KMT2B rare missense variants in generalized dystonia

Area of Science:

• Genetics and Genomics
• Neuroscience
• Molecular Biology

Background:

• A novel syndrome of childhood-onset generalized dystonia has been linked to mutations in lysine-specific methyltransferase 2B (KMT2B).
• Understanding the genetic underpinnings of dystonia is crucial for diagnosis and potential therapeutic strategies.

Purpose of the Study:

• To investigate novel genetic variants in KMT2B associated with generalized dystonia.
• To identify and characterize potential causal mutations in KMT2B for generalized dystonia.

Main Methods:

• Whole-exome sequencing was performed on four generalized dystonia probands.
• Bioinformatics analysis identified candidate causal variants in known dystonia-related genes.
• Cosegregation testing and American College of Medical Genetics and Genomics criteria were used to assess variant pathogenicity.

Main Results:

• Three novel, predicted protein-damaging missense variants in KMT2B (p.Glu1234Lys, p.Ala1541Val, p.Arg1779Gln) were identified.
• The de novo variant p.Glu1234Lys met pathogenicity criteria, was absent in controls, and located in a key protein domain.
• The phenotype associated with p.Glu1234Lys included adolescence-onset generalized isolated dystonia with significant speech impairment.

Conclusions:

• Rare missense variation in KMT2B is an additional genetic cause of generalized dystonia.
• Rigorous application of sequence interpretation standards is necessary to confirm the pathogenicity of KMT2B missense variants.