SEARCH · Search PubMed

Results for “Pathogenic variant”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 199 records · Page 11Linked to original sources

PubMed2026

Potential contributors to variable penetrance of NOTCH3 p.Arg1231Cys Variant.

Missense mutations in NOTCH3, especially cysteine-altering pathogenic variants, are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. The NOTCH3 p.Arg1231Cys variant, located in EGFr domain 31, is classified as low-risk under the three-tiered EGFr domain risk stratification system. We report two cases of p.Arg1231Cys heterozygosity presenting with early-onset dementia, strokes, and extensive leukoencephalopathy. These cases highlight the potential contributing factors to increasing penetrance of p.Arg1231Cys variant, and the need for functional evaluation to improve the clinical utility of genetic testing in hereditary small vessel disease.

Humans↗

PubMed2026

A Second Report of a Missense Variant in AMMECR1 Causing Midface Hypoplasia, Hearing Impairment, Elliptocytosis, and Nephrocalcinosis: Case Report and Literature Review.

Pathogenic variants in AMMECR1 have been associated with a rare multisystem disorder characterized by midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MFHIEN). To date, most reported cases involve copy number variants or presumed loss-of-function alterations, with only a single prior report describing a missense variant supported by functional studies. Here, we report a patient with a heterozygous de novo AMMECR1 missense variant, NM_015365.3:c.649G>A p.(Val217Met) presenting with clinical features consistent with MFHIEN, including midface hypoplasia, partial hearing impairment, nephrocalcinosis, and elliptocytosis identified on peripheral blood smear. Comparative review of the literature highlights that while previously reported missense variants in AMMECR1 demonstrated altered intranuclear protein distribution and reduced expression in functional assays, clinical evidence supporting pathogenicity of non-truncating variants remains limited. The phenotypic overlap between our patient and prior report strengthens the association between missense variations and the MFHIEN phenotype. Our findings support the pathogenic relevance of missense variation in AMMECR1 and emphasize the importance of integrating detailed phenotyping, including hematologic evaluation, with genomic data in the diagnosis of rare multisystem disorders. Additional cases and functional studies are needed to clarify genotype-phenotype correlations and underlying disease mechanisms.

Humans↗

PubMed2026

A novel missense mutation in tropomyosin 1 gene associated with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder that can lead to heart failure or sudden death. Family-based identification of rare sarcomeric variants can support molecular diagnosis and cascade screening in inherited HCM. This study aimed to identify and evaluate a novel TPM1 variant found in a Vietnamese family with HCM. The proband, a 3-year-old boy diagnosed with HCM, and eight relatives from three generations underwent clinical and genetic evaluation. A candidate variant initially identified by targeted next-generation sequencing was validated by PCR and Sanger sequencing. Familial segregation analysis was performed, and variant pathogenicity was assessed according to ACMG guidelines with support from in silico prediction and structural modeling. Sanger sequencing confirmed a heterozygous missense variant in exon 6 of TPM1 NM_001018005.2:c.576G > C, p.(Glu192Asp), in the proband, his father, and paternal grandfather, all of whom exhibited clinical signs of HCM. The variant was absent in unaffected relatives and in public population databases. Based on ACMG criteria (PM1, PM2, PM5, and PP3), the variant was classified as likely pathogenic. This novel TPM1 variant segregated with HCM in a Vietnamese family, expands the known mutational spectrum of TPM1 in hypertrophic cardiomyopathy, and warrants further functional investigation and familial genetic evaluation.

American College of Medical Genetics and Genomics ↗

PubMed2026

Novel genetic variants identification and immune profiling in ataxia telangiectasia patients.

