GAA-FGF14 Expansions and CACNA1A Variants: Phenotypic Overlap and Diagnostic Implications.

Background: An intronic (GAA)•(TTC) repeat expansion in FGF14 was recently identified as the cause of spinocerebellar ataxia 27B (SCA27B), a disorder presenting with both chronic cerebellar ataxia and episodic symptoms. The phenotype of SCA27B overlaps with that of CACNA1A spectrum disorders.

Objective: The objective of this work was to investigate the prevalence of GAA-FGF14 repeat expansions in patients with ataxia so far considered to be related to underlying CACNA1A variants.

Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.

Defects in mitochondrial dynamics are a common cause of Charcot-Marie-Tooth disease (CMT), while primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this etiology. This study aims to report COX18 as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV (CIV) that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane.

Next-generation sequencing for pediatric-onset neuromuscular disorders unresolved by conventional diagnostic methods.

Background: Neuromuscular disorders (NMDs), rare diseases affecting the peripheral nervous system, often cause progressive weakness and systemic complications. Despite advances in genetic diagnostics, data from Southeast Asia remain limited. Ancestral variation may influence mutation spectra, revealing novel alleles and phenotypic diversity.

Charcot-Marie-Tooth disease type 1E: clinical natural history and molecular impact of PMP22 variants.

Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare, autosomal dominant peripheral neuropathy caused by missense variants, deletions, and truncations within the peripheral myelin protein-22 (PMP22) gene. CMT1E phenotypes vary depending on the specific variant, ranging from mild to severe, and there is little natural history and phenotypic progression data on individuals with CMT1E. Patients with CMT1E were evaluated during initial and follow-up visits at sites within the Inherited Neuropathy Consortium.

Diagnostic yield and limitations of whole-genome sequencing for hereditary cerebellar ataxia.

Less than half of the individuals with hereditary cerebellar ataxia receives a genetic diagnosis. Repeat expansions account for disproportionate number of hereditary cerebellar ataxia and have genetically heterogeneous causes. These genetic loci include , , , , , , , , , and This study aims to assess the yield of short-read whole genome sequencing in the molecular diagnosis of hereditary cerebellar ataxia.

A genome-wide approach for the discovery of novel repeat expansion disorders in the Undiagnosed Diseases Network cohort.

Purpose: The Undiagnosed Diseases Network is a National Institutes of Health funded research study that aims to solve a broad clinical spectrum of challenging rare disease cases. Participants receive care from multiple clinical specialists, who collaborate to perform deep phenotyping and state-of-the-art multiomics analyses. As bioinformatics of short-read sequencing has matured, the discovery of repeat expansion disorders (REDs) is accelerating.

Charcot-Marie-Tooth disease type 1E: Clinical Natural History and Molecular Impact of Variants.

Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare, autosomal dominant peripheral neuropathy caused by missense variants, deletions, and truncations within the () gene. CMT1E phenotypes vary depending on the specific variant, ranging from mild to severe, and there is little natural history and phenotypic progression data on individuals with CMT1E. Patients with CMT1E were evaluated during initial and follow-up visits at sites within the Inherited Neuropathy Consortium.

Biallelic variants in the RFC4 gene cause a rapidly progressive congenital myopathy with severe hypotonia and axial weakness.

The RFC4 gene has recently been linked to a multisystemic disorder Morimoto-Ryu-Malicdan neuromuscular syndrome, with myopathy being one of the key symptoms described in nine patients. We report the case of two brothers with a rapidly progressive congenital myopathy characterized by severe hypotonia and axial muscle weakness associated with previously unpublished biallelic variants in the RFC4 gene. Whole exome sequencing revealed biallelic variants NM_002916.

Genetic ancestry and population structure in the All of Us Research Program cohort.

We analyzed participant genomic variant data to characterize population structure and genetic ancestry for the All of Us cohort (n = 297,549). There is substantial population structure in the cohort, with clusters of closely related participants interspersed among less related individuals. Participants show diverse genetic ancestry, with major contributions from European (66.

The genetic landscape of sporadic adult-onset degenerative ataxia: a multi-modal genetic study of 377 consecutive patients from the longitudinal multi-centre SPORTAX cohort.

Background: While most sporadic adult-onset neurodegenerative diseases have only a minor monogenic component, given several recently identified late adult-onset ataxia genes, the genetic burden may be substantial in sporadic adult-onset ataxias. We report systematic mapping of the genetic landscape of sporadic adult-onset ataxia in a well-characterised, multi-centre cohort, combining several multi-modal genetic screening techniques, plus longitudinal natural history data.

Methods: Systematic clinico-genetic analysis of a prospective longitudinal multi-centre cohort of 377 consecutive patients with sporadic adult-onset ataxia (SPORTAX cohort), including clinically defined sporadic adult-onset ataxia of unknown aetiology (SAOA) (n = 229) and 'clinically probable multiple system atrophy of cerebellar type' (MSA-C) (n = 148).

Intronic FGF14 GAA repeat expansions impact progression and survival in multiple system atrophy.

Partial phenotypic overlap has been suggested between multiple system atrophy and spinocerebellar ataxia 27B, the autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. In this study, we investigated the frequency of FGF14 GAA•TTC repeat expansion in clinically diagnosed and pathologically confirmed multiple system atrophy cases. We screened 657 multiple system atrophy cases (193 clinically diagnosed and 464 pathologically confirmed) and 1003 controls.

The continued promise of genomic technologies and software in neurogenetics.

