Heterozygous<i>RFX6</i>protein truncating variants are associated with Maturity-Onset Diabetes of the Young (MODY) with reduced penetrance
説明
<jats:title>Abstract</jats:title><jats:p>Finding new genetic causes of monogenic diabetes can help to understand development and function of the human pancreas. We aimed to find novel protein–truncating variants causing Maturity–Onset Diabetes of the Young (MODY), a subtype of monogenic diabetes. We used a combination of next–generation sequencing of MODY cases with unknown aetiology along with comparisons to the ExAC database to identify new MODY genes. In the discovery cohort of 36 European patients, we identified two probands with novel<jats:italic>RFX6</jats:italic>heterozygous nonsense variants.<jats:italic>RFX6</jats:italic>protein truncating variants were enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio, OR=131, P=l×l0<jats:sup>‐4</jats:sup>). We found similar results in non–Finnish European (n=348, OR=43, P=5×l0<jats:sup>‐5</jats:sup>) and Finnish (n=80, OR=22, P=1×l0<jats:sup>‐6</jats:sup>) replication cohorts. The overall meta–analysis OR was 34 (P=l×l0<jats:sup>‐16</jats:sup>).<jats:italic>RFX6</jats:italic>heterozygotes had reduced penetrance of diabetes compared to common<jats:italic>HNF1A</jats:italic>and<jats:italic>HNF4A</jats:italic>–MODY mutations (27%, 70% and 55% at 25 years of age, respectively). The hyperglycaemia resulted from beta–cell dysfunction and was associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous<jats:italic>RFX6</jats:italic>protein truncating variants are associated with MODY with reduced penetrance.</jats:p>
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詳細情報 詳細情報について
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- CRID
- 1360022307166387456
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- DOI
- 10.1101/101881
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- 資料種別
- preprint
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- データソース種別
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- Crossref
- OpenAIRE