Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders.

Introduction: Variable expressivity is an emerging characteristic of KMT2B-related dystonia. However, it remains poorly understood whether variants reoccurring at specific sites of lysine-specific methlytransferase-2B (KMT2B) can drive intra- and interfamilial clinical heterogeneity. Our goal was to ascertain independent families with variants affecting residue Arg2565 of KMT2B.

Big data and transformative bioinformatics in genomic diagnostics and beyond.

The current era of high-throughput analysis-driven research offers invaluable insights into disease etiologies, accurate diagnostics, pathogenesis, and personalized therapy. In the field of movement disorders, investigators are facing an increasing growth in the volume of produced patient-derived datasets, providing substantial opportunities for precision medicine approaches based on extensive information accessibility and advanced annotation practices. Integrating data from multiple sources, including phenomics, genomics, and multi-omics, is crucial for comprehensively understanding different types of movement disorders.

ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures.

Purpose: ATP2B2 encodes the variant-constrained plasma-membrane calcium-transporting ATPase-2, expressed in sensory ear cells and specialized neurons. ATP2B2/Atp2b2 variants were previously linked to isolated hearing loss in patients and neurodevelopmental deficits with ataxia in mice. We aimed to establish the association between ATP2B2 and human neurological disorders.

Dystonia genes and their biological pathways.

High-throughput sequencing has been instrumental in uncovering the spectrum of pathogenic genetic alterations that contribute to the etiology of dystonia. Despite the immense heterogeneity in monogenic causes, studies performed during the past few years have highlighted that many rare deleterious variants associated with dystonic presentations affect genes that have roles in certain conserved pathways in neural physiology. These various gene mutations that appear to converge towards the disruption of interconnected cellular networks were shown to produce a wide range of different dystonic disease phenotypes, including isolated and combined dystonias as well as numerous clinically complex, often neurodevelopmental disorder-related conditions that can manifest with dystonic features in the context of multisystem disturbances.

De novo retinoic acid receptor beta (RARB) variant associated with microphthalmia and dystonia.

Background: Definition of the individual genotypes that cause a Mendelian phenotype is of great importance both to clinical diagnostics and disease characterization. Heterozygous de novo gain-of-function missense variants in RARB are associated with syndromic microphthalmia 12 (MCOPS12), a developmental disorder characterized by eye malformations and variable involvement of other organs. A subset of patients were described with poorly delineated movement disorders.

Genetic intersection between dystonia and neurodevelopmental disorders: Insights from genomic sequencing.

Animal and human brain-imaging studies have suggested a role for neurodevelopmental abnormalities in the pathophysiology of dystonia. Variants in neurodevelopmental genes have also been sporadically implicated, although no systematic investigation has been undertaken before the more widespread availability of genome-wide sequencing techniques. Here, we review findings from recent whole-exome and whole-genome sequencing approaches in individuals with dystonic conditions, indicating that more than 50% of molecularly diagnosed cases may have variants in neurodevelopmental disorder-associated genes.

AOPEP variants as a novel cause of recessive dystonia: Generalized dystonia and dystonia-parkinsonism.

Introduction: The genetic basis of autosomal-recessive dystonia remains poorly understood. Our objective was to report identification of additional individuals with variants in AOPEP, a recently described gene for recessively inherited dystonic disorders (OMIM:619565).

Methods: Ongoing analysis on a high-throughput genetic platform and international case-recruitment efforts were undertaken.

Dystonia as a prominent presenting feature in developmental and epileptic encephalopathies: A case series.

Introduction: Although there has been increasing recognition of the occurrence of non-epileptic involuntary movements in developmental and epileptic encephalopathies (DEEs), the spectrum of dystonic presentations associated with these conditions remains poorly described. We sought to expand the catalogue of dystonia-predominant phenotypes in monogenic DEEs, building on the recently introduced concept of an epilepsy-movement disorder spectrum.

Methods: Cases were identified from a whole-exome-sequenced cohort of 45 pediatric index patients with complex dystonia (67% sequenced as parent-child trios).

Clinically relevant copy-number variants in exome sequencing data of patients with dystonia.

Introduction: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia.

Methods: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement).

Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia.

Introduction: The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation.