Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene

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Abstract
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 thePAX6gene 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 ofPAX6- 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 firstPAX6missense mutation that is likely pathogenic for autosomal-dominant adult-onset diabetes without eye abnormalities.

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