Abstract
Dominant gain-of-function mutations of the KCNMA1 gene, encoding the pore-forming subunit of the large conductance voltage- and Ca2+-activated K+ channel, have been described in a few patients with the syndrome of epilepsy, paroxysmal dyskinesias and developmental delay. In this report, we describe the loss-of-function phenotype of this newly described disease gene. In two siblings from a consanguineous family with epilepsy, developmental delay and severe cerebellar atrophy, combined exome/autozygome analysis identified a homozygous frameshift duplication in KCNMA1 (c.2026dupT; p. (Tyr676 Leufs*7)) in both children. Our report defines a novel autosomal recessive KCNMA1-related epileptic phenotype that encompasses cerebellar atrophy without paroxysmal dyskinesia, and highlights the sensitivity of the developing brain to both increased and decreased activity of the KCNMA1-encoded channels.
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Acknowledgments
We thank the study family for their enthusiastic participation. This work was supported by KACST Grant 13-BIO1113-20 (FSA).
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Written informed consent was obtained from the patient for publication of this paper and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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The authors declare that they have no competing interests.
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B. Tabarki and R. Shaheen have contributed equally.
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Tabarki, B., AlMajhad, N., AlHashem, A. et al. Homozygous KCNMA1 mutation as a cause of cerebellar atrophy, developmental delay and seizures. Hum Genet 135, 1295–1298 (2016). https://doi.org/10.1007/s00439-016-1726-y
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DOI: https://doi.org/10.1007/s00439-016-1726-y