Early onset or syndromic epilepsy
Gene: KCNJ11
Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded. Therefore based on PMID:27181099 plus OMIM plus review by West Midlands, Oxford and Wessex GLH, have updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic'.Created: 13 Aug 2019, 11:43 a.m. | Last Modified: 14 Oct 2019, 3:22 p.m.
Panel Version: 1.364
Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor. Suggested gene rating: Green.Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189
Comment on list classification: Promoted from amber to green. Conformed for Diabetes, permanent neonatal, with or without neurologic features (PNDM) on OMIM but not on Gene2Phenotype, which lists only Diabetes mellitus, KCNJ11-related transient neonatal. It should be noted that in the OMIM (606176), developmental delay, epilepsy, and neonatal diabetes (DEND) is also included, which is a more severe form of the disease. Only OMIM lists seizures as one of the phenotypes of the disease. KCNJ11 is also a green gene in the Intellectual disability gene panel.
There are 4 studies (PMID: 25678012,16670688,16609879,27681997) describing, in total, 27 unrelated probands with DEND or PNDM who have different KCNJ11 variants and have seizures.Created: 19 Nov 2018, 5:05 p.m.
Comment on mode of pathogenicity: Gain-of-function mutations are responsible for the phenotype (PMID: 17065345).Created: 19 Nov 2018, 4:50 p.m.
There is evidence to suggest there is a distinct neurological syndrome associated with activating mutations in this gene, and that the seizures observed are not secondary to hypoglycaemia.Created: 16 Aug 2018, 1:17 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Diabetes, permanent neonatal, with or without neurologic features, MIM#606176
Publications
Variants in this GENE are reported as part of current diagnostic practice
Mode of inheritance for gene: KCNJ11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KCNJ11 were set to 25678012; 16670688; 16609879; 27681997; 17065345; 28943513
Mode of inheritance for gene: KCNJ11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Source Wessex and West Midlands GLH was added to KCNJ11.
Source NHS GMS was added to KCNJ11.
Publications for gene: KCNJ11 were set to 25678012; 16670688; 16609879; 27681997; 17065345
Zornitza Stark: There is evidence to suggest t
Gene: kcnj11 has been classified as Green List (High Evidence).
Publications for gene: KCNJ11 were set to
Mode of pathogenicity for gene: KCNJ11 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mode of inheritance for gene: KCNJ11 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: KCNJ11 were changed from Diabetes, permanent neonatal, with or without neurologic features, 606176 to Diabetes, permanent neonatal, with or without neurologic features, 606176; DEND syndrome
Phenotypes for gene: KCNJ11 were changed from to Diabetes, permanent neonatal, with or without neurologic features, 606176
Expert Review Amber was added to KCNJ11. Panel: Genetic Epilepsy Syndromes
KCNJ11 was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services
KCNJ11 was created by Sarah Leigh