KCNJ11

Inheritance Pattern: AD

Disease ID:MONDO:0015967

Submitter: Natera

Inheritance Pattern: AD

Disease ID:MONDO:0100164

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0019207

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0011153

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014589

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0011153

Submitter: Myriad Women's Health

Inheritance Pattern: AR

Disease ID:MONDO:0011153

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0017185

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0020569

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0017188

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0007455

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0019334

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018911

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0000426

Submitter: Natera

Inheritance Pattern: AD

Disease ID:MONDO:0015967

Submitter: ClinGen

*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.

Inheritance Pattern: AR

Disease ID:MONDO:0011153

Submitter: ClinGen

*KCNJ11*, which encodes a subunit of the β‐cell ATP‐sensitive potassium channel, was first reported in relation to familial hyperinsulinemic hypoglycemia 2 (OMIM: 601820) in 1997 (Nestorowicz et al., PMID: 9356020). We have curated the inheritance pattern for *KCNJ11*-related hyperinsulinemic hypoglycemia as autosomal recessive, although there have been autosomal dominant cases reported which will be curated separately. A subset of cases are caused by paternally inherited heterozygous mutations that lead to focal disease due to somatic loss of heterozygosity. Loss of heterozygosity results in expression of this AR condition in a histologically focal manner. Individuals with pathogenic, inactivating *KCNJ11* variants typically present with hypoglycemia due to unregulated insulin secretion. Cases may present as diffuse, with all β-cells impacted, or focal, with the abnormality confined to a region of the pancreas. Recessive bi-allelic variants, including truncating, missense, and small indel variants (PMID 32027066), lead to an absent, nonfunctional or less functional KATP channel, resulting in persistent beta-cell membrane depolarization, calcium influx, and dysregulated insulin release. Focal hyperinsulinism, typically characterized by a small lesion of endocrine cells, within an otherwise histologically unremarkable pancreas, is caused by a single paternally-inherited recessive inactivating variant followed by a somatic loss of the maternal chromosome 11p.15 region because of paternal uniparental isodisomy. The focal lesion develops because the chromosome 11p15.5 region contains several imprinted genes including the maternally-expressed *H19* (a candidate tumor suppressor gene) and *CDKN1C* (a negative regulator of cell proliferation) and paternally-expressed growth factor genes such as *IGF2*. When paternal uniparental isodisomy occurs within a pancreatic beta-cell during fetal development, the imbalance between imprinted genes (increased IGF2 and diminished *H19* and *CDKN1C*) gives rise to the increase in proliferation of a population of beta-cells resulting in the focal lesion. As this cell contains a heterozygous *KCNJ11* recessive variant on the paternal allele, the uniparental unmasks the variant causing it to be homozygous which results in dysregulated insulin secretion from the focal lesion. Rapid parental testing should be performed for all individuals with a single heterozygous recessive *KCNJ11* variant as paternal inheritance offers a positive predictive value up to 94% for focal HI (PMIDs: 23275527, 24401662). For these individuals pancreatic imaging using 18F-DOPA PET scan is recommended to assess for focal disease and localize the lesion prior to lesionectomy which is curative in >97% of cases. For these cases consultation with an HI expert is recommended. Evidence supporting the relationship of this gene with autosomal recessive hyperinsulinism includes case-level data, segregation data, and experimental data. A large number of variants have been reported in *KCNJ11* in individuals with congenital hyperinsulinism (PMID: 32027066). For the purpose of this curation, 10 probands from 7 publications are included (PMIDs: 9356020, 18250167, 20589481, 20980454, 20686794, 28442472, 15998776). More evidence is available to support the gene-disease relationship in the literature, but as the maximum score for genetic evidence (12 points) has been reached; this has not been curated exhaustively. Variants in this gene have also been shown to segregate with disease in at least five family members (PMID: 24421282). The aggregated score for case and segregation-level data is 12 points. This gene-disease relationship is supported by functional assays, mouse models, expression studies, and protein interactions (PMIDS: 9488482, 9724715, 20694718, 14699091, 8549751, 854975, 11310506). Of note, we have reduced the points allotted to the mouse models, as they do not fully recapitulate the human phenotype. The mouse models described do not have sustained neonatal hypoglycemia, but rather stabilize blood glucose within a few days of birth, and develop glucose intolerance later in life (PMIDs: 9724715, 20694718, 11310506). Total points for experimental evidence are 5. Total points for genetic and experimental evidence together are 17. In summary, *KCNJ11* is definitively associated with autosomal recessive hyperinsulinemic hypoglycemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the Monogenic Diabetes GCEP on February 4, 2026. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP11.

