Early onset or syndromic epilepsy

Gene: KCNMA1

Green List (high evidence)

AD PNKD3 with or without generalised epilepsy and AR CADEDS : Takiri et al, 2016 (27567911) 2 sisters of consang Saudi parents with myoclonic seizures occuring around 1 year of age - 1 patient these were controlled with medication, in the other they progressed to tonic and generalised tonic-clonic seizures. Both had hom 1bp duplication, Carrier parents unaffected - suggests this variant is a LOF mutation. In this paper they mention the previously reported cases Du et al 2005 (15937479) - seizures as part of phenotype, missense variant and suggest AD inheritance, Zhang et al, 2015 (26195193) - 2 unrelated cases - both had seizures as part of phenotype - de novo het missense variants. Peng et al, 2019 (29933521) - 3 patients with missense variants (likely to be disease causing) in KCNMA1 all had drug-resistant epilepsy - 1 arose de novo, 1 inherited patoernally and 1 inherited maternally. No info re family history (supp table 1). Yesil et al, 2018 (29545233) - patient with a novel hom truncating mutation (Arg458*), parents both healthy - doesn't mention whether they have been tested.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Green List (high evidence)

In a recent extensive review of the literature, Bailey et al. (2019 - PMID: 31427379) summarize the phenotype of KCNMA1-related channelopathy. Overall the features of 37 subjects with 16 KCNMA1 pathogenic variants are discussed in detail. [An also relevant report by Liang et al. published in 6/2019 - PMID: 31152168 - was also considered for this review].

KCNMA1 encodes the pore-forming α subunit of large-conductance voltage- and Ca(2+)-activated K+ channel (also called BK channel). BK channels have highest expression levels in brain (acting as regulators of neuronal exciatbility) and muscle.

Variants in the review are distinguished in GoF, LoF and VUS (the latter used for variants of unknown/uncharacterized effect on BK channel activity) [NM_002247.3 mentioned as RefSeq]:
- GoF variants included D434G (a variant reported in 13 individuals) and N995S (also reported as N999S or N1053S).
- LoF variants included S351Y, G356R, G375R, N449fs*, I663V, C413Y, P805L, D984N, G354S.
- Uncharacterized variants included R458Ter, Y676Lfs*7 (both presumed to result to LoF), K518N, E656A, N1195S, E884K.

The disorder exhibited in most cases aut. dominant inheritance (either as de novo occurrence of a variant or identification in successive generations), with autosomal recessive inheritance reported in one pedigree (sibs with Y676Lfs*fs) (Tabarki et al. 2016 - PMID: 27567911).

As the authors comment, the hallmark of KCNMA1-related channelopathy is neurological dysfunction incl. seizures, movement disorders, DD and ID.

Epilepsy was a feature in approx. half individuals (18/37) irrespective of mutation type (eg. 9/20 in the case of GoF, 6/13 in LoF variants). Seizure characteristics were highly variable as for the onset, type, EEG pattern, frequency/duration and response to medication. Overlapping types were noted for GoF and LoF mutations incl. myoclonic, GTCS, absence seizures with few being more frequent or specific in certain mutation types.

Individuals with the same variant may present or not certain features eg. 6/13 members of a large family with D434G or 3/7 (all unrelated) individuals with N1053S developed epilepsy.

Animal studies support a role for both LoF and GoF alterations in BK channel activity as for the seizures, with more solid evidence/correlation with GoF mutations. (Other phenotypes eg. movement disorders are also supported by animal models).

Similarly developmental delay has been reported in 21/37 individuals and intellectual disability in 12/37 (both GoF and LoF) with severe presentation in certain cases (eg. in 3 individuals with G375R) while on several occasions severity (or presence of this feature(?)) has probably not been commented on.

The KCNMA1-related disorders in OMIM are the following :
?Cerebellar atrophy, developmental delay, and seizures, 617643 (AR)
Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 (AD)

KCNMA1 is part of the DD panel of G2P associated with Generalized epilepsy and paroxysmal dyskinesia (monoallelic, activating mutations / disease confidence : possible).

KCNMA1 is included in several gene panels for epilepsy incl. those of Radboudumc and Victorian Clinical Genetics and several other panels summarized in the supplement of the review. The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).

As a result upgrade to green rating can be considered for the epilepsy panel. The gene could possibly be upgraded to amber (or green) in the ID panel, too.

Created: 25 Aug 2019, 7:31 p.m. | Last Modified: 25 Aug 2019, 8:14 p.m.

Panel Version: 1.256

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 31427379
• 31152168
• 27567911

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

Green List (high evidence)

In addition to the information already detailed in other the reviews below: Additional information in PMID 29933521 (supp table 1) details three individuals with epilepsy (generalised epilepsy and paroxysmal dyskinesia) and missense variants in this gene; one was de novo and the others were inherited.

