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

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

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.

Identification of Nuclear Genetic Loci Linked to Clinical Features of the m.3243A>G Mitochondrial DNA Variant

Background and Objectives Mitochondrial DNA (mtDNA) disorders exhibit striking clinical variability that is poorly explained by known factors such as variant heteroplasmy, age, or sex. Nuclear genetic modifiers likely play a significant role in this heterogeneity. We aimed to characterize the nature of nuclear genetic involvement for 2 common syndromic presentations of the common pathogenic mtDNA variant, m.3243A>G: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD). Methods We assembled a multicenter cohort of clinically ascertained carriers of m.3243A>G (total n = 488), identifying 198 individuals across 76 pedigrees suitable for genetic linkage analysis. We investigated 4 clinical features characteristic of MELAS and MIDD: diabetes, hearing impairment, stroke-like episodes, and encephalopathy. Haseman-Elston regression-based genetic linkage analysis was performed to identify regions of the nuclear genome cosegregating with these features. The effects of m.3243A>G heteroplasmy, age, and sex were accounted for using logistic regression; empirical significance thresholds were determined through feature-specific gene-dropping simulations. Association analyses were performed in 247 individuals using single-variant (SAIGE) and gene-based approaches (SAIGE-GENE+ and MAGMA) to refine candidate loci within a significant linkage region. Results We identified significant genetic linkage to encephalopathy (chromosome 7q22; LOD = 3.72), and regions suggestive of genetic linkage on chromosomes 1, 5, 6, 11, and 13, for encephalopathy and stroke-like episodes. No linkage was identified for diabetes or hearing impairment. Association analysis within the chromosome 7 region identified variant rs62500792 (intergenic between SDHAF3 and TAC1) with the lowest p value (3.7 × 10−5), yet no variants reached the proportional significance threshold (5.3 × 10−6). Gene-based analyses highlighted PLOD3 (p = 3.9 × 10−3) and IMMP2L (p = 6.4 × 10−3) as candidates, as each showed the strongest gene-level signals within the linkage region across complementary burden-testing methods, although neither reached corrected significance thresholds. Discussion The nuclear genetic architecture modifying m.3243A>G differs across clinical features. Severe neurologic features (encephalopathy and stroke-like episodes) may be influenced by a small number of nuclear genes with relatively large effect sizes, whereas the nuclear contribution to diabetes and hearing impairment appears more polygenic. This study highlights the value of large, well-characterized patient cohorts in identifying modifier loci and advancing knowledge of the mechanisms underlying phenotypic variability in mtDNA disease.

Novel Homozygous Mitochondrial Calcium Uptake Protein 1 Variant (c.38T>C, p.Leu13Pro) in a 7-year-old Girl with Congenital Ptosis and Proximal Myopathy: Expanding the Phenotypic Spectrum.

ABSTRACT Myopathy with extrapyramidal signs (OMIM #615673) is a rare autosomal recessive mitochondrial disorder caused by biallelic loss-of-function variants in Mitochondrial calcium uptake protein 1 (MICU1), which encodes the gatekeeper of the mitochondrial calcium uniporter complex. We report a 7-year-old Indian girl with global developmental delay, congenital nonfatiguable right ptosis, proximal-predominant myopathy without calf hypertrophy, multi-system dysmorphism (elongated facies, baggy cheeks, large prominent ears, partial webbed neck, bilateral clinodactyly, fetal finger pads, pes planus, and sandal gap), and thickened corpus callosum on magnetic resonance imaging. Creatine kinase ranged between 4068 and 4732 U/L; electromyography demonstrated a myogenic pattern with normal nerve conduction and nondecremental repetitive nerve stimulation. Whole-exome sequencing identified a novel homozygous missense variant, c.38T>C (p.Leu13Pro), in exon 1 of MICU1, classified as a variant of uncertain significance. To our knowledge, this is the first reported pediatric MICU1 case with congenital ptosis, absence of calf hypertrophy, and a structural corpus callosum abnormality, substantially broadening the phenotypic spectrum of MICU1-related myopathy.

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

Novel Compound Heterozygous Variants in SLC13A3 Associated With ARLIAK: A Case Report and Review of the Literature

SLC13A3 pathogenic variants are associated with acute reversible leukoencephalopathy and α‐ketoglutarate accumulation (ARLIAK), a rare neurological disorder characterized by recurrent episodes of encephalopathy and transient white matter abnormalities. Pathogenic variants reported so far include missense, nonsense and small deletion variants, highlighting substantial allelic heterogeneity. We describe a patient presenting with multiple episodes of acute encephalopathy, elevated urinary α‐ketoglutarate and reversible white matter lesions on MRI, consistent with SLC13A3‐related ARLIAK. Genetic analysis identified novel compound heterozygous variants: a missense variant (p.Leu46Pro) in a highly conserved region and a larger deletion encompassing exons 2–3. Our findings indicate that conventional sequencing alone may miss larger deletions, suggesting the need for copy number analysis as part of the diagnostic protocol for suspected ARLIAK cases. The elevated urinary α‐ketoglutarate in our patient supports its potential as a noninvasive biomarker. MRI findings demonstrated typical transient and reversible white matter abnormalities, aligning with previously reported cases. This study expands the molecular and phenotypic spectrum of SLC13A3‐related ARLIAK and underscores the importance of combining sequencing with copy number analysis for accurate diagnosis. The identification of novel variants contributes to a better understanding of the disease mechanism and suggests a broader allelic heterogeneity than previously recognized.

Case Report: Three pathogenic molecular findings in a patient with myotonia congenita, pseudohypoparathyroidism, and a glaucoma-suspect phenotype

Background The presence of multiple rare Mendelian disorders in a single patient may mask clinical recognition when phenotypes overlap. We describe a patient with longstanding myotonia congenita due to a CLCN1 variant in whom an incidental discovery of severe hypocalcemia led to the diagnosis of GNAS-related pseudohypoparathyroidism (PHP). Exome reanalysis also identified an incidental homozygous pathogenic CYP1B1 variant associated with autosomal recessive glaucoma. Case presentation A 23-year-old man born to consanguineous parents was referred for management of chronic myotonia congenita, manifested by delayed motor milestones, frequent falls, contractures, and muscle hypertrophy. Electrophysiological assessment demonstrated myotonic discharges, and whole-exome sequencing (WES) identified a homozygous CLCN1 splice-site variant (NM_000083.3:c.1167-10T>C) known to cause myotonia congenita. During subsequent evaluation, he was found to have severe hypocalcemia, hyperphosphatemia, markedly elevated parathyroid hormone, basal ganglia and dentate calcifications, brachydactyly, subcutaneous calcifications, and mild hypothyroidism, raising suspicion for PHP. Genetic and ophthalmologic findings Reanalysis of WES data demonstrated a heterozygous frameshift GNAS variant (NM_080425.4:c.2494_2497delCTGA) and a homozygous CYP1B1 variant (NM_000104.4:c.182G>A; p.Gly61Glu) in addition to the CLCN1 defect. Sanger sequencing confirmed all three variants. The CYP1B1 finding prompted glaucoma-specialist evaluation. Visual acuity was 20/22 in the right eye and 20/25 in the left eye; intraocular pressures were 8 and 12 mmHg, respectively. The corneas were clear, cup-to-disc ratios were 0.4 and 0.5, and average retinal nerve fiber layer thicknesses were 74 and 75 µm. No definite glaucomatous damage was identified, and the patient was classified as a glaucoma suspect. After treatment with calcium, calcitriol, and ergocalciferol, serum calcium improved, parathyroid hormone levels declined, creatine kinase normalized, and the patient reported improved muscle stiffness and function. Conclusion This case demonstrates two clinically expressed Mendelian disorders together with a third actionable molecular finding. It highlights the importance of careful phenotyping, molecular testing, and cautious genotype-phenotype interpretation, particularly in consanguineous populations.