A Novel SLC25A4 Variant Causing Mitochondrial Dysfunction, Myopathy and Cardiomyopathy: A Functional and Molecular Characterization

INPP5K-related muscular dystrophy caused by a novel synonymous splicing variant in a Chinese patient: a case report.

KCNQ2 p.(Arg214Trp): systematic review with retrospective analysis and expanding the phenotype

Heterozygous pathogenic variants in the KCNQ2 gene underlie a broad phenotypic spectrum ranging from self-limited (familial) neonatal epilepsy (SeLNE) to developmental and epileptic encephalopathy or isolated intellectual disability. The KCNQ2 gene encodes subunits of a voltage-gated potassium channel involved in neuronal excitability, and its mutations are known to have both loss-of-function (LoF) and gain-of-function (GoF) effects, resulting in distinct neurological syndromes. The recurrent missense LoF variant KCNQ2 p.(Arg214Trp) has been previously reported in a single family with a presumed SeLNE phenotype, without detailed adult follow-up and with additional database-reported evidence suggesting a broader phenotype associated with this recurrent variant. Here, we report a family with two adult carriers of the heterozygous KCNQ2 p.(Arg214Trp) variant identified through whole-exome sequencing, including long-term follow-up into late adulthood. In addition, a literature review of previously reported cases carrying the same recurrent variant was performed. Both individuals presented with early-onset focal epilepsy with a relapsing course, characterized by prolonged seizure-free periods followed by recurrence in adulthood. The proband demonstrated transient motor regression, developmental delay, moderate intellectual disability, ataxia and fine motor impairment. The father exhibited milder cognitive impairment and additional comorbidities in later life. These findings challenge the concept of KCNQ2 p.(Arg214Trp) as a self-limited epilepsy-associated variant and indicate a broader phenotypic spectrum, with persistence of epilepsy and associated neurological and non-neurological comorbidities into adulthood. Our report provides new insights into adult outcomes, aiding in genetic counseling and the long-term management of affected individuals. More extensive studies with larger cohorts carrying this variant are necessary to better define the full phenotypic spectrum and to distinguish comorbidities associated with different etiological factors, including perinatal factors.

Wilson disease associated with a novel variant in the ATP7B gene

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.

Identification of a novel likely pathogenic MT-TS2 variant in a patient with mitochondrial myopathy, retinitis pigmentosa and sensorineural hearing loss.

Mitochondrial diseases are a prevalent cause of metabolic disorders arising from nuclear or mitochondrial DNA mutations. Their clinical and genetic heterogeneity highlight their diagnostic complexity. A 55-year-old male patient with Kallmann syndrome, retinitis pigmentosa and congenital sensorineural hearing loss presented with a one-year history of generalized weakness and imbalance. Examination revealed generalized muscle atrophy, hyporeflexia, and mild tetraparesis. Following an electromyography suggestive of proximal myopathy, muscle biopsy was consistent with mitochondrial myopathy. Mitochondrial respiratory chain analysis demonstrated increased activity of complex II and residual increases in complex I and cytochrome C. Full mitochondrial DNA sequencing identified a heteroplasmic MT-TS2 variant (m.12257G>A), with 15% heteroplasmy in blood and nearly 100% in muscle tissue. This variant was classified as likely pathogenic. This case illustrates a new potentially pathogenic variant in the MT-TS2 gene. Comprehensive analysis of mitochondrial DNA is essential to establish a definitive diagnosis.

Identification of a Novel homozygous Splice-Site Deletion in KCTD7 Gene Associated with Progressive Myoclonic Epilepsy

Objective: To study the Progressive myoclonic epilepsies (PME) that is genetic disorders resulting from mutations in different genes, all characterized by the early onset of myoclonic seizures, and cognitive decline. The Potassium Channel Tetramerization Domain Containing seven (KCTD7) gene encodes for the BRC (broad complex), ttk (tramtrack), and bab/pox virus, and zinc finger domain, containing KCTD7 protein. Methodology: The study was done in the Center of Excellence in Genomic Medicine and Research (CEGMR). The affected patient, a three-year-old Saudi female born to consanguineous parents, she underwent laboratory tests, EEG assessments, and Whole-Exome Sequencing (WES). Results: Our results showed a novel five base pair deletion that was detected in homozygous state in the KCTD7 gene. Both the unaffected parents showed heterozygous mutation of the KCTD7 gene. Segregation analysis via Sanger sequencing supported the existence of the homozygous splice donor variant in NM_153033.4:c.493+2_493+6delTGA of KCTD7 gene in the patient. Conclusion: The mutation is not reported in the literature yet; the particular phenotype that was observed in our patient is comparable to the ones that are described in the KCTD7 related pathologies, combined with segregation analysis indicating both parents carried the variant heterogeneously present is a strong indication that the identified mutation consists of probably pathogenic mutation. This finding will further increase our insight of the genetic basis of PMEs and role of KCTD7 gene mutations in Saudi population.

Identification of a Novel SLC18A2 Splicing Variant in a Case of Infantile Parkinsonism–Dystonia Type 2

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.