Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore.
Department of Internal Medicine I, Ulm University Medical Centre, Ulm, Germany.
Eur J Hum Genet. 2023 Jan;31(1):89-96. doi: 10.1038/s41431-022-01182-y. Epub 2022 Oct 7.
Pathogenic variants in more than 14 genes have been implicated in monogenic diabetes; however, a significant fraction of individuals with young-onset diabetes and a strong family history of diabetes have unknown genetic etiology. To identify novel pathogenic alleles for monogenic diabetes, we performed whole-genome sequencing (WGS) on four related individuals with type 2 diabetes - including one individual diagnosed at the age of 31 years - that were negative for mutations in known monogenic diabetes genes. The individuals were ascertained from a large case-control study and had a multi-generation family history of diabetes. Identity-by-descent (IBD) analysis revealed that the four individuals represent two sib-pairs that are third-degree relatives. A novel missense mutation (p.P81S) in the PAX6 gene was one of eight rare coding variants across the genome shared IBD by all individuals and was inherited from affected mothers in both sib-pairs. The mutation affects a highly conserved amino acid located in the paired-domain of PAX6 - a hotspot for missense mutations that cause aniridia and other eye abnormalities. However, no eye-related phenotype was observed in any individual. The well-established functional role of PAX6 in glucose-induced insulin secretion and the co-segregation of diabetes in families with aniridia provide compelling support for the pathogenicity of this mutation for diabetes. The mutation could be classified as "likely pathogenic" with a posterior probability of 0.975 according to the ACMG/AMP guidelines. This is the first PAX6 missense mutation that is likely pathogenic for autosomal-dominant adult-onset diabetes without eye abnormalities.
已有 14 多个基因的致病变异被认为与单基因糖尿病有关；然而，相当一部分有早发糖尿病和强烈家族糖尿病史的个体，其遗传病因尚不清楚。为了鉴定单基因糖尿病的新致病等位基因，我们对 4 名 2 型糖尿病相关个体（包括一名 31 岁确诊的个体）进行了全基因组测序（WGS），这些个体在已知的单基因糖尿病基因中未发现突变。这些个体是从一项大型病例对照研究中确定的，并且有糖尿病的多代家族史。同源性分析（IBD）表明，这 4 名个体代表两个三代表亲的同胞对。PAX6 基因中的一个新错义突变（p.P81S）是全基因组中 8 个罕见编码变异之一，所有个体均共享 IBD，并且从两个同胞对的受影响母亲遗传。该突变影响了 PAX6 配对结构域中高度保守的氨基酸，该区域是导致无虹膜和其他眼部异常的错义突变热点。然而，在任何个体中都没有观察到与眼睛相关的表型。PAX6 在葡萄糖诱导的胰岛素分泌中的既定功能作用以及无虹膜家族中糖尿病的共分离为该突变对糖尿病的致病性提供了强有力的支持。根据 ACMG/AMP 指南，该突变可归类为“可能致病性”，后验概率为 0.975。这是第一个在没有眼部异常的情况下，可能导致常染色体显性成年发病型糖尿病的 PAX6 错义突变。
