出，上述两个基因的杂合功能丧失型突变联合作用可导致综合征型视网膜退行性疾病，其潜在机制可能为至少两个基因座之间的遗传相互作用。仅单个基因座的单倍体剂量不足（haploinsufficiency）均不足以引发明显的病理改变。