BACKGROUND: Ataxia telangiectasia (AT) is an autosomal recessive neurodegenerative disease. While heterozygous relatives of AT patients are known to be clinically healthy, a predisposition to various pathologies has been reported. Our aim was firstly, to further characterize the clinical features and broaden the spectrum of genetic pathogenic variants in AT patients. Secondly, we aimed to study the immune profiles of AT patients and their relatives to identify similarities or common biomarkers. METHODS: A Target Gene Sequencing for six patients suspected with AT was performed. Computational analysis was conducted to assess the pathogenicity of novel variants. The distribution of immune cells was assessed by flow cytometry in patients with AT, AT-like disorder, Friedreich ataxia, and in AT relatives. The expression pattern of candidate genes was evaluated by RT-qPCR. RESULTS: We identified and predicted the pathogenicity of novel variants in the ATM gene. Computational analysis suggested that the novel identified missense mutation could affect ATP binding pattern and ATM protein flexibility, while Alu element insertion could probably induces a premature stop codon. Furthermore, our results confirm the pathogenic effect of identified splicing mutations on the ATM transcript. Moreover, we noticed a high percentage of LTCD4 + and LTCD8 + senescent subsets in AT patients and a relative increase of the of intermediate and non-classical monocytes accompanied with a decrease of classical monocytes specifically in AT patients with truncated biallelic mutations which was intriguingly similar to the immune profile of AT parents. In addition, a difference of immune pattern was observed between AT patients with biallelic truncated mutations compared to those with at least one non-truncated mutation, with a variability intragroup. Gene expression analysis identified FOXO3, IL33 and METTL3 as putative genes that may yield clues into AT pathogenesis. CONCLUSION: Taken together, our study expands the mutational spectrum of AT disease worldwide and further characterize the immune profile of AT patients uncovering a possible difference in some immune cellular subsets related to ATM mutation type and delineate putative immune abnormalities related to ATM heterozygosity among AT parents. Furthermore, dysregulation in FOXO3, IL33 and METTL3 expression could be related to disease severity.

Humans↗

PubMed2026

X-linked spondyloepiphyseal dysplasia tarda misdiagnosed as growth hormone deficiency: identification of a novel intronic TRAPPC2 variant by whole-genome sequencing.

BACKGROUND: X-linked spondyloepiphyseal dysplasia tarda (SEDT) is a rare skeletal dysplasia caused by pathogenic variants in TRAPPC2 and typically presents in late childhood or adolescence with short-trunk disproportion and vertebral dysplasia. CASE PRESENTATION: We describe a family series centered on an adolescent male initially diagnosed with GHD due to reduced height velocity and subnormal GH stimulation results, who received recombinant human GH (rhGH) therapy for three years with negligible improvement. During puberty, he developed progressive short-trunk disproportion and characteristic radiographic features, including platyspondyly and posterior hump-shaped vertebral endplates, suggestive of SEDT. Whole-exome sequencing (WES) was nondiagnostic, whereas whole-genome sequencing (WGS) identified a novel intronic TRAPPC2 variant, c.239-20_239-12delinsAATGAA, initially classified as a variant of uncertain significance (VUS). Segregation analysis across the family enabled reclassification of the variant to likely pathogenic, confirming X-linked SEDT. The proband's younger brother exhibited earlier radiologic abnormalities and, notably, a favorable response to rhGH, whereas the younger sister-an asymptomatic heterozygous carrier-showed normal spinal morphology, consistent with expected female carrier phenotypes. CONCLUSIONS: This family-based report underscores the generally limited therapeutic effect of rhGH in SEDT while highlighting potential interindividual variability, as evidenced by the younger male sibling's response. It further emphasizes the diagnostic utility of WGS for detecting deep intronic variants missed by WES and the importance of segregation analysis in resolving VUS in rare skeletal dysplasias.

Humans↗

PubMed2025

A functional assay to classify RB1 variants of uncertain significance.

PURPOSE: The RB1 gene encodes the retinoblastoma protein (pRB) playing a major role in cell cycle control, particularly by its interaction with E2F transcription factors. Familial forms of retinoblastoma are caused by germline pathogenic variants in the RB1 gene predisposing to retinoblastoma and other tumors. By analyzing the RB1 gene in patients with retinoblastoma, we found that missense variants often remain variants of uncertain significance (VUS). METHODS: To classify RB1 VUS, we developed a functional assay evaluating their impact on the ability of pRB to inhibit the activity of the E2F1 promoter, with a luciferase reporter gene. A set of 14 pathogenic/likely pathogenic and benign/likely benign RB1 variants was used for validation. RESULTS: We tested 16 VUS detected in patients with retinoblastoma and found that 9 VUS reduced the ability of pRB to inhibit E2F1 promoter. Among them, the (RB1) c.2263T>G p.(Phe755Val) variant showed a reduced level of pRB on Western blot, suggesting a defect in pRB stability. By applying the criterion PS3_moderate of the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification to this functional assay, 5 of the 9 VUS with functional impact could be classified as likely pathogenic. CONCLUSION: This functional assay can improve the molecular diagnosis of retinoblastoma predisposition by a better determination of pathogenic/likely pathogenic RB1 variants.

Humans↗

PubMed1997

Novel mutations in Sanfilippo A syndrome: implications for enzyme function.

Sanfilippo syndrome type A or mucopolysaccharidosis IIIA (MPS IIIA) is an autosomal recessive lysosomal storage disorder caused by the deficiency of sulfamidase. The resulting lysosomal storage of heparan sulfate may lead to severe neurodegeneration preceded by progressive dementia, often combined with aggressive and hyperactive behaviour. A total of 109 patients from four different geographic areas were screened for the common mutation R245H and two other previously identified mutations. SSCP analysis of exons was used to characterize the unknown alleles. We identified 16 novel sequence variants, 12 of them likely to be pathogenic. The majority of the pathogenic variants were single base pair changes leading to missense mutations. Several single base pair deletions/insertions and one nonsense mutation were also identified. Altogether, we were able to characterize 55% of the pathogenic alleles. Sequence homology between sulfamidase and N-acetylgalactosamine 4-sulfatase, the first sulfatase to have its tertiary structure defined, suggests that amino acid residues R74 and T79, which were found to be mutated, are likely to be involved in the formation of the active site of sulfamidase. R245H accounts for 31% of the Sanfilippo A alleles in Australasia, for 19.2% of the alleles in patients from the UK and has a high frequency of 57.8% in patients from The Netherlands. The identification of mutations common in certain geographic regions or ethnic groups will help in the diagnosis of MPS IIIA and allow carrier testing and improved genetic counselling.

DNA Primers↗

PubMed2025

Differential expression of a disease-associated MRE11 variant reveals distinct phenotypic outcomes.

The MRE11 DNA nuclease plays central roles in the repair of DNA double-strand breaks (DSBs) as a core component of the heterotrimeric MRE11/RAD50/NBS1 (MRN) complex. MRN localizes to chromosomal DSBs and recruits and activates the apical DSB repair protein kinase, ATM, which phosphorylates downstream substrates to elicit cellular DNA damage responses. Pathogenic variants in MRE11 cause the genome instability disorder ataxia-telangiectasia-like disorder (ATLD). The first ATLD patient allele identified, ATLD1, is a nonsense mutation that deletes 76 amino acids from the MRE11 C-terminus and results in markedly reduced levels of MRE11-ATLD1 and the entire MRN complex. This region of the C-terminus has been demonstrated to function in DNA binding, mediate functional protein interactions, and undergo post-translational modifications that regulate MRE11 nucleolytic activities. We previously demonstrated that transgenic mice expressing low wildtype MRN exhibit severe phenotypes, including small body size, anemia, and cellular DNA DSB repair defects. Thus, it is currently unknown whether reduced MRE11-ATLD1 and MRN levels, loss of the C-terminus, or both cause disease-associated phenotypes. In this study, we generated transgenic mouse models that express near endogenous or significantly reduced levels of MRE11-ATLD1 to determine the in vivo importance of the MRE11 C-terminus. We observe that reduced MRE11-ATLD1 expression leads to anemia, bone marrow failure, extramedullary hematopoiesis, and impaired lymphocyte development, similar to mice expressing low wildtype MRE11. In contrast, higher expression of MRE11-ATLD1 results in a subset of moderate phenotypes, indicating that loss of C-terminus has limited impact on MRN functions in vivo. These findings have implications for clinical predictions of ATLD patients harboring pathogenic MRE11 variants that impair MRE11 function and/or impact MRN protein levels.

Journal Article↗

PubMed2025

Increased yield of genetic diagnoses in inherited heart diseases using expanded genome and RNA-splicing analyses.

PURPOSE: The Australian Genomics Cardiovascular Disorders Flagship investigated genome sequencing as a first-line genetic test in 600 individuals with cardiomyopathy, primary arrhythmia syndromes, or congenital heart disease. Analysis of disease-specific virtual gene panels achieved a genetic diagnosis in 38% of participants. We sought to increase genetic diagnosis yields by analyzing lesser-evidenced disease genes, the mitochondrial genome, and by functional analysis of predicted splice-altering variants. METHODS: Genome sequences of 520 participants with cardiomyopathy or primary arrhythmia syndromes were reanalyzed in 572 cardiac genes and the mitochondrial genome. Participants with congenital heart disease were excluded. Variants predicted in silico to disrupt splicing were assessed with blood RNA and minigenes. RESULTS: A new genetic diagnosis was achieved in 4% (19/520) of participants, including deep intronic and mitochondrial genome variants. Ten participants had diagnostic variants in lesser evidenced disease genes; 9 had splicing variant pathogenicity functionally validated. Eleven participants had a newly identified variant of uncertain significance with high suspicion of pathogenicity, warranting clinical review. Our data supported the gene-disease association of 1 new cardiomyopathy gene, TBX20. CONCLUSION: Identifying new gene-disease relationships, maintaining contemporary gene panels, and integrating functional studies to refine splicing variant classifications increase genetic diagnoses for cardiomyopathies and primary arrhythmia syndromes.

Humans↗

PubMed2025

Early mortality in children with homozygous familial hypercholesterolemia: Case reports of deaths at ages 5 and 7 and a systematic review of global evidence.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a leading cause of premature atherosclerotic cardiovascular disease (ASCVD) and early mortality if left untreated or inadequately treated. OBJECTIVE: This study presents 2 pediatric cases of early death from Pakistan due to familial hypercholesterolemia (FH) and provides a systematic review of similar cases reported globally. METHODS: Genetic analysis was conducted using next-generation sequencing to confirm pathogenic variants. For the systematic review, published reports of individuals with FH who died before the age of 18 years were identified. Data were extracted on demographic features, personal and family history, genetic variants, treatment given, and cause of death. RESULTS: Both patients, born to consanguineous families, presented with markedly elevated low-density lipoprotein cholesterol (LDL-C) levels (792 mg/dL [20.48 mmol/L] and 896 mg/dL [23 mmol/L], respectively), multiple xanthomas, and early-onset myocardial infarction, and died at the ages of 5 and 7 years, respectively. Their genetic analysis revealed a pathogenic frameshift variant in the LDLR gene: NM_000527.5: c.2416dupG (p.Val806GlyfsTer11). The systematic review included 12 studies reporting pediatric FH-related mortality. Common clinical features included tendon xanthomas, elevated LDL-C levels, family history, and early-onset ASCVD. Genetic testing was performed in a few cases, which revealed pathogenic variations in the LDLR gene. Most of the patients received inadequate lipid-lowering therapy. The most common causes of death were severe coronary artery disease, myocardial infarction, and sudden cardiac arrest. CONCLUSION: Our 2 cases and the accompanying systematic review identified additional cases of premature mortality. Collectively, these findings highlight diagnostic delays and inadequate treatment as common factors among patients who died prematurely.

Child↗

PubMed2026

Novel splice-site and recurrent p.Arg729* CNKSR2 variants in ESES/CSWS: insights into sex-dependent expression.

PURPOSE: Pathogenic variants in CNKSR2 (Xp22.12) cause an X-linked neurodevelopmental disorder with intellectual disability, language impairment, and a distinctive epilepsy phenotype, including encephalopathy with status epilepticus during slow-wave sleep (ESES/CSWS). Hemizygous males are typically severely affected, whereas symptomatic females remain rare and incompletely characterized. We describe two unrelated patients with de novo CNKSR2 variants to expand the mutational and sex-dependent phenotypic spectrum of this disorder. METHODS: Both patients underwent clinical, electroencephalographic, and neuroimaging evaluation. CNKSR2 variants were identified by whole exome sequencing with parental segregation, and the splice-site variant was assessed in silico (SpliceAI, MaxEntScan, Human Splicing Finder). RESULTS: Patient 1, a 17-year-old female, harbored a novel canonical splice-site variant (c.64+1G>A) in the N-terminal region and presented with a relatively mild phenotype. In silico analysis supported abolition of the canonical donor splice site. Patient 2, an 8-year-old male, carried a de novo nonsense variant (c.2185C>T, p.Arg729*) and exhibited drug-resistant ESES, autism, and severe language impairment. p.Arg729* had previously been reported in one independent male. Our case represents its second independent occurrence, a CGA>TGA transition at a CpG dinucleotide consistent with a mutational hotspot. CONCLUSION: Together, these cases expand the mutational spectrum and provide further evidence for sex-dependent phenotypic variability in CNKSR2-related epilepsy. Our observations support the hypothesis that X-chromosome inactivation may contribute to phenotypic variability in females, although XCI was not assessed here, and support inclusion of CNKSR2 in epilepsy gene panels regardless of sex.

