全外显子组新一代靶向捕获测序探寻非综合征先天性小耳畸形的致病基因及功能研究

Microtia can occur as the only clinical abnormality or as part of a syndrome. Microtia can have a genetic or environmental predisposition. Existing data indicate that Mendelian inheritance with an autosomal dominant or recessive mode of inheritance is more likely in syndromic and familial cases of microtia, and some forms due to chromosomal aberrations have been reported. whereas multifactorial or polygenic causes are more probable in sporadic cases. Although a number of genes have now been identified on syndromes associated with microtia, no genes have been reported as causal genetic mutation associated with isolated microtia.Very recently, advances in targeting capture sequencing,DNA enrichment and next-generation sequencing technology have made it possible to quickly and cost-effectively sequence all the genes in the ‘exome’ the protein-coding portion of the genome, and then to rapidly identify alleles responsible for Mendelian disorders. Our subject group have collected a large pedigree with isolated microtia during former work, and try to apply whole exome sequencing with targeting capture sequencing to identify the gene responsible for this isolated microtia family. Furthermore, functional study will be applied to demonstrate the pathogenic role of the causing mutation of the candidate gene, with the mouse models or other appropriate tools.

小耳畸形可作为单独的临床表现或者综合征的一部分出现，一般认为致病因素包括遗传和环境因素两大类。研究表明综合征型和家系遗传小耳畸形的遗传方式更可能符合孟德尔遗传规律，为常染色体显隐性遗传方式，也有一部分是由于染色体的部分缺失导致的；而非综合征型小耳畸形多为散发病例，可能为多因素多基因疾病。尽管很多研究中，已经发现了一些综合征型小耳畸形的候选致病基因，但迄今为止，还没有确认一个非综合征型小耳畸形的致病基因。最近，随着新一代靶向捕获测序技术、DNA的富集技术和第二代测序技术的进步，外显子组测序，即对基因组编码蛋白质部分序列的测序，变得相对快捷和高性价比，可以高效的定位符合孟德尔遗传规律的疾病。本课题组前期已经收集到一个遗传性小耳畸形的的大家系，拟应用全外显子靶向捕获测序技术方法定位和克隆致病基因，并且将在转基因动物等平台上对该基因的分子生物学功能进行研究，以明确相关的分子致病机理和遗传易感基因。