Syndromic Monogenic Diabetes Genes Should Be Tested in Patients With a Clinical Suspicion of Maturity-Onset Diabetes of the Young

Abstract

At present, outside of infancy, genetic testing for monogenic diabetes is typically for mutations in maturity-onset diabetes of the young (MODY) genes that predominantly result in isolated diabetes. Monogenic diabetes syndromes are usually only tested for when supported by specific syndromic clinical features. How frequently patients with suspected MODY have a mutation in a monogenic syndromic diabetes gene is unknown and thus missed by present testing regimes. We performed genetic testing of 27 monogenic diabetes genes (including 18 associated with syndromic diabetes) for 1,280 patients with a clinical suspicion of MODY who were not suspected of having monogenic syndromic diabetes. We confirmed monogenic diabetes in 297 (23%) patients. Mutations in seven different syndromic diabetes genes accounted for 19% (95% CI 15-24%) of all monogenic diabetes. The mitochondrial m.3243A>G and mutations in HNF1B were responsible for the majority of mutations in syndromic diabetes genes. They were also the 4th and 5th most common causes of monogenic diabetes overall. These patients lacked typical features, and their diabetes phenotypes overlapped with patients with nonsyndromic monogenic diabetes. Syndromic monogenic diabetes genes (particularly m.3243A>G and HNF1B) should be routinely tested in patients with suspected MODY who do not have typical features of a genetic syndrome.

Figure 1

Bar chart showing number of cases for each monogenic diabetes gene. Filled bars are syndromic monogenic diabetes genes and open bars are non-syndromic monogenic diabetes genes.

Figure 2

Comparison of clinical features in patients with m.3243A>G diabetes diagnosed by unselected testing using tNGS and by clinically suspected testing using a TaqMan genotyping assay undertaken as requested by the referring clinician. Filled bars are patients with diabetes and the m.3243A>G mutation identified by targeted tNGS in a suspected MODY cohort and unfilled bars are patients with m.3243A>G identified when clinically suspected of having MIDD.

Figure 3

Comparison of clinical features in patients with HNF1B diabetes diagnosed by unselected testing using tNGS and by clinically suspected testing using Sanger sequencing and MLPA analysis undertaken as requested by the referring clinician. Filled bars are patients with an HNF1B mutation identified by targeted NGS in a suspected MODY cohort and non-filled bars are patients with an HNF1B mutation identified when clinically suspected of having HNF1B-related disease.