# Whole-exome sequencing in familial type 2 diabetes identifies an atypical missense variant in the RyR2 gene

## TL;DR

Researchers found a rare genetic variant in the RyR2 gene linked to type 2 diabetes in a family, without causing a known heart condition.

## Contribution

A novel RyR2 missense variant (p.N2291D) is identified as a potential high-penetrance cause of familial T2DM.

## Key findings

- The p.N2291D variant in RyR2 is shared among four related T2DM individuals and absent in population databases.
- The variant affects a conserved amino acid in a CPVT mutation hotspot and is associated with glucose intolerance.
- Lower resting heart rate was observed in two individuals, similar to CPVT cases with RyR2 mutations.

## Abstract

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 – 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 (RyR2) 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 (< 60 bpm) in two individuals – a phenotype observed in CPVT individuals with RyR2 mutations. RyR2-mediated Ca2+ release contributes to glucose-mediated insulin secretion and pathogenic RyR2 mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region – overlapping the p.N2291D variant – are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the RyR2 gene that co-segregates with diabetes in the absence of overt CPVT.