Adult-onset KMT2B-related dystonia

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• KMT2B-related dystonia (DYT-KMT2B or DYT28) is an autosomal dominant disorder typically presenting before age 10 with generalized dystonia, developmental delay, intellectual disability, and short stature.
• The genetic basis and phenotypic spectrum of KMT2B-related disorders are not fully elucidated, particularly concerning adult-onset presentations.

Purpose of the Study:

• To investigate the clinical and genetic findings in individuals with adult-onset neurological conditions carrying rare heterozygous KMT2B variants.
• To explore the role of KMT2B variants in adult-onset dystonia, hearing loss, and intellectual disability.

Main Methods:

• Clinical and genetic analysis of twelve cases from five unrelated families with rare heterozygous KMT2B missense variants.
• Genome-wide DNA methylation profiling to differentiate adult-onset dystonia cases from controls and early-onset DYT-KMT2B patients.

Main Results:

• Four rare KMT2B missense variants were identified in twelve affected individuals.
• Seven subjects presented with adult-onset focal or segmental dystonia, three with progressive hearing loss, and one with intellectual disability and short stature.
• DNA methylation profiling distinguished adult-onset dystonia cases from controls and early-onset DYT-KMT2B patients.

Conclusions:

• Heterozygous KMT2B variants are implicated as a potential genetic cause of adult-onset dystonia.
• The study expands the phenotypic spectrum of KMT2B-related disorders to include adult-onset dystonia and isolated hearing loss.
• Further investigation of KMT2B carriers is warranted to characterize non-dystonic features.