Intellectual disability - microarray and sequencing
Gene: KCNMA1The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)Created: 23 Dec 2020, 2:46 p.m. | Last Modified: 23 Dec 2020, 2:46 p.m.
Panel Version: 3.679
Multiple individuals reported with either mono- or biallelic variants. Developmental delay and intellectual disability of relevant severity has been reported in a sufficient number of cases for inclusion on this panel. Although in most cases the phenotypes are primarily characterised by seizures or dyskinesia, it is plausible that these individuals may still be tested under the ID panel in context of the severe intellectual impairment that may be observed.
Furthermore, several individuals have been reported with severe GDD/ID and other variable feature such as craniofacial dysmorphism, ataxia, bone dysplasia, visceral malformations, and brain imaging anomalies, but without epilepsy or paroxysmal dyskinesia (namely Liang-Wang syndrome, PMID: 31152168). In less severely affected cases DD with significant speech delay has been noted as the main clinical indication of the presenting phenotypes, further indicating benefit of inclusion on a diagnostic ID panel.Created: 23 Dec 2020, 2:44 p.m. | Last Modified: 23 Dec 2020, 2:52 p.m.
Panel Version: 3.681
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886; {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596; Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827
Publications
Multiple individuals with KCNMA1-related channelopathy described, both mono allelic and bi-allelic disease reported; a variety of neurologic symptoms, including ID; some variants are LoF and some are gain of function, some correlation between mechanism of pathogenicity and phenotype. Overall, there are sufficiently large number of individuals with ID to merit inclusion of this gene as Green on the ID panel.Created: 8 Feb 2020, 9:30 a.m. | Last Modified: 8 Feb 2020, 9:30 a.m.
Panel Version: 3.0
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Cerebellar atrophy, developmental delay, and seizures, MIM# 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM#609446
Publications
Mode of pathogenicity
Other
KCNMA1 implicated in a broad spectrum of patient phenotypes, principally characterised by seizures and movement disorders. Bailey et al (PMID: 31427379) summarised all 37 reported subjects from 16 families with variants in KCNMA1. Developmental delay reported in 21/37 individuals and intellectual disability in 12/37, with various severity reported although some cases had no information on severity or if DD/ID was present.
As pedigree and penetrance information is limited, upgrading KCNMA1 from Red to Amber.Created: 30 Sep 2019, 10:34 a.m. | Last Modified: 30 Sep 2019, 10:34 a.m.
Panel Version: 2.1047
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Cerebellar atrophy, developmental delay, and seizures, 617643
Publications
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, 7:32 p.m. | Last Modified: 25 Aug 2019, 7:32 p.m.
Panel Version: 2.1015
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications
Variants in this GENE are reported as part of current diagnostic practice
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
GENERALIZED EPILEPSY AND PAROXYSMAL DYSKINESIA
Publications
There are some animal models linking variants in this gene to cerebral phentoypes, as well as some stronger evidence supporting a link with variants and seizures, epilepsy and autism. However, there is insufficient evidence to say with any weight that mutations in this gene are linked to Intellectual disability.Created: 31 Oct 2017, 10:36 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Tag for-review was removed from gene: KCNMA1.
Source Expert Review Green was added to KCNMA1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Phenotypes for gene: KCNMA1 were changed from Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886; {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596; Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827
Publications for gene: KCNMA1 were set to 15937479; 31427379; 31152168; 27567911; 29545233; 26195193
Gene: kcnma1 has been classified as Amber List (Moderate Evidence).
Tag for-review tag was added to gene: KCNMA1.
Publications for gene: KCNMA1 were set to 15937479; 31427379; 31152168; 27567911
Phenotypes for gene: KCNMA1 were changed from GENERALIZED EPILEPSY AND PAROXYSMAL DYSKINESIA to Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446
Publications for gene: KCNMA1 were set to 15937479
Mode of inheritance for gene: KCNMA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Gene: kcnma1 has been classified as Amber List (Moderate Evidence).
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Model of inheritance for gene KCNMA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
KCNMA1 was added to Intellectual disabilitypanel. Sources: Expert Review Red
KCNMA1 was created by ellenmcdonagh