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PubMed2026

Molecular Characterisation of Treacher Collins Syndrome in a South African Cohort: Novel Disease-Causing Variants in TCOF1 and POLR1D.

BACKGROUND: Treacher Collins syndrome (TCS) is a rare craniofacial disorder characterised by variable expressivity. It is caused by pathogenic variants in the TCOF1, POLR1D, POLR1C, or POLR1B genes. Common clinical features include hypoplasia of the zygomatic complex and mandible, downward-slanting palpebral fissures, lower eyelid anomalies, microtia, and hearing loss. Owing to its phenotypic overlap with other craniofacial syndromes, molecular testing is essential for establishing an accurate diagnosis and guiding effective clinical management. METHODS: Ten South African patients with a suspected clinical diagnosis of TCS underwent targeted next-generation sequencing (NGS) using a custom gene panel including TCOF1, POLR1C, and POLR1D genes. Variants were classified according to ACMG/AMP guidelines, with validation by Sanger sequencing where necessary. RESULTS: Disease-causing variants were identified in six of the ten patients (60%). These included five heterozygous variants in TCOF1 and one homozygous variant in POLR1D. Notably, five of the six variants were identified for the first time in this study. Additionally, a recurrent TCOF1 deletion was identified for the first time in an African family. CONCLUSION: This study expands the mutational spectrum of TCS in general and provides African data in particular. Findings support the use of panel-based NGS for diagnosis in resource-limited settings and highlight the need for population-specific variant data to improve diagnostic accuracy, guide clinical care, and support genetic counselling for affected individuals and their families.

Humans↗

PubMed2026

Mechanisms underlying disease-causing variants in promoters and enhancers.

The study of human monogenic disorders has been a powerful tool for generating a deep understanding of protein function/dysfunction and for uncovering underlying biological mechanisms. Here we explore the insights that an expanding catalog of noncoding monogenic disease variants can provide into the functions of the noncoding genome. We focus on small genetic alterations (one to a few tens of base pairs) in cis-regulatory elements-promoters, enhancers and silencers-and their potential mechanisms of action, such as loss or gain of function. We discuss the challenges in determining pathogenicity for variants in the noncoding genome, discuss why there might be so few concrete examples and highlight the opportunities for advancing this area of human genetics by using experimental and machine-learning tools.

Journal Article↗

PubMed2026

The Animal Variant Classification Guidelines v2: An Update With New Criteria and Improved Clarifications.

The Animal Variant Classification Guidelines (AVCG) were developed to standardize and objectify the classification of putative disease-causing variants. These guidelines are sufficiently reproducible and are used to classify previously published and new disease-causing variants across species. Here, the guidelines are updated (AVCG.v2), based on a three-phase decision process. Overall, four new criteria and seven clarifying comments were added. The number of criteria has increased from 23 to 27, with three new criteria supporting pathogenicity and one new criterion supporting benign classification. Pharmacogenomic variants were determined to fall within the scope of the guidelines. These updated guidelines are being used by the Variant Pathogenicity Working Group (VPWG), part of the Animal Genetic Testing Standardization standing committee, which is a committee of elected members of the International Society for Animal Genetics (ISAG). Under the auspices of ISAG, the VPWG retrospectively classifies published putative disease-causing variants. The pathogenicity label for a variant will be presented in the variant tables of Online Mendelian Inheritance in Animals (OMIA; https://omia.org/). The AVCGv.2 criteria and recommendations were developed by the expertise of the animal genetics community and the ISAG Executive Committee through the Animal Genetics Testing Standardization Committee endorses and strongly encourages their use to evaluate the evidence supporting pathogenicity of putative disease-causing variants.

Animals↗

PubMed2026

Integrated exome and mitochondrial genome sequencing reveals the genetic landscape of primary mitochondrial diseases: findings from a large Tunisian cohort.

Primary mitochondrial diseases are a heterogeneous group of neurometabolic disorders recognized as the most common metabolic genetic diseases. They manifest at any age, affecting any tissue or organ, especially those with high energy demands, and are caused by pathogenic variants in both mitochondrial and nuclear genomes. Here, we aimed to describe the genetic spectrum of a Tunisian pediatric cohort with suspected mitochondrial diseases. We recruited 47 unrelated families who underwent exome sequencing as a first-tier test followed by whole mitochondrial genome sequencing for unsolved cases. Dedicated bioinformatic pipelines and prediction tools were used to determine the potential disease-causing variants. Sanger sequencing confirmed the presence and segregation within parents. For the newly identified variants, structural modeling was conducted to study the impact of these variants on protein structure and motions. Dual genome sequencing yielded a molecular diagnosis in 33/47 families (70%) and 18/47 (38%) showed disease-causing variants in genes encoding mitochondrial proteins. Among them, four families disclosed novel variants in FASTKD2, SERAC1 and GATB, which were supported by in-depth in silico and structural analyses demonstrating their deleterious effect. The remaining families (32%, 15/47) disclosed other metabolic and neurological disorders. An exome-first strategy delivers a high diagnostic yield in Tunisia, where consanguinity remains high and simultaneously captures mitochondrial and non-mitochondrial etiologies. Mitochondrial sequencing remains indispensable in the case of an inconclusive exome. Thus, our data expand the clinical and genetic spectrum of primary mitochondrial diseases in Tunisia, an underrepresented and admixed population.

