KCNMA1 – Liang-Wang syndrome

Liang-Wang syndrome is a recently defined multiple malformation syndrome characterized by global developmental delay, intellectual disability, ataxia and paroxysmal dyskinesia. Loss-of-function variants in the pore-forming BK channel α-subunit gene KCNMA1 have been implicated in this syndrome, which exhibits a broad neurodevelopmental and neurological phenotype including connective tissue and cardiac malformations (PMID:35156297).

Genetic studies identified two unrelated probands with de novo KCNMA1 missense variants p.Ala172Thr and p.Ala314Thr detected by exome sequencing; both variants were absent from parental genomes and arose spontaneously in affected individuals (PMID:35156297). The clinical presentation in these probands included developmental delay, cognitive impairment, mild ataxia and, in one case, generalized epilepsy. No additional multiplex families have been reported, and no further affected relatives were identified.

Functional assays of these two variants using heterologous expression and patch-clamp electrophysiology demonstrated complete abolition (p.Ala172Thr) or marked suppression (p.Ala314Thr) of BK channel currents. Both variants shifted conductance-voltage relationships toward more positive potentials and disrupted Mg²⁺-dependent gating when coexpressed with wild-type channels. Western blot analysis further revealed reduced total and membrane expression of BK channel protein, indicating a loss-of-function mechanism (PMID:35156297).

In addition, two patients harboring previously reported gain-of-function variants p.Asn536His and p.Asn995Ser also exhibited overlapping features of cognitive impairment and dysmorphic presentations, expanding the phenotypic spectrum and underscoring convergent developmental manifestations across KCNMA1 allele classes (PMID:35156297).

Taken together, the consistent de novo occurrence of LOF variants, the concordant electrophysiological and expression data, and phenotypic overlap in both LOF and GOF carriers fulfill moderate ClinGen criteria for gene–disease validity. These findings delineate a haploinsufficiency mechanism in KCNMA1 and establish a new neurodevelopmental syndrome with broad clinical utility.

Key take-home: Screening for KCNMA1 variants should be considered in patients with developmental delay, ataxia and paroxysmal dyskinesia, as functional data directly support a loss-of-function mechanism amenable to targeted channel-modulating therapies.

References

• Acta physiologica (Oxford, England) • 2022 • Identification and functional analysis of two new de novo KCNMA1 variants associated with Liang-Wang syndrome. PMID:35156297

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