{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T19:44:52Z","timestamp":1792698292414,"version":"4.5.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T00:00:00Z","timestamp":1708387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes are known to cause monogenic diabetes that overlaps clinically with T2DM. Whole-exome sequencing of related individuals with T2DM is a powerful approach to identify novel high-penetrance disease variants in coding regions of the genome. We performed whole-exome sequencing on four related individuals with T2DM \u2013 including one individual diagnosed at the age of 33 years. The individuals were negative for mutations in monogenic diabetes genes, had a strong family history of T2DM, and presented with several characteristics of metabolic syndrome. A missense variant (p.N2291D) in the type 2 ryanodine receptor (<jats:italic>RyR2)<\/jats:italic> gene was one of eight rare coding variants shared by all individuals. The variant was absent in large population databases and affects a highly conserved amino acid located in a mutational hotspot for pathogenic variants in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrocardiogram data did not reveal any cardiac abnormalities except a lower-than-normal resting heart rate (&amp;lt; 60 bpm) in two individuals \u2013 a phenotype observed in CPVT individuals with <jats:italic>RyR2<\/jats:italic> mutations. RyR2-mediated Ca<jats:sup>2+<\/jats:sup> release contributes to glucose-mediated insulin secretion and pathogenic <jats:italic>RyR2<\/jats:italic> mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region \u2013 overlapping the p.N2291D variant \u2013 are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the <jats:italic>RyR2<\/jats:italic> gene that co-segregates with diabetes in the absence of overt CPVT.<\/jats:p>","DOI":"10.3389\/fendo.2024.1258982","type":"journal-article","created":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T10:43:26Z","timestamp":1708425806000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Whole-exome sequencing in familial type 2 diabetes identifies an atypical missense variant in the RyR2 gene"],"prefix":"10.3389","volume":"15","author":[{"given":"Vikas","family":"Bansal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard R.","family":"Winkelmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes W.","family":"Dietrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard O.","family":"Boehm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62219-9","article-title":"The many faces of diabetes: a disease with increasing heterogeneity","volume":"383","author":"Tuomi","year":"2014","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-019-4909-y","article-title":"Type 2 diabetes: a multifaceted disease","volume":"62","author":"Pearson","year":"2019","journal-title":"Diabetologia"},{"key":"B3","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/s41574-019-0308-1","article-title":"Harnessing heterogeneity in type 2 diabetes mellitus","volume":"16","author":"Philipson","year":"2020","journal-title":"Nat Rev Endocrinol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-022-01462-3","article-title":"Genetics of type 2 diabetes: implications from large-scale studies","volume":"22","author":"DeForest","year":"2022","journal-title":"Curr Diab Rep"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2252","DOI":"10.1038\/s41467-018-04611-z","article-title":"Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes","volume":"9","author":"Gusarova","year":"2018","journal-title":"Nat Commun"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1231-2","article-title":"Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls","volume":"570","author":"Flannick","year":"2019","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.6511","article-title":"Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population","volume":"311","author":"Estrada","year":"2014","journal-title":"JAMA"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2337\/db17-0187","article-title":"A loss-of-function splice acceptor variant in IGF2 is protective for type 2 diabetes","volume":"66","author":"Mercader","year":"2017","journal-title":"Diabetes"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2915","article-title":"Loss-of-function mutations in SLC30A8 protect against type 2 diabetes","volume":"46","author":"Flannick","year":"2014","journal-title":"Nat Genet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.05.011","article-title":"Loss-of-function mutations in APPL1 in familial diabetes mellitus","volume":"97","author":"Prudente","year":"2015","journal-title":"Am J Hum Genet"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1712262115","article-title":"MAFA missense mutation causes familial insulinomatosis and diabetes mellitus","volume":"115","author":"Iacovazzo","year":"2018","journal-title":"Proc Natl Acad Sci U. 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