Created: 23 Aug 2019, 10:04 a.m. | Last Modified: 23 Aug 2019, 10:04 a.m.

Panel Version: 1.256

Phenotypes
Generalised epilepsy and paroxysmal dyskinesia

Publications

• 29933521

I don't know

A large family was reported in PMID 1597479 to have a KCNMA1 variant, a case was reported in PMID 27567911 with a homozygous loss of fuction variant with features including epilepsy, and additionally, a patient homozygous for a truncating mutation with paroxysmal dyskinesia, epilepsy, intellectual delay, and corticospinal-cerebellar tract atrophy was reported in PMID 29545233.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
?Cerebellar atrophy developmental delay and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia 3 with or without generalized epilepsy, 609446

I don't know

Comment on list classification: Updated rating of KCNMA1 from Amber to Green based on post-Webex reviews from Helen Lord, Allison Callaway and Konstantinos Varvagiannis.

Created: 7 Sep 2019, 10:05 a.m. | Last Modified: 7 Sep 2019, 10:05 a.m.

Panel Version: 1.266

Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex reviews from Helen Lord and Konstantinos Varvagiannis.

Created: 7 Sep 2019, 10:04 a.m. | Last Modified: 7 Sep 2019, 10:04 a.m.

Panel Version: 1.265

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

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: Alison Callaway and John Taylor. Suggested gene rating: Amber.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Comment on phenotypes: MIM:617643 has AR inheritance in OMIM. MIM:609446 has monoallelic inheritance in OMIM.

Created: 8 Jul 2019, 12:57 p.m. | Last Modified: 8 Jul 2019, 12:57 p.m.

Panel Version: 1.132

PMID:29545233. Yesil et al., 2018 report a patient with a novel homozygous truncating variant in KCNMA1 (p.Arg458Ter) presentint with paroxysmal dyskinesia, epileptic seizures, ID, and corticospinal–cerebellar tract atrophy.

Created: 8 Jul 2019, 12:54 p.m. | Last Modified: 8 Jul 2019, 12:54 p.m.

Panel Version: 1.130

PMID:15937479. Du et al., 2005 studied a large family with generalized epilepsy and paroxysmal dyskinesia (GEPD). 5/16 had seizures + paroxysmal dyskinesia (PNKD), and a further 4/16 had seizures only. c.1301A>G (Asp434Gly). They identified a heterozygous c.1301A>G (Asp434Gly) in KCNMA1 in the proband (IV-8) of the family and in all 13 affected individuals that were genotyped. The variant was absent in 5 unaffected individuals.

Created: 8 Jul 2019, 12:46 p.m. | Last Modified: 8 Jul 2019, 12:46 p.m.

Panel Version: 1.130

PMID:26195193. Zhang et al 2015 describe 2 unrelated children with early-onset PNKD and developmental delay carrying de novo mutations in KCNMA1. Seizures were not reported until age 2 and 7. Two de novo heterozygous missense mutations in KCNMA1 were identified in these cases: c.2650G>A (p.Glu884Lys) and c.3158A>G (p.Asn1053Ser).

Created: 8 Jul 2019, 12:34 p.m. | Last Modified: 8 Jul 2019, 12:34 p.m.

Panel Version: 1.130

PMID:27567911: Tabarki et al., 2016 report 2 siblings from a consanguineous family with epilepsy, DD and cerebellar atrophy. Both siblings had a homozygous frameshift duplication in KCNMA1: c.2026dupT; p. (Tyr676 Leufs*7). Segregation of the variant with the disease with recessive MOI was confirmed in all affected and unaffected family members, including heterozygosity in both parents. Seizures were myoclonic evolving to tonic and GTCS (Patient 1) and myoclonic (Patient 2).

Created: 8 Jul 2019, 12:31 p.m. | Last Modified: 8 Jul 2019, 12:31 p.m.

Panel Version: 1.130

Red List (low evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Please note additional family described in 27567911 with bi-allelic LoF variants in this gene, and cerebellar atrophy, ID and seizures (no paroxysmal dyskinesia), lending further support of the association between variants in this gene and epilepsy. 29545233 also described another family with bi-allelic LoF variants and complex neurological phenotype including seizures.

Created: 16 Aug 2018, 1:36 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 27567911
• 29545233

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

Comment on list classification: Associated with relevant phenotypes in OMIM and as possible Gen2Phen gene for paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy6 09446. At least 4 variants reported in unrelated cases, but only one of these had seizures.

Created: 21 Jun 2018, 10:34 a.m.

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Comment on list classification: Insufficient data

Created: 8 May 2016, 7 p.m.