Gene Panel Sequencing of Patients With Monogenic Diabetes Brings to Light Genes Typically Associated With Syndromic Presentations

Gene panel sequencing (NGS) offers the possibility of analyzing rare forms of monogenic diabetes (MgD). To that end, 18 genes were analyzed in 1,676 patients referred for maturity-onset diabetes of the young genetic testing. Among the 307 patients with a molecular diagnosis of MgD, 55 (17.9%) had a mutation in a gene associated with a genetic syndrome. Of the patients with mutations, 8% (n = 25) carried the m.3243A>G variant associated with maternally inherited diabetes and deafness. At the time of referral very few had reported hearing loss or any other element of the typical syndromic presentation. Of the patients, 6% had mutation in HNF1B even though the typical extrapancreatic features were not known at the time of referral. Surprisingly, the third most prominent etiology in these rare forms was the WFS1 gene, accounting for 2.9% of the patients with pathogenic mutations (n = 9). None of them displayed a Wolfram syndrome presentation even though some features were reported in six of nine patients. To restrict the analysis of certain genes to patients with the respective specific phenotypes would be to miss those with partial presentations. These results therefore underlie the undisputable benefit of NGS strategies even though the situation implies cascade consequences both for the molecular biologist and for the clinician.

Automated summary

Gene panel sequencing is used to analyze rare forms of monogenic diabetes. In this study, 18 genes were analyzed in 1,676 patients and mutations were found in genes associated with genetic syndromes. The most common mutation was the m.3243A>G variant, which is associated with maternally inherited diabetes and deafness. Other mutations unrelated to diabetes were also found, suggesting that restricting gene analysis to specific phenotypes may miss patients.