Humans↗

PubMed2024

BICEP: Bayesian inference for rare genomic variant causality evaluation in pedigrees.

Next-generation sequencing is widely applied to the investigation of pedigree data for gene discovery. However, identifying plausible disease-causing variants within a robust statistical framework is challenging. Here, we introduce BICEP: a Bayesian inference tool for rare variant causality evaluation in pedigree-based cohorts. BICEP calculates the posterior odds that a genomic variant is causal for a phenotype based on the variant cosegregation as well as a priori evidence such as deleteriousness and functional consequence. BICEP can correctly identify causal variants for phenotypes with both Mendelian and complex genetic architectures, outperforming existing methodologies. Additionally, BICEP can correctly down-weight common variants that are unlikely to be involved in phenotypic liability in the context of a pedigree, even if they have reasonable cosegregation patterns. The output metrics from BICEP allow for the quantitative comparison of variant causality within and across pedigrees, which is not possible with existing approaches.

Pedigree↗

PubMed2024

Identification of a novel intronic variant in COL4A2 gene associated with fetal severe cerebral encephalomalacia and subdural hemorrhage.

BACKGROUND: Genetic variants in COL4A2 are less common than those of COL4A1 and their fetal clinical phenotype has not been well described to date. We present a fetus from China with an intronic variant in COL4A2 associated with a prenatal diagnosis of severe cerebral encephalomalacia and subdural hemorrhage. METHODS: Whole exome sequencing (WES) was applied to screen potential genetic causes. Bioinformatic analysis was performed to predict the pathogenicity of the variant. In in vitro experiment, the minigene assays were performed to assess the variant's effect. RESULTS: In this proband, we observed ventriculomegaly, subdural hemorrhage, and extensive encephalomalacia that initially suggested cerebral hypoxic-ischemic and/or hemorrhagic lesions. WES identified a de novo heterozygous variant c.549 + 5G > A in COL4A2 gene. This novel variant leads to the skipping of exon 8, which induces the loss of 24 native amino acids, resulting in a shortened COL4A2 protein (p.Pro161_Gly184del). CONCLUSION: Our study demonstrated that c.549 + 5G > A in COL4A2 gene is a disease-causing variant by aberrant splicing. This finding enriches the variant spectrum of COL4A2 gene, which not only improves the understanding of the fetal neurological disorders associated with hypoxic-ischemic and hemorrhagic lesions from a clinical perspective but also provides guidance on genetic diagnosis and counseling.

Female↗

PubMed2026

Molecular diagnostic yield and barriers in inherited retinal diseases: a retrospective cohort study.

OBJECTIVE: To evaluate the diagnostic yield of panel-based genetic testing for inherited retinal diseases (IRDs) and identify barriers to molecular resolution. DESIGN: Retrospective cohort. PARTICIPANTS: A total of 404 patients with clinically confirmed IRDs who were evaluated at the Adult Inherited Retinal Dystrophy Service, Ontario, Canada (October 2021-September 2024). METHODS: Patients underwent targeted massive parallel sequencing panel testing. Diagnostic yield was calculated, and unresolved cases were reviewed. Associations between yield, phenotype, ethnicity, and sex were assessed using χ² analysis. RESULTS: Of 685 referrals, 570 had confirmed IRDs. After we excluded 140 pending results and 26 patients who declined testing, 404 patients were analyzed. At referral, 94 patients (23.2%) had a previous molecular diagnosis, and 138 (34.0%) were diagnosed through clinic-initiated testing, giving an overall yield of 57.4%. Yield varied significantly by phenotype (χ², P = 1.4 × 10⁻⁶), from 94.4% in vitelliform macular dystrophies to 25.0% in vitreoretinopathies, with no sex association (P = 1.0). Disease-causing variants were identified in 83 IRD-associated genes, most frequently ABCA4, USH2A, and BEST1. Of 172 unresolved cases, 62 (36.0%) had negative panels, and 110 (63.9%) were inconclusive, including 30 with unphased pathogenic variants in recessive genes and 10 with high-suspicion variants of uncertain significance. Key barriers included limited family availability for phasing, restricted access to functional assays, and lack of public coverage for whole-exome or whole-genome sequencing. CONCLUSIONS: Massive parallel sequencing-based panel testing achieved a 57% diagnostic yield in this IRD population. Success was strongly phenotype-dependent with substantial heterogeneity. Whole-exome sequencing, whole-genome sequencing, family segregation, and functional genomics could improve diagnostic outcomes and management.

Humans↗

PubMed2026

The importance of integrating genetic testing into reproductive medicine: a retrospective observational study investigating the monogenic causes of human infertility in couples considering ICSI.

The genetic landscape of human infertility is complex with diverse etiologies. Identifying the underlying etiology is crucial for guiding reproductive decisions and improving management for infertile couples. Here, we aim to report on the molecular spectrum of monogenic genetic causes of reproductive failure. Over a 3-year period, we recruited all infertile couples considering assisted reproductive technologies (ART) for whom the underlying genetic cause had been identified, in either partner, using exome sequencing (ES). Clinical data of all participants along with their hormonal profiles, sonographic findings and spermograms were recorded. The study included 50 couples with primary infertility. Clinically, male factor infertility was documented in 26 patients, female factor infertility in 10, while reproductive failure was unexplained in the remaining 14 couples. All participating couples had potentially disease-causing variants in infertility genes. ES identified variants related to male infertility in 26 men, while variants in female infertility-related genes were detected in the remaining couples (n = 24). According to ACMG classification criteria, 78% (39/50) of couples harbored pathogenic/likely pathogenic (P/LP) variants, whereas 22% (11/50) carried variants of uncertain significance (VUS). In view of the identified genetic etiologies, the cohort was stratified into two groups based on the predicted reproductive outcome: (1) couples with significantly impaired reproductive potential, and (2) couples who can have biological children using appropriate medical interventions. However, classifications involving VUS were interpreted cautiously and considered exploratory. This study provides further evidence for the molecular heterogeneity of human infertility and highlights the usefulness of genetic testing for infertile couples pursuing ARTs.

Humans↗

PubMed2024

A novel frameshift variant in the TMPRSS3 gene causes nonsyndromic hearing loss in a consanguineous family.

BACKGROUND: Hearing Loss (HL) is the most common sensorineural condition in humans. Mutations in the TMPRSS3 gene (DNFB8/10 locus) have been linked to autosomal recessive non-syndromic hearing loss (ARNSHL). METHODS: Whole-exome sequencing (WES) was utilized to identify disease-causing variants in a proband from Iran with ARNSHL who presented clinically with sensorineural, bilateral, and prelingual HL. The pathogenicity and novelty of the identified variant were assessed using various databases. A co-segregation study was also performed to confirm the presence of the variant in the proband's parents. Additionally, the secondary and tertiary structures of the mutant TMPRSS3 protein were predicted using bioinformatics tools. Furthermore, a global mutational spectrum of TMPRSS3 was created and statistically analyzed. The Iranome database was also used to identify other putative mutations in the TMPRSS3 gene in the Iranian population. RESULTS: We identified a novel homozygous single nucleotide deletion in TMPRSS3 (c.297delA, p.Asp100ThrfsTer52) in the proband. This is the first report of this mutation in a patient with ARNSHL. Sanger sequencing confirmed that this variant co-segregated from the proband's parents. Bioinformatic tools classified this novel variant as likely pathogenic. Additionally, 49.55% of families with TMPRSS3-related HL patients were shown to have consanguinity, consistent with our study. The Iranome database also revealed the c.268G > A variant as a putative novel mutation in TMPRSS3. CONCLUSION: This research expanded the pool of evidence regarding the association between mutations in the TMPRSS3 gene and ARNSHL. The finding confirmed that a single nucleotide deletion caused HL in the proband, suggesting that genetic testing, such as WES, is a robust technique for diagnosing patients with this condition.

Humans↗

PubMed2025

A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1.

BACKGROUND: NOTCH1 is associated with two disorders of vascular development, Adams-Oliver Syndrome 5 (AOS5) and aortic valve disease 1 (AOVD1). Here we report a disease-causing variant in NOTCH1 that has a previously undemonstrated effect on splicing. Additionally, we found that the proband has the optic phenotype of familial exudative vitreoretinopathy (FEVR) which has been reported for probands with pathogenic variants in genes in the notch signaling pathway, but never for NOTCