Aug 2026· Journal of the peripheral nervous system· Vol 31· 0 citations· 4 references
Medicine
TL;DR
There is moderate evidence that the two identified HARS1 variants are responsible for the recessive phenotype, suggesting that the allelic and clinical heterogeneity of HARS1‐related disease is expanded.
Abstract
ABSTRACT Background and Aims The HARS1 gene encodes cytoplasmic histidyl‐tRNA synthetase, which catalyzes the ligation of histidine to tRNAHIS in the cytoplasm as an early step in protein biosynthesis and is essential for cell viability. Pathogenic variants in HARS1 have been associated with three phenotypes: autosomal dominant Charcot–Marie–Tooth (CMT) disease, a multisystem recessive syndrome with prominent ataxia, and autosomal recessive Usher syndrome. Here, we present a patient who is compound heterozygous for HARS1 variants and who has a complex recessive phenotype that includes a neuropathy with demyelinating features and active denervation. Our computational and functional analyses support the pathogenicity of these alleles, suggesting that our findings expand the allelic and clinical heterogeneity of HARS1‐related disease. Methods The individual found to have pathogenic compound heterozygous HARS1 variants was evaluated in a neuromuscular clinic and was further investigated in research studies. Functional consequences of the HARS1 variants were tested in yeast complementation assays; the phase of these alleles was confirmed via long‐range PCR and long‐read sequencing on DNA isolated from the proband, the mother, and the father. Results A 25‐year‐old male with CMT1 and mild intellectual disability had a maternally inherited variant (p.Q410*) and a de novo variant in the HARS1 gene (p.R375C) identified via trio exome sequencing. Studies in yeast revealed ablated function for p.Q410* and reduced function for p.R375C. Of 2480 informative sequencing reads generated from the proband: (a) 1765 (71%) included only p.R375C or only p.Q410*; (b) 237 (10%) included both alleles; and (c) 478 (19%) included neither allele. Interpretation Studies in yeast revealed loss‐of‐function characteristics for both p.Q410* and p.R375C HARS1, consistent with these variants being pathogenic. Allele‐specific sequencing analyses are consistent with the proband having a compound heterozygous genotype and with p.R375C being a de novo variant that arose on the chromosome 5 transmitted by the father. There is therefore moderate evidence that the two identified HARS1 variants are responsible for the recessive phenotype. This case report expands the allelic and phenotypic heterogeneity of biallelic HARS1 pathogenic variants.
BACKGROUND
Pathogenic missense variants in the MORC2 gene are associated with two distinct disorders: Charcot-Marie-Tooth disease type 2Z (CMT2Z) and the recently described DIGFAN (developmental delay, impaired growth, dysmorphic facies and axonal neuropathy) phenotype, which encompasses a broad range of clinical manifestations that vary significantly between individuals.
METHODS
Clinical and imaging data from 16 patients were collected. Western blot analysis was performed on 10 identified variants in affected patients as well as on two novel variants without clinical data. Those missense variants were introduced into the wild-type vector transfected into HEK293T cells, and western blot analysis was performed to assess protein expression level.
RESULTS
A total of 11 different missense variants in the MORC2 gene were identified in our cohort, including four novel variants. We demonstrate that early-onset MORC2-associated disorders segregate into two principal neurological phenotypes: a predominantly neuromuscular form and a central nervous system-predominant form. The p.Ser87Leu variant, which defines the neuromuscular cluster, was uniquely characterised by a significant reduction in MORC2 protein levels, distinguishing it mechanistically from other variants. Overall, western blot analysis revealed no statistically significant difference in protein expression levels between variants related to CMT2Z and DIGFAN cases.
CONCLUSION
A comparison of our patients with previously reported cases revealed an intriguing trend suggesting a probable dependence of the leading clinical features on specific variants in the MORC2 gene. Further accumulation of patient data is required to determine whether this observation correlates with other specific variants.
A. Murtazina, Eugenii Tatarsky, I. Viakhireva et al.· Journal of Medical Genetics· 0 citations
Introduction Wilson disease is an autosomal recessive monogenic disorder caused by mutations in the copper-transporting P-type ATPase beta gene (ATP7B) located on human chromosome 13. This gene encodes copper-transporting P-type ATPase. This article reports a case of Wilson disease with a novel ATP7B deletion variant. Case report We report a case of Wilson disease in a Chinese female patient. Cirrhosis was detected during routine examination at the age of 24 and was accompanied by reduced serum ceruloplasmin levels. At the age of 27, she gradually developed tremors and dystonia. Brain magnetic resonance imaging (MRI) revealed abnormal signals in the basal ganglia. Genetic testing for ATP7B was performed on the patient and her family members. Results Genetic testing revealed that the patient harbored compound heterozygous variants, including a previously reported c.1543+40G>A variant and a novel c.837delT variant in exon 2, which has not been previously reported. The c.1543+40G>A variant is registered in the ClinVar database with conflicting interpretations of pathogenicity (likely pathogenic/likely benign), The c.837delT variant is predicted to result in a frameshift (p.Ile279Metfs*5), introducing a premature termination codon, and is thus likely to impair the function of the copper-transporting P-type ATPase. Conclusion We identified a novel deletion variant in a Wilson disease patient harboring compound heterozygous variants in ATP7B. This finding expands the known spectrum of pathogenic ATP7B variants.
