中国大陆地区405例眼皮肤白化病家系的致病基因变异谱研究

Spectrum of pathological genetic variants among 405 Chinese pedigrees affected with oculocutaneous albinism

目的研究中国大陆地区眼皮肤白化病群体的临床遗传学特点。方法收集因眼皮肤白化病症状就诊的家系共405例,应用目标区域捕获高通量测序技术(基因包包括TYR、OCA2、TYRP1、SLC45A2基因)进行眼皮肤白化病基因变异分析并经Sanger测序验证,通过多重连接探针扩增技术(multiplex ligation-dependent probe amplification,MLPA)进行小片段缺失或重复分析,总结各亚型变异的规律。结果基因变异总体检出率为79.9%(647/810),变异种类包括错义变异(57.3%,371/647)、移码变异(22.9%,148/647)、无义变异(13.9%,90/647)、剪接区变异(5.6%,36/647)、小片段缺失(0.3%,2/647)。应用本检测方法共检出45个新变异。405例白化病家系中,306例患者携带双等位基因变异(75.6%,306/405),35例患者携带单等位基因变异(8.6%,35/405),64例患者未检出变异(15.8%,64/405)。306例双等位基因变异眼皮肤白化病患者中OCA1为228例(74.5%,228/306)、OCA2为46例(15.0%,46/306)、OCA3为2例(0.7%,2/306)、OCA4为30例(9.8%,30/306)。2例OCA3中国人群病例中,1例为c.1262-4_1262-3insTAGA纯合变异OCA3病例尚未见报道,另一例为既往报道的c.1214C>A(p.T405N)和c.1338delinsCG(p.V447Gfs*19)复合杂合变异OCA3病例。结论靶向捕获高通量测序、Sanger测序结合MLPA能够有效检出眼皮肤白化病相关基因变异,本研究结果拓展了眼皮肤白化病基因变异谱,同时可为眼皮肤白化病的基因诊断和产前诊断提供参考和帮助。

Objective To determine the spectrum of pathological genetic variants among 405 Chinese pedigrees affected with oculocutaneous albinism(OCA).Methods A total of 405 OCA patients were collected.High-throughput sequencing(The panel included TYR,OCA2,TYRP1 and SLC45A2 genes),Sanger sequencing and multiplex ligation-dependent probe amplification(MLPA)were used to analyze the genetic variants and patterns of each subtype.Results The overall detection rate of genetic variants was 79.9%(647/810),and the variants included missense variants(57.3%,371/647),frameshift variants(22.9%,148/647),nonsense variant(13.9%,90/647),splicing variant(5.6%,36/647),and microdeletions(0.3%,2/647).Thirty-six novel variants were detected.Of the 405 patients,306 have carried 2 variant alleles(75.6%,306/405),35 carried 1 variant alleles(8.6%,35/405),while no variant was detected in 64 patients.Among the 306 genetically diagnosed OCA patients,OCA1 was the most common form(74.5%,228/306),compared with OCA2(15.0%,46/306),OCA3(0.7%,2/306)and OCA4(9.8%,30/306),respectively.One patient was found to harbor homozygous c.1262-4_c.1262-3insTAGA variant of the TYRP1 gene.Another patient was found to carry compound heterozygous variants of c.1214C>A(p.T405N)and c.1338delinsCG(p.V447Gfs*19)of the TYRP1 gene.Conclusion High-throughput sequencing in combination with Sanger sequencing and MLPA can effectively detect genetic variants associated with OCA.Above finding has expanded variant spectrum of OCA,which can facilitate genetic and prenatal diagnosis of this disease in China.