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.
Highlights
Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans
Maturity-onset diabetes of the young (MODY) is monogenic diabetes resulting from beta-cell dysfunction which usually present before the age of 25 years in non-obese patients who are non-insulin-dependent and have an autosomal dominant inheritance of diabetes[2]
Our study shows that heterozygous Regulatory Factor X 6 (RFX6) protein-truncating variants (PTVs) are associated with maturity-onset diabetes of the young (MODY)
Summary
Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. Rarevariant association testing for comparing the frequency of novel protein-truncating variants (PTVs) in monogenic cases with unknown aetiology to the frequency in large control cohorts is possible because of the availability of resources such as ExAC – a database of protein coding variants in large control populations[12]. This allows burden testing of the frequency of novel or rare coding variants in diseases of interest and a comparison to rates in controls to identify new genetic causes of monogenic disease. Our study shows that heterozygous RFX6 PTVs are associated with MODY
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