KMT2B rare missense variants in generalized dystonia

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Abstract
Background: Recently a novel syndrome of childhood‐onset generalized dystonia originating from mutations in lysine‐specific methyltransferase 2B (KMT2B) has been reported.Methods: We sequenced the exomes of 4 generalized dystonia‐affected probands recruited from a Prague movement disorders center (Czech Republic). Bioinformatics analyses were conducted to select candidate causal variants in described dystonia‐mutated genes. After cosegregation testing, checklists from the American College of Medical Genetics and Genomics were adopted to judge variant pathogenicity.Results: Three novel, predicted protein‐damaging missense variants in KMT2B were identified (p.Glu1234Lys, p.Ala1541Val, p.Arg1779Gln). Meeting pathogenicity criteria, p.Glu1234Lys was absent from population‐based controls, situated in a key protein domain, and had occurred de novo. The associated phenotype comprised adolescence‐onset generalized isolated dystonia with prominent speech impairment. Although linked to a similar clinical expression, p.Ala1541Val and p.Arg1779Gln remained of uncertain significance.Conclusions: Rare missense variation in KMT2B represents an additional cause of generalized dystonia. Application of sequence interpretation standards is required before assigning pathogenicity to a KMT2B missense variant. © 2017 International Parkinson and Movement Disorder Society

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