遗传性肾病综合征候选致病基因筛选策略

The Strategy of Discovering Candidate Causative Genes for Hereditary Nephrotic Syndrome

部分遗传性肾病综合征(NS)与编码足细胞蛋白的单基因突变有关,目前,仍有80%的遗传性NS致病基因不明。大家系单基因遗传病筛选候选致病基因首选定位克隆,而小家系候选致病基因筛选优先选择外显子组测序。对致病基因不明的遗传性NS小家系核心成员进行外显子组测序,挑选出非同义、罕见、位于保守区域、软件预测有致病性、基因型与表型共分离的变异,携带该变异的基因即为候选致病基因。

Mutations in more than 20 different genes which are highly expressed in glomerular podocytes have been identified to lead to hereditary nephrotic syndrome （NS） in a subset of patients. However, the genetic cause of the majority（ 〉 80% ） of hereditary NS remains unknown. Positional linkage based disease gene identification is a proven reliable strategy and will remain the gold-standard if suitable families are available. However, exome sequencing opens up a new road in the elucidation of genetic defects causing monogenic disorders of small families. Exome sequencing is performed on several core members of a family with hereditary NS to discover candidate causative genes. Non-synonymous and rare variants which affect highly con- served sequences and are predicted to have functional impacts and are completely co-segregated with the phenotypes are chosen, and the genes carrying the variants are identified as candidate causative genes.