Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

Abstract

Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10−4). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10−5) and Finnish (n = 80, odds ratio = 22, P = 1 × 10−6) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

Prediction algorithms: pitfalls in interpreting genetic variants of autosomal dominant monogenic diabetes

“…Other examples include the CEL gene, where only variants within the first or fourth repeats of the VNTR region are pathogenic(15); RFX6, where there is only evidence to implicate protein truncating variants(16); and the sole heterozygous PDX1 pathogenic variant, p.P63fs, known to cause monogenic diabetes through a dominant negative effect…”

HDAC4 mutations cause diabetes and induce β‐cell FoxO1 nuclear exclusion

“…Most cases of monogenic diabetes were often misdiagnosed as having type 2 or type 1 diabetes (Delvecchio et al, ; Johansson et al, ). Furthermore, Mendelian diabetes mutations were previously thought to be highly penetrant, but were found to have reduced or incomplete penetrance, and therefore can be identified more frequently in age‐matched normoglycemic individuals compared with other highly penetrant mutations (Patel et al, ). The reduced penetrance of the mutation is important to genetic counseling of at‐risk relatives undergoing predictive tests because the chance of presenting with diabetes is no longer based simply on the odds of inheriting the mutation.…”

Congenital Diabetes: Comprehensive Genetic Testing Allows for Improved Diagnosis and Treatment of Diabetes and Other Associated Features

“…Recent cases have been described with an expanded phenotype, including compound heterozygous cases with childhood-onset diabetes [51] and heterozygous cases with a MODY-like phenotype with reduced penetrance [52•]. …”