Early onset or syndromic epilepsy

Gene: KCNJ11

I don't know

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

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hyperinsulinemic hypoglycemia, familial, 601820

Publications

• 19254908
• 16670688

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.

Green List (high evidence)

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

• 16670688

Variants in this GENE are reported as part of current diagnostic practice