De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes.

Fiche publication

Date publication

juin 2019


Human molecular genetics


Membres identifiés du Cancéropôle Est :
Pr FAIVRE Laurence, Dr NAMBOT Sophie

Tous les auteurs :
Liang L, Li X, Moutton S, Schrier Vergano SA, Cogné B, de Saint-Martin A, Hurst ACE, Hu Y, Bodamer O, Thevenon J, Hung CY, Isidor B, Gerard B, Rega A, Nambot S, Lehalle D, Duffourd Y, Thauvin-Robinet C, Faivre L, Bézieau S, Dure LS, Helbling DC, Bick D, Xu C, Chen Q, Mancini GMS, Vitobello A, Wang QK


KCNMA1 encodes the BK potassium channel α-subunit and pathogenic gain-of-function variants in this gene have been associated with a dominant form of generalized epilepsy and paroxysmal dyskinesia. Here, we genetically and functionally characterize 8 novel loss-of-function (LoF) variants of KCNMA1. Genome or exome sequencing and the participation in the International Matchmaker Exchange effort allowed for the identification of novel KCNMA1 variants. Patch-clamping was used to assess functionality of mutant BK channels. The KCNMA1 variants p.(Ser351Tyr), p.(Gly356Arg), p.(Gly375Arg), p.(Asn449fs), and p.(Ile663Val) abolished the BK current, whereas p.(Cys413Tyr) and p.(Pro805Leu) reduced the BK current amplitude and shifted the activation curves towards positive potentials. The p.(Asp984Asn) variant reduced the current amplitude without affecting kinetics. Phenotypic analysis of the patients carrying the recurrent p.(Gly375Arg) de novo missense LoF variant revealed a novel syndromic neurodevelopmental disorder associated with severe developmental delay, visceral and cardiac malformations, connective tissue presentations with arterial involvement, bone dysplasia and characteristic dysmorphic features. Patients with other LoF variants presented with neurological and developmental symptoms including developmental delay, intellectual disability, ataxia, axial hypotonia, cerebral atrophy, and speech delay/apraxia/dysarthria. Therefore, LoF KCNMA1 variants are associated with a new syndrome characterized by a broad spectrum of neurological phenotypes and developmental disorders. LoF variants of KCNMA1 cause a new syndrome distinctly different from gain-of-function variants in the same gene.


Hum. Mol. Genet.. 2019 Jun 1;: