Large-Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Genetic variants in several genes are linked to dystonia.
• The full spectrum and frequency of these variants, especially in co-occurring movement disorders like Parkinson's disease (PD), remain unclear.

Purpose of the Study:

• To screen over 2000 patients with dystonia or PD for rare variants in known dystonia-associated genes.
• To elucidate the genetic landscape of dystonia and its overlap with PD.

Main Methods:

• Next-generation sequencing gene panel used to screen 1207 dystonia patients and 1036 PD patients.
• DNA methylation impact of KMT2B variants analyzed via episignature.

Main Results:

• 171 carriers of 131 rare variants identified (109 dystonia, 62 PD).
• 52 patients (48 dystonia, 4 PD) carried 33 likely pathogenic variants, 17 novel.
• KMT2B variant analysis confirmed pathogenicity for only two variants via episignature.

Conclusions:

• Pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A are confirmed causes of dystonia, expanding the known genetic spectrum.
• Likely pathogenic GCH1 variants were also identified in PD patients.
• Episignature analysis proved effective for assessing the functional impact of new DYT-KMT2B variants.