Inheritance Pattern: SD

Disease ID:MONDO:0011153

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0030087

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014589

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0011153

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: SD

Disease ID:MONDO:0011153

Submitter: Natera

Inheritance Pattern: AD

Disease ID:MONDO:0030087

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0011153

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0012522

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012522

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0011153

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0014589

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0011153

Submitter: ClinGen

*KCNJ11*, which encodes the Kir6.2 subunit of the β‐cell ATP‐sensitive potassium channel, was first reported in relation to familial hyperinsulinemic hypoglycemia 2 (OMIM: 601820) in 1996 (Thomas et al., PMID: 8923010). Both autosomal dominant and autosomal recessive inheritances have been described in congenital hyperinsulinism for *KCNJ11* variants; in keeping with ClinGen curation practice, these inheritance patterns are evaluated separately. Of note, a subset of cases are caused by paternally inherited heterozygous variants that are usually implicated in recessively inherited congenital hyperinsulinism but in these cases lead to focal disease due to somatic loss-of-heterozygosity within an area of the pancreas, resulting in expression of this AR condition in a histologically focal manner; this has been curated with the autosomal recessive inheritance pattern. Individuals with pathogenic *KCNJ11* variants typically present with hypoglycemia due to dysregulated insulin secretion. Autosomal dominant cases, which include missense and other in-frame alterations, typically cause gating defects in channels but do not disrupt the channels’ ability to reach the cell surface, whereas autosomal recessive variants typically cause trafficking defects or severe loss of function where the channels are absent or non-functional (PMIDs: 16332676, 37056678). Evidence supporting relationship of this gene with hyperinsulinemic hypoglycemia includes case-level data and experimental data. A limited number of confirmed autosomal dominant cases have been identified. For this curation we have scored 10 probands from 5 publications (PMIDs: 31464105, 18596924, 23275527, 31997554, 16332676). While there are additional cases in the literature that may be examples of autosomal dominant inheritance, given the possibility of focal disease we have restricted this curation to cases where the disease is confirmed to be diffuse, and, when variants were paternally inherited, required either functional data consistent with a dominant mechanism (for example, a gating defect in a channel that traffics normally) or informative parental phenotyping. The aggregated score for case and segregation-level data is 5 points. This gene–disease relationship is further supported by experimental data. *KCNJ11* is highly expressed in pancreatic β cells, and Kir6.2 has been shown to coimmunoprecipitate and physically associate with SUR1 (encoded by ABCC8), forming the hetero‐octameric channel complex (PMIDs: 8549751, 9488482). Functional studies in cells expressing patient variants have also demonstrated that variants result in reduced intrinsic open probability or other gating abnormalities in channels that reach the plasma membrane, consistent with a dominant loss‐of‐function mechanism (PMIDs: 31464105, 16332676). Total points for experimental evidence are 1. Total points for genetic and experimental evidence together are 6. Taken together, the available genetic and experimental data support a limited level of evidence for the association of *KCNJ11* with autosomal dominant hyperinsulinemic hypoglycemia under the ClinGen gene–disease validity framework. The association of KCNJ11 with autosomal recessive hyperinsulinemic hypoglycemia and autosomal dominant monogenic diabetes have been split and curated separately. This classification was approved by the Monogenic Diabetes GCEP on April 1st, 2026. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP12.

Inheritance Pattern: AD

Disease ID:MONDO:0012522

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0012522

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0020525

Submitter: Orphanet