Lipeng Yang, Jun Li, Si Xie et al.· Frontiers in Neurology· 0 citations
Background Distal hereditary motor neuropathy (dHMN) is characterized by slowly progressive distal muscle weakness and amyotrophy, and it exhibits clinical overlap with Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis (ALS). Biallelic variants in SIGMAR1, encoding sigma nonopioid intracellular receptor 1, have been linked to autosomal recessive dHMN with pyramidal features. This study investigated the clinical and genetic features of patients with dHMN associated with SIGMAR1 variants in Japan. Methods We conducted genetic screening of Japanese patients with clinically suspected inherited peripheral neuropathies using targeted gene panels and whole-exome sequencing. SIGMAR1 variants were evaluated via segregation analysis using Sanger sequencing. Detailed clinical and electrophysiological data were systematically reviewed. Results Biallelic SIGMAR1 variants, including three novel variants and one previously reported variant, were identified in six patients from five unrelated families. The genotypes comprised compound heterozygous variants in four patients and homozygous variants in two patients. All patients presented with early-onset distal muscle weakness and atrophy. Enhanced tendon reflexes and pyramidal tract signs were frequently observed, whereas bulbar or respiratory involvement was absent. Nerve conduction studies consistently revealed motor-predominant axonal neuropathy with minimal sensory involvement. Disease progression was slow, and all patients remained ambulatory for years to decades after onset. Conclusion Our findings expand the clinical and genetic spectrum of SIGMAR1-associated disease and support its classification as dHMN rather than ALS. SIGMAR1 variants should be considered in the genetic evaluation of early-onset motor neuropathies, particularly in patients with dHMN accompanied by pyramidal features.
Kento Kodama, M. Ando, Y. Higuchi et al.· Journal of Neuromuscular Dis...· 0 citations
ABSTRACT Background and Aims SCO2 encodes a mitochondrial copper chaperone required for cytochrome c oxidase (COX) assembly and is classically associated with severe multisystem mitochondrial disease. We characterize a motor‐predominant axonal neuropathy presentation associated with biallelic SCO2 variants. Methods Clinical, genetic, and functional studies were performed in a 15‐year‐old female presenting with axonal neuropathy. Functional studies were conducted in patient‐derived fibroblasts, including Western blot analysis and spectrophotometric cytochrome c oxidation assay. Structural modeling was performed using ChimeraX. Results The patient presented with a motor‐predominant axonal neuropathy consistent with Charcot‐Marie‐Tooth (CMT) disease. Clinical genetic testing identified compound heterozygous SCO2 variants of uncertain significance: a missense variant (p.Arg120Trp) and a frameshift variant (p.Asp252ValfsTer24). Structural modeling predicted disruption of protein stability for both variants. Functional studies in patient‐derived fibroblasts demonstrated complete absence of SCO2 protein and reduced mitochondrial complex IV activity, supporting a loss‐of‐function mechanism. Interpretation These findings demonstrate that SCO2‐related disease can present as an isolated axonal neuropathy, a phenotype that remains rarely reported. Our study also highlights the value of integrating in silico prediction tools with functional assays to establish pathogenicity in rare sporadic cases of inherited neuropathy.
A. Rebelo, Katie L. Lutz, T. Grider et al.· Journal of the peripheral ne...· 0 citations
ABSTRACT Background Biallelic variants in VPS41, encoding a subunit of the HOPS complex, cause autosomal recessive spinocerebellar ataxia 29 (SCAR29), a rare neurodevelopmental disorder with an incompletely defined phenotypic and molecular spectrum. Methods We investigated a 24‐year‐old man with cerebellar ataxia, hypotonia, and intellectual disability. Exome sequencing identified four candidate VPS41 variants. Because maternal DNA was unavailable, long‐read genome sequencing was performed to determine allelic configuration, followed by RNA and protein analyses. Results In addition to typical SCAR29 features, the patient showed previously unreported findings, including swan‐neck deformities and pes cavus. Long‐read genome sequencing demonstrated that two VPS41 variants were in trans. RNA analysis revealed distinct splicing consequences: one allele produced an out‐of‐frame transcript predicted to undergo nonsense‐mediated decay, whereas the other generated an in‐frame exon‐skipped transcript. These complementary defects reduced VPS41 expression at both transcript and protein levels, supporting pathogenicity and variant reclassification. Conclusion Our findings expand the phenotypic spectrum of VPS41‐related disease and highlight the value of long‐read allelic resolution in clarifying pathogenic mechanisms in rare genetic disorders.
Natsuki Nakamura, Y. Nishio, Hiromi Nyuzuki et al.· Molecular Genetics & Genomic...· 0 citations
The novel DNAJC6 p.Cys325* variant is associated with severe, early-onset parkinsonism and developmental regression and should be considered in children and adolescents presenting with parkinsonism plus neurodevelopmental decline, particularly when levodopa benefit is modest, and dose-related adverse motor crises occur.
André Luiz Santos Pessoa, T. Guimarães, Diego de Castro Dos Santos et al.· Movement Disorders Clinical...· 0 citations