The 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.
Abstract
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.
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.
Christina Del Greco, Allison R. Cale, Karl Haeberlein et al.· Journal of the peripheral ne...· 0 citations
A patient with cerebellar atrophy, ataxia, and global developmental delay is described, and trio exome sequencing identified compound heterozygous variants in the final subunit EXOSC6.
Khondakar Sayef Ahammed, Renzo Guerrini, Milo B. Fasken et al.· medRxiv· 0 citations
Parkinsonism–dystonia Type 2 (PKDYS2) is a rare autosomal recessive disorder caused by SLC18A2 variants affecting the vesicular monoamine transporter 2 (VMAT2). We report the first genetically confirmed Iranian patient, an 18‐month‐old boy presenting with profound developmental delay, axial hypotonia, limb hypertonia, dystonia, oculogyric crises, ptosis, and autonomic dysfunction. Brain MRI, metabolic studies, and neurophysiological evaluations were normal. Whole‐exome sequencing identified a novel homozygous canonical splice‐site variant in SLC18A2 (NM_003054.6:c.1071‐2A > G), confirmed by Sanger sequencing and absent from population databases. SpliceAI predicted loss of the native splice acceptor site (DS_AL = 0.74), supporting a deleterious effect on RNA splicing. According to ACMG criteria, the variant was classified as likely pathogenic. Levodopa–benserazide failed to provide sustained benefit and caused irritability and insomnia, whereas pramipexole produced modest improvement in bradykinesia, ptosis, and sweating with persistence of dystonia and oculogyric crises. Comparison with reported international cases shows a consistent phenotype and limited therapeutic response. This case expands the mutational spectrum of SLC18A2‐related disease and highlights the importance of early genetic diagnosis.
Ali Nikkhah, R. Badv, S. Habibi et al.· Case Reports in Neurological...· 0 citations
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both upper and lower motor neurons, disturbing communication between the brain and muscles. So far, few reports have been published for the SPG11-associated ALS, and this is the first documented case from Pakistan. We report a rare subtype of ALS with an autosomal recessive mode of inheritance with juvenile onset before 25 years of age in the five affected individuals from two unrelated families. Whole-exome sequencing was performed to identify disease-causing variants, and selected variants were further prioritized based on predicted pathogenicity and similarity to clinical phenotypes. Two homozygous variants within the SPG11 gene were identified as pathogenic according to the ACMG and ClinGen Sequence Variant Interpretation (SVI) Working Group recommendations: a novel truncation (NM_025137.4:c.6738dup, p.Glu2247Ter) variant as validated by Sanger sequencing and a recurrent nonsense (NM_025137.4: c.782C>A, p.Ser261Ter) variant (rs765477482) previously reported in a family affected with autosomal recessive hereditary spastic paraplegia (ARHSP). In silico prediction tools further confirmed their pathogenicity. Five patients with juvenile-onset ALS born to consanguineous parents were found to have homozygous SPG11 gene variants. Our findings describe the overlapping phenotypes ofSPG11-related autosomal recessive juvenile ALS and ARHSP, suggesting that these disorders show a clear overlapping phenotype with common genetic defects. In clinical practice, it is challenging to distinguish between these two disorders. Additional Mendelian cases should be included to clarify further and investigate whether these represent two diverse diseases caused by variants in a single gene.
Riaz Ahmad, Muhammad Naeem, H. Houlden· Molecular Biology Reports· 0 citations
BACKGROUND
Inherited retinal degenerations are a group of genetically heterogeneous disorders characterized by progressive photoreceptor degeneration. Despite the widespread use of targeted gene panels and exome sequencing, many cases remain genetically unresolved because structural and other complex variants may be missed. CEP290 is a major cause of early-onset retinal degeneration, and although most pathogenic variants are sequence-level changes, structural rearrangements have increasingly been recognized through genome-wide sequencing approaches. This study aimed to identify the genetic cause in a child with early-onset retinal degeneration and to characterize the molecular mechanism of the underlying variant.
METHODS
A 4-year-old boy with presumed rod-cone dystrophy underwent comprehensive clinical evaluation and trio whole-genome sequencing. Compound heterozygous CEP290 variants, consisting of a maternally inherited splice-site variant and a paternally inherited large intragenic duplication, were identified and evaluated. The duplication breakpoint was subsequently characterized by structural variant analysis, gap-PCR, and Sanger sequencing, followed by analysis of breakpoint-associated microhomology, GC content, and repeat elements. Variants were interpreted according to ACMG/AMP and ClinGen recommendations, as appropriate.
RESULTS
Trio-WGS detected compound heterozygous CEP290 variants: a maternal splice-site variant c.6012-2 A > G and a paternal exons 31-53 tandem duplication (chr12:88050034-88089159dup). Gap-PCR and Sanger sequencing validated this rearrangement and defined a 7-bp junction microhomology (AAATTCT). Breakpoint analysis showed low GC and abundant repeats, supporting FoSTeS/MMBIR as the causal replicative mechanism. This duplication is predicted to alter CEP290 transcripts, triggering frameshift, premature termination and C-terminal domain loss.
CONCLUSIONS
To our knowledge, this study represents the first breakpoint-resolved characterization of a pathogenic CEP290 tandem duplication encompassing exons 31-53 identified in compound heterozygosity with a pathogenic splice-site variant in a patient with early-onset retinal degeneration. The duplication is predicted to disrupt the CEP290 coding sequence, resulting in a frameshift, premature termination codon, and loss of the C-terminal functional domain. These findings expand the spectrum of pathogenic structural variants in CEP290 and underscore the value of whole-genome sequencing and breakpoint-level analysis for resolving genetically unexplained inherited retinal disorders.
Shumei Xu, Jia Geng, W. Xiong et al.· BMC Medical Genomics· 0 citations
This study expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism.
Mohamed Baity, Khalid K Alharbi, Eman Alobeid et al.· International Journal of Mol...· 0 citations
