KMT2B – Childhood-onset Dystonia 28

Heterozygous variants in KMT2B, encoding a histone H3K4 methyltransferase, cause Dystonia 28, childhood-onset (Disease Name), an autosomal dominant movement disorder presenting before age 10 with limb-onset dystonia that generalizes in a caudo-cranial pattern and involves prominent oromandibular, laryngeal, and cervical muscles ([PMID:31768667]).

Genetic evidence includes ~149 unrelated probands harboring 66 frameshift, 17 nonsense, 7 splice-site, and >60 missense KMT2B variants across multiple cohorts: 76 patients ([PMID:31768667]), 20 Chinese patients ([PMID:32634684]), and 53 in a deep brain stimulation study ([PMID:39990802]). De novo events account for >60% of cases, and segregation of c.4960T>C (p.Cys1654Arg) in a multigenerational family (proband, mother, two cousins) provides additional support (3 affected relatives) ([PMID:32546208]).

A representative pathogenic allele is c.4960T>C (p.Cys1654Arg), detected in the SET domain of KMT2B and segregating with disease in four family members ([PMID:32546208]). The full variant spectrum underscores haploinsufficiency as the underlying mechanism.

Functional studies demonstrate that KMT2B haploinsufficiency leads to a distinctive genome-wide promoter hypermethylation signature in 18 patients (episignature) ([PMID:34380541]), and EPIC methylation assays reclassified p.Tyr2515Cys as pathogenic while ruling out p.Leu1720Phe ([PMID:39587624]). Clinically, deep brain stimulation yields sustained motor improvement in >90% of treated patients ([PMID:31768667], [PMID:39990802]).

The phenotypic spectrum extends beyond motor features to include developmental delay, short stature, microcephaly, and failure to thrive due to orolingual dysfunction ([PMID:32546208]). Adult-onset presentations with dystonic tremor have also been reported ([PMID:35022352]). No studies have refuted the association.

Integrated genetic and experimental evidence meets ClinGen criteria for a Definitive gene-disease relationship. Precise molecular diagnosis of KMT2B variants enables accurate counseling and guides deep brain stimulation to improve outcomes in childhood-onset dystonia.

References

• Current neurology and neuroscience reports • 2019 • Update on KMT2B-Related Dystonia. PMID:31768667
• Parkinsonism & related disorders • 2020 • Clinical phenotypes, genotypes and treatment in Chinese dystonia patients with KMT2B variants. PMID:32634684
• ArXiv • 2025 • KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. PMID:39990802
• BMC neurology • 2020 • Failure to thrive – an overlooked manifestation of KMT2B-related dystonia: a case presentation. PMID:32546208
• Clinical epigenetics • 2021 • Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile. PMID:34380541
• Clinical epigenetics • 2024 • Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool. PMID:39587624
• Internal medicine (Tokyo, Japan) • 2022 • Dystonic Tremor in Adult-onset DYT-KMT2B. PMID:35022352

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