KCNC1 – Progressive Myoclonic Epilepsy Type 7 (MEAK)

Progressive myoclonic epilepsy type 7 (PME7; MONDO:0014521) is characterized by childhood‐onset action myoclonus and generalized tonic‐clonic seizures with ataxia and mild cognitive impairment. KCNC1 (HGNC:6233) encodes the Kv3.1 voltage‐gated potassium channel subunit expressed in GABAergic interneurons. Heterozygous variants in KCNC1 underlie an autosomal dominant PME subtype named myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK) (KCNC1).

In an exome sequencing study of 84 unrelated PME patients, a recurrent de novo c.959G>A (p.Arg320His) variant was identified in 11 individuals (13%) with PME7 (PMID:25401298). Two additional affected individuals in a secondary cohort harbored the same variant (PMID:25401298). Familial MEAK was further confirmed in two brothers sharing c.959G>A (p.Arg320His) inherited from an asymptomatic mosaic mother, demonstrating parental mosaicism and recurrence risk (PMID:29428275).

The inheritance mode is autosomal dominant. Segregation analysis includes two affected siblings across one pedigree, confirming maternal somatic mosaic transmission (PMID:29428275). No biallelic or X-linked patterns have been observed for PME7 in KCNC1.

Variant spectrum in KCNC1-associated PME7 is dominated by the recurrent missense c.959G>A (p.Arg320His) in the voltage-sensing domain. Population databases show negligible allele frequency. Other KCNC1 variants cause related neurologic disorders but have not been linked to PME7.

Functional assays in Xenopus laevis oocytes showed that Kv3.1 p.Arg320His exerts a dominant-negative loss-of-function effect with slowed activation kinetics (PMID:25401298). Cortical interneurons expressing Kv3.1b R320H displayed impaired high-frequency firing, reduced excitability, and defective neurite development, indicating a developmental dendritopathy consistent with MEAK (PMID:33735526).

No conflicting studies dispute the KCNC1–PME7 association. The weight of evidence—recurrent de novo variants, familial segregation, and concordant functional data—supports a ClinGen "Strong" gene-disease validity for KCNC1 and PME7.

Key take-home: KCNC1 c.959G>A (p.Arg320His) is a validated diagnostic marker for autosomal dominant PME7 and should be included in genetic testing panels to guide clinical management.

References

• Nature genetics • 2015 • A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. PMID:25401298
• Brain & development • 2018 • Familial cases of progressive myoclonic epilepsy caused by maternal somatic mosaicism of a recurrent KCNC1 p.Arg320His mutation. PMID:29428275
• Epilepsia • 2021 • Progressive myoclonus epilepsy KCNC1 variant causes a developmental dendritopathy. PMID:33735526

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