Submission Details

KCNJ11 was first reported in relation to autosomal dominant monogenic diabetes in 2004 (Gloyn et al., PMID: 15115830). Dozens of unique missense variants have been reported in humans in association with diabetes in published cases, with nearly 100 classified as pathogenic or likely pathogenic for diabetes in a recent review article (PMID: 32027066). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level and experimental data: 17 points. Variants in this gene have been reported in at least 26 probands in 9 publications (PMIDs: 15784703, 28938416, 26958039, 27681997, 16670688, 24150202, 16205880, 22701567, 27420379). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The usual mechanism for disease is heterozygous gain of function (mutated channels remain open due to reduced ATP sensitivity and/or disruption of channel gating and prevent insulin secretion despite hyperglycemia; PMID: 32376986). A single exception to the autosomal dominant inheritance was reported in 2016 in which an infant homozygous for the G324R variant had neonatal diabetes but his heterozygous parents did not have diabetes. The variant was found to have modestly decreased ATP sensitivity (PMID: 27118464). This gene-disease association is supported by animal models and expression studies. In summary, KCNJ11 is definitively associated with autosomal dominant monogenic diabetes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Per criteria outline by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms, inheritance pattern, and phenotypic variability underlying the three disease entities associated with KCNJ11. Therefore, we have split curations for these disease entities. The present curation includes (1) autosomal dominant monogenic diabetes, which presents as three phenotypic disease sub-entities: (1A) Permanent neonatal diabetes mellitus, (MIM:606176), (1B) Transient neonatal diabetes, 3 (MIM:125853), and less commonly, (1C) Maturity-onset diabetes of the young, type 13 (MODY13) (MIM:616329). Another entity requiring separate curation is (2) hyperinsulinemic hypoglycemia, familial, 2 (MIM:601820). The role of KCNJ11 variation in (3) risk for type 2 diabetes (polygenic; MIM:125853) will not be curated at this time since the contribution of KCNJ11 is in the form of common variants with a small effect.