The continued evolution of genomic technologies over the past few decades has revolutionized the field of neurogenetics, offering profound insights into the genetic underpinnings of neurological disorders. Identification of causal genes for numerous monogenic neurological conditions has informed key aspects of disease mechanisms and facilitated research into critical proteins and molecular pathways, laying the groundwork for therapeutic interventions. However, the question remains: has this transformative trend reached its zenith? In this review, we suggest that despite significant strides in genome sequencing and advanced computational analyses, there is still ample room for methodological refinement.

Heterozygous RAB3A variants cause cerebellar ataxia by a partial loss-of-function mechanism.

RAB3A encodes a small GTP-binding protein that is abundant in brain synaptic vesicles and crucial for the release of neurotransmitters and synaptic plasticity. Here, we identified RAB3A as a candidate gene for autosomal dominant cerebellar ataxia by two independent approaches: linkage in a large dominant ataxia family and, in parallel, an untargeted computational genetic association approach, analysing the 100 000 Genomes Project datasets. To validate the role of RAB3A in ataxia, we next screened large rare disease databases for rare heterozygous RAB3A variants in probands with ataxia features.

Integration of transcriptomics and long-read genomics prioritizes structural variants in rare disease.

Rare structural variants (SVs)-insertions, deletions, and complex rearrangements-can cause Mendelian disease, yet they remain difficult to accurately detect and interpret. We sequenced and analyzed Oxford Nanopore Technologies long-read genomes of 68 individuals from the undiagnosed disease network (UDN) with no previously identified diagnostic mutations from short-read sequencing. Using our optimized SV detection pipelines and 571 control long-read genomes, we detected 716 long-read rare (MAF < 0.

Late-onset vestibulocerebellar ataxia: clinical and genetic studies in a long follow-up series of 50 patients.

Background: To describe the epidemiology, clinical features, degree of disability and genetic characteristics of a cohort of patients with a vestibulo-cerebellar ataxia of very late onset (LOVCA).

Methods: We analysed the clinical, radiological, and genetic characteristics of a cohort of 50 patients with LOVCA. Where possible, patients were followed over the full course of the disease, including clinical, and molecular genetic analysis of genes known to cause episodic ataxia.

Heterozygous loss-of-function variants in SPTAN1 cause an early childhood onset distal myopathy.

Purpose: Heterozygous pathogenic variants in SPTAN1 cause a diverse spectrum of neurogenetic disorders ranging from peripheral and central nervous system involvement to complex syndromic presentations. We set out to investigate the role of SPTAN1 in genetically unsolved hereditary myopathies.

Methods: Through international collaboration we identified 14 families with distal weakness and heterozygous SPTAN1 loss-of-function variants.

The Spastic Paraplegia-Centers of Excellence Research Network (SP-CERN): Clinical Trial Readiness for Hereditary Spastic Paraplegia.

Objectives: The primary objective of this paper was to present the establishment of the Spastic Paraplegia-Centers of Excellence Research Network (SP-CERN) aimed at promoting clinical trial readiness for hereditary spastic paraplegia (HSP). SP-CERN is unique in its approach to addressing the diagnostic and therapeutic challenges associated with HSP through a large-scale, collaborative effort.

Methods: Participants with HSP are identified through multicenter collaborations across 11 institutions in the United States.

Involvement of the Superior Cerebellar Peduncles in GAA- Ataxia.

Objectives: GAA- ataxia (SCA27B) is a recently reported late-onset ataxia caused by a GAA repeat expansion in intron 1 of the gene. After the clinical observation of superior cerebellar peduncle (SCP) involvement in some affected patients, we sought to verify the prevalence of this finding in our cohort and 4 additional independent cohorts of patients with SCA27B.

Methods: We performed a retrospective review of the brain MRI scans of a total of 87 patients (median age at MRI 69 years; range 28-88 years) from different independent cohorts to assess the presence of SCP involvement, defined as abnormally high T2 signal along the SCP tract.

Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD.

Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause the most common recessive type of Charcot-Marie-Tooth disease (CMT), CMT-SORD. However, the full genotype-phenotype spectrum and progression of the disease remain to be defined. Notably, a multicenter phase 2/3 study to test the efficacy of govorestat (NCT05397665), a new aldose reductase inhibitor, is currently ongoing.

Detailed tandem repeat allele profiling in 1,027 long-read genomes reveals genome-wide patterns of pathogenicity.

Tandem repeats are a highly polymorphic class of genomic variation that play causal roles in rare diseases but are notoriously difficult to sequence using short-read techniques. Most previous studies profiling tandem repeats genome-wide have reduced the description of each locus to the singular value of the length of the entire repetitive locus. Here we introduce a comprehensive database of 3.

Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions.

Purpose Of Review: Autosomal dominant cerebellar ataxias, also known as spinocerebellar ataxias (SCAs), are genetically and clinically diverse neurodegenerative disorders characterized by progressive cerebellar dysfunction. Despite advances in sequencing technologies, a large proportion of patients with SCA still lack a definitive genetic diagnosis. The advent of advanced bioinformatic tools and emerging genomics technologies, such as long-read sequencing, offers an unparalleled opportunity to close the diagnostic gap for hereditary ataxias.

The GAA repeat expansion is a major cause of ataxia in the Cypriot population.

Dominantly inherited intronic GAA repeat expansions in the fibroblast growth factor 14 gene have recently been shown to cause spinocerebellar ataxia 27B. Currently, the pathogenic threshold of (GAA) repeat units is considered highly penetrant, while (GAA) is likely pathogenic with reduced penetrance. This study investigated the frequency of the GAA repeat expansion and the phenotypic profile in a Cypriot cohort with unresolved late-onset cerebellar ataxia.