Novel heterozygous mutation in KMT2B causing an unusual phenotypic presentation: a comprehensive clinical and...

KMT2B-related dystonia is a childhood-onset movement disorder. This study investigated a novel KMT2B gene variant using whole exome sequencing (WES) and bioinformatics analysis, and expanded the known clinical spectrum of KMT2B-related dystonia by characterizing an atypical dystonic pattern.

A pediatric neurologist performed a comprehensive clinical evaluation of a 13-year-old girl who presented with left leg and right-hand spasms (cross-dystonia), which resulted in gait and writing difficulties over the past two years. The evaluation was complemented by brain magnetic resonance imaging and detailed neuro-metabolic testing. Genomic DNA underwent WES, and the newly identified variant was validated through Sanger sequencing, followed by trio analysis in the family. Various in silico prediction tools were used to assess the mutation's pathogenicity. Bioinformatics tools, including SMART, PROSITE, CDD, COACH, and COFACTOR, -were employed to provide a thorough analysis of the structural and functional characteristics associated with this mutation.

Molecular investigations through WES analysis revealed a novel pathogenic variant: a heterozygous G→T nonsense mutation at position 1363 in exon 3 of the KMT2B gene (NM_014727.3) (c.1363G > T), predicting pathogenic amino acid change to a premature stop codon (NP_055542: p.E455X). Bioinformatic analysis using the SEG program showed that the mutation was located in a low compositional complexity region spanning residues 392-463. Predictions from SVM, neural networks, and sequence information indicated both the changes in energy values and sign of energy change, showing decreased stability in the mutated protein structure.

This newly identified KMT2B mutation with an unusual clinical phenotype highlighted its regulatory role and underscored the connection between protein structure, function, and disease manifestation.