This first report of a Chinese patient with INPP5K-related muscular dystrophy broadens both the genetic and clinical spectrum of the disorder and identifies the first disease-causing synonymous variant and a novel hypomorphic missense variant, the combination of which explains the attenuated phenotype lacking intellectual disability.
The molecular and functional spectrum of SLC25A4-associated disease is expanded and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.
Mazhor Aldosary, Hanan Alqudairy, Nourah Alshalan et al.· International Journal of Mol...· 0 citations
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 is reported, expanding the mutational spectrum of SLC18A2‐related disease and highlighting the importance of early genetic diagnosis.
Ali Nikkhah, R. Badv, S. Habibi et al.· Case Reports in Neurological...· 0 citations
ABCA13 encodes ATP-binding cassette subfamily A member 13, one of the largest members of the ABC transporter family. Rare ABCA13 variants have been reported in neuropsychiatric and neurodevelopmental phenotypes, including schizophrenia, bipolar disorder, autism spectrum disorder, intellectual disability, and developmental delay; however, the mode of inheritance remains uncertain, and most published cases have focused on heterozygous variants in the context of a possible dominant or susceptibility model. We report a 5-year-old boy with neurodevelopmental delay, skeletal foot deformities, nonspecific dysmorphic features, convergent strabismus, and behavioral abnormalities. Initial genome sequencing analysis was nondiagnostic. Reanalysis after 6 months identified two rare predicted loss-of-function variants in ABCA13 in trans: c.2510del, p.(Leu837TyrfsTer21), a frameshift variant, and c.12064C>T, p.(Arg4022Ter), a nonsense variant previously reported in a patient with unexplained intellectual disability. The identification of compound heterozygous predicted loss-of-function variants supports the possibility that biallelic disruption of ABCA13 may contribute to neurodevelopmental disease, whereas previously reported heterozygous variants may represent incompletely penetrant risk alleles, susceptibility factors, or candidate findings rather than fully penetrant dominant causes. This case expands the emerging clinical and genetic spectrum associated with ABCA13 and supports further evaluation of a recessive model in patients with intellectual disability and neurodevelopmental delay.
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
Dystrophinopathies, including Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), are X-linked neuromuscular disorders caused by mutations in the DMD gene. We describe two male patients with dystrophinopathies due to large deletions in the DMD gene. Case 1 is a 23-year-old male with adult-onset proximal muscle weakness and preserved ambulation. Genetic analysis revealed an in-frame deletion of exons 45–48, consistent with Becker muscular dystrophy. Case 2 is a 7-year-old child presenting with early-onset progressive muscle weakness, a positive Gower’s sign, loss of ambulation, and markedly elevated creatine kinase levels. Multiplex ligation-dependent probe amplification (MLPA) identified an out-of-frame deletion spanning exons 46–57, confirming a diagnosis of Duchenne muscular dystrophy. Reading-frame status produced notably distinct clinical manifestations, despite the same gene and comparable mutational processes. The dystrophin reading-frame rule remains valid in this comparative case report, which also emphasises the importance of accurate molecular diagnosis for prognosis, genetic counselling, and treatment stratification in the era of precision medicine. To our knowledge, comparative genotype–phenotype case documentation from South Asian populations remains limited. This comparative case report adds valuable data from an underrepresented population.
Geerthana Balasubramaniam, Guhan Ramamurthy· International Journal of Res...· 0 citations
The broad clinical spectrum associated with the SEPTIN9 R106W mutation in a Chinese pedigree spanning from childhood to adulthood is delineated, highlighting the critical role of active inter vention in childhood-onset HNA.
Jing Chen, Shuang Chen, Xin-Yi Zhu et al.· Frontiers in Genetics· 0 citations
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