靶向基因捕获和高通量测序识别遗传相关性甲状腺功能减退症相关致病基因

Hereditary hypothyroidism, ocurring in about 1:2000 newborns,is one of the most common preventable causes of mental retardation. Neonatal hypothyroidism screening is currently the major manner of identification of congenital hypothyroidism,which is the major part of hereditary hypothyroidism. however, this method exists some shortages, such as not identifying later-onset hypothyroidis, not determinating the causes of hypothroidsm, and not treating according to the causes of hypothroidism. Genetic diagnosis has already been used in patient treatment, management and counseling. But the found rate of genetic mutation is too low for using classically detectation manner of single gene and the cost is too expensive for multiple genes using that manner. In our study, we are going to development of Targeted genetic capture and to combine with massively pallele sequecing for identify genetic mutations of multiple genes of hereditary hypothyroidism in one test. Then，we are going to confirm the mutation of gene using Sanger sequecing and to research the function of the mutatinal gene. Genetic screening of multiple genes involved in hereditary hypothyroidism based on these technologies may therefore significantly enhance the care of people who are affected by hypothyroidism due to genetic causes.

遗传性甲状腺功能减退症（甲减）是最常见的内分泌系统遗传性疾病，发病率高达1：2000；是最常见智障、畸形和生长发育迟缓性原因，也是为数极少的可防治性疾病。多为先天性遗传病。与甲减相关基因众多，至今发现达与90余个。现行新生儿甲减（TSH测定）筛查策略在发现先天性甲减、防治甲减危害中起到了最为重要的作用。但此法也存有不足,如不能发现中枢性、迟发性和轻度先天性甲减、不能早起开始针对病因的治疗、不能提供产前遗传咨询信息，不能防治宫内胎儿甲减等。基因检测能弥补筛查部分缺陷，但传统基因检测技术多为单个基因或突变热点检测，突变发现率很低。急需改进技术。本研究拟借助OMIM等生物信息中有关遗传性甲减基因相关信息，通过基因靶向捕获技术，建立遗传性甲减所有已知基因靶向捕获平台，结合高通量测序该技术对整组相关基因突变情况检测分析，通过验证直至功能分析，确定突变基因。以期提高遗传性甲减诊治水平，提高人口素质

本研究对遗传性甲状腺功能减退症相关基因信息进行了收集并建立了相应的数据库；建立了可疑遗传性甲状腺功能减退症患者的临床资料和家系资料库；采集了患者及其家系成员的外周血，提取了基因组DNA，建立基因组DNA库。对遗传性甲状腺功能减退症及其相关性疾病涉及的10个主要基因，在部分患者及家系成员中进行了突变检测。这10个基因分别为TPO、DUOX2、DUOXA2、IYD、SLC26A4、Tg、TSHR、THRα、THRβ、TBG。在近40个患者及其家系成员中发现了24个患者及其家系成员，分别在5个基因上存在已知或新发的突变。如对患有甲状腺有机化障碍的7个家系进行TPO、DUOX2、DUOXA2、IYD等相关基因检测时，发现了3个家系存在TPO基因突变，2个为新发突变；2个家系存在DUOX2基因突变，其中1个为新发突变；发现了1个家系存在SLC26A4基因突变。本研究同时对部分基因单核苷酸多态性的生物信息学进行了研究，特别是对其错义SNP的致病性进行了预测。通过本研究为下一步遗传相关性甲状腺疾病的整体研究打下了研究基础。