Humans↗

PubMed2026

Rare variant analysis of whole genome sequenced juvenile idiopathic arthritis multiplex pedigrees identifies rare variants in NOD2 and ACVR1.

Juvenile idiopathic arthritis is a complex rheumatic disease that is influenced by environmental and genetic factors. Linkage and genome-wide association studies have identified genes that contribute to the risk of developing juvenile idiopathic arthritis but are limited in their ability to identify disease-risk variants of large effect. Penetrant, heritable risk variants can be detected in high-risk families, but such cases are uncommon due to the low prevalence of juvenile idiopathic arthritis. This study utilizes whole-genome sequencing of 23 multiplex families, the largest such cohort to date, to discover variants and genes relevant to JIA pathogenesis. Pathogenic variants in NOD2 associated with Blau syndrome, an ultra-rare Mendelian inflammatory disorder, are the most recurrent variants in the cohort, consistent with previous reports that milder presentations of Blau syndrome are oftentimes misdiagnosed as juvenile idiopathic arthritis. For the first time, however, rare variants in ACVR1 and SMAD6, integral components of the Bone Morphogenic Protein pathway, are found to be associated with juvenile idiopathic arthritis. Identified ACVR1 variants map to critical protein domains. AlphaFold modeling predicts that the ACVR1 interaction with its inhibitor OGT is disrupted by these variants, indicating that the patient-mutated protein has a gain-of-function phenotype. Drosophila melanogaster expressing either a wild-type or patient-mutated version of ACVR1 exhibit embryonic lethality, with the mutant exhibiting 1.4-fold greater lethality than wild-type. The combination of family-based cohorts for gene discovery, AI-based computational tools, and animal model studies for tests of variant function underscores shared disease pathogenesis between JIA and monogenic disorders of immunity and connective tissue.

Arthritis, Juvenile↗

PubMed2026

Exploring the Melanoma and Pancreatic Cancer Phenotype of a Potential CDKN2A Founder Variant, I49T (c.146T>C; p.Ile49Thr), in Individuals of Predominantly Mexican Ancestry.

PURPOSE: Pathogenic/likely pathogenic variants (P/LPVs) in the CDKN2A gene cause an increased risk of melanoma (MEL) and pancreatic cancer (PANC). The CDKN2A variant I49T (c.146T>C), reported to be recurrent in Hispanics, has conflicting pathogenicity classifications at laboratories, affecting clinical care. Multiple genetics clinics collaborated to explore cancers associated with I49T. METHODS: Institutional clinical databases were queried for the CDKN2A variants, I49T, known P/LPVs, and c.-2G>A (a benign variant [BV]), and history of PANC and MEL was abstracted. A combination of statistical tests was used to investigate cancer history associations. RESULTS: Data on 203 individuals, with qualifying CDKN2A variants detected on multigene testing between 2012 and 2023, were analyzed (I49T, n = 101; known CDKN2A P/LPVs, n = 57; BV, n = 45). Those with I49T were 91% less likely to have MEL than known CDKN2A P/LPVs (odd ratio [OR] = 0.089 [95% CI, 0.031 to 0.025]; P < .001) and were also less likely to have PANC (OR = 0.45 [95% CI, 0.14 to 1.41]; P = .17). However, mean age at PANC diagnosis for I49T was 56.0 years, significantly younger than known CDKN2A P/LPVs (μ = 71.0 years; P = .026). CONCLUSION: In the largest I49T study to date to our knowledge, MEL was significantly less frequent compared with known CDKN2A P/LPVs. Although a nonsignificant trend was observed for less PANC in I49T than known P/LPVs, individuals with I49T presented with PANC at a significantly younger age than those with known CDKN2A P/LPVs. The presence of I49T in Hispanics of mostly Mexican ancestry supports that it is a founder variant, relevant to understanding cancer risk in a large proportion of Hispanics in the United States.

Humans↗

PubMed2026

Postzygotic biallelic inactivation of FDFT1 underlies solitary lesion formation in porokeratosis of Mibelli.

BACKGROUND: Porokeratosis reflects clonal expansion of keratinocytes with biallelic inactivation of mevalonate-cholesterol biosynthesis pathway genes. In disseminated porokeratosis (DP), lesions arise through independent somatic second hits in carriers of heterozygous germline pathogenic variants, whereas porokeratosis of Mibelli (PM) is usually solitary, and its molecular basis remains incompletely defined. OBJECTIVE: To elucidate the molecular basis of solitary PM. METHODS: We analyzed blood and lesional epidermis from seven patients with solitary PM within a 156-patient porokeratosis cohort using deep sequencing, copy-number/SNP profiling, and methylation analysis. RESULTS: Solitary PM plaques were larger and more irregular than the annular DP lesions. No pathogenic germline variants were detected in MVK, PMVK, MVD, FDPS, or FDFT1. Three patients had somatic biallelic genetic inactivation of FDFT1 through putative deleterious variants and/or focal microdeletions. The remaining four showed FDFT1 promoter hypermethylation with loss of heterozygosity (LOH) at the FDFT1 locus due to copy-neutral LOH or a monoallelic 8p deletion, consistent with early monoallelic epigenetic silencing, followed by genetic loss of the remaining active allele. In one patient, part of the plaque expanded centrifugally over 7.5 years. CONCLUSION: Solitary PM can be driven by postzygotic, lesion-restricted, biallelic inactivation of FDFT1 through genetic or epigenetic mechanisms within a single epidermal clone, promoting clonal expansion. This model may explain the tendency toward solitary PM lesions. The low probability of acquiring postzygotic biallelic inactivation without germline predisposition may underlie solitary PM and suggest a low recurrence risk for offspring, unlike DP driven by germline heterozygosity.

General dermatology↗

PubMed2026

Expanding the clinical spectrum of ARV1-related disease beyond classical developmental and epileptic encephalopathy.

PURPOSE: Biallelic pathogenic variants in ARV1 are classically associated with developmental and epileptic encephalopathy-38 (DEE38), a severe infantile-onset disorder characterized by drug-resistant epilepsy, profound neurodevelopmental impairment, and early mortality. However, emerging evidence suggests broader phenotypic variability. We aimed to expand the clinical and molecular spectrum of ARV1-related disease through a retrospective case series and structured literature review. METHODS: We retrospectively identified five unrelated Saudi Arabian families with biallelic pathogenic or likely pathogenic ARV1 variants confirmed by whole-exome sequencing. Clinical, neurodevelopmental, neurophysiological, neuroimaging, and multisystem findings were reviewed. A structured literature review was performed to integrate previously reported cases. RESULTS: We identified marked clinical heterogeneity, including a novel ARV1 missense variant (c.214G>T; p.Asp72Tyr), which remains classified as a variant of uncertain significance according to ACMG/AMP criteria despite multiple computational predictions supporting a deleterious effect. Clinical severity ranged from severe developmental and epileptic encephalopathy with drug-resistant epilepsy and early mortality to milder static neurodevelopmental phenotypes with sustained seizure remission and long-term survival into adulthood. Families harboring the same homozygous frameshift variant exhibited markedly different clinical severity, supporting the absence of a strict genotype-phenotype correlation. Multisystem involvement included neurological, cardiac, skeletal, sensory, gastrointestinal, and genitourinary manifestations, and metabolic phenocopies contributed to diagnostic delays. CONCLUSION: Our findings demonstrate that ARV1-related disease represents a broad multisystem clinical spectrum, with classical DEE38 representing its most severe presentation rather than its sole manifestation. Recognition of milder phenotypes, prolonged seizure remission, and marked phenotypic variability has important implications for diagnosis, prognostic counseling, and multidisciplinary long-term surveillance. Early genomic testing should be considered in patients with early-onset epilepsy and multisystem involvement, particularly in consanguineous populations.

ARV1↗

PubMed2026

COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.

Primary mitochondrial diseases (PMDs) affect approximately 1 in 4300 individuals and cause early-onset neuromuscular and multisystem dysfunction with reduced lifespan. They result from pathogenic variants in mitochondrial or nuclear DNA that impair oxidative phosphorylation. Cytochrome c oxidase (COX; complex IV) deficiency is a well-established cause of PMD, leading to a broad spectrum of phenotypes. COXFA4 (cytochrome c oxidase subunit FA4), formerly NDUFA4, is a nuclear-encoded COX subunit, but its role in disease remains poorly defined. We report the largest genetically confirmed cohort of COXFA4-related PMD to date, comprising 13 individuals from 12 families with biallelic pathogenic COXFA4 variants. All present with Leigh-like encephalopathy and complete loss of COXFA4 protein; however, patient-derived fibroblasts retain residual COX activity, with upregulation of COXFA4L2 (cytochrome c oxidase subunit FA4-like 2), a poorly characterised paralog. Here, we show that COXFA4 is a late-stage COX assembly subunit and identify a paralog-mediated compensatory mechanism with translational potential.

Humans↗

PubMed2026

Clinical Variability and Genotype-Driven Outcomes in CHRND-Related Congenital Myasthenic Syndrome.

BACKGROUND: Congenital myasthenic syndromes (CMS) caused by pathogenic variants in CHRND, encoding the δ-subunit of the nicotinic acetylcholine receptor (AChR), are rare, and data on genotype-phenotype correlations and long-term outcomes are limited. METHODS: We performed a retrospective, multicenter study of nine patients with genetically confirmed CHRND-related CMS from specialized neuromuscular centers. Clinical, electrophysiological, genetic, and therapeutic data were systematically collected. All diagnoses were established by exome sequencing during routine clinical work-up. RESULTS: Eight patients were compound heterozygous and one was homozygous for pathogenic CHRND variants, including nonsense, missense, splice-site variants, and one microdeletion. Disease onset ranged from the neonatal period (n = 7) to adolescence (n = 2). Three patients were followed longitudinally for 22-43 years. Ocular involvement, particularly ptosis and ophthalmoparesis, was present in all patients. Generalized fatigable weakness was common, whereas bulbar and respiratory involvement occurred in a subset and reflected overall disease severity. Genotypes including a null allele or a homozygous missense variant tended to be associated with more severe phenotypes, while compound heterozygous missense variants were linked to a broader and generally milder spectrum, sometimes limited to ocular symptoms. Long-term outcomes ranged from minimal symptoms under therapy to severe motor impairment with respiratory insufficiency, highlighting substantial interindividual variability. CONCLUSIONS: This study expands the phenotypic and genotypic spectrum of CHRND-related CMS and underscores the critical role of genotype in determining disease severity. Comprehensive genetic testing, longitudinal phenotyping, and genotype-informed management are essential for optimal diagnosis and care in this rare disorder.

Humans↗

PubMed2026

Establishment of human induced pluripotent stem cell lines and isogenic gene-corrected controls from three patients with prolidase deficiency.

Prolidase deficiency is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the PEPD gene. To date, close to 200 patients have been reported worldwide with a poorly understood pathomechanism. The PEPD gene encodes an enzyme that is involved in the final steps of collagen degradation. Urine amino acid analysis or specific dipeptide analysis can establish the biochemical diagnosis. In this study, we reprogrammed peripheral blood mononuclear cells (PBMCs) from three prolidase deficient patients into induced pluripotent stem cell (iPSC) lines and additionally generated isogenic controls using CRISPR-Cas9 genome editing. The pathogenic PEPD variants identified in our patients were NP_000276.2:p.? (NIHTVBi032-A), NP_000276.2:p.(Ile415Asn)/NP_000276.2:p.(Trp326Ter) (NIHTVBi033-A), and NP_000276.2:p.(Arg265Ter) (NIHTVBi034-A). These iPSC lines are valuable models to help investigate the pathomechanism of prolidase deficiency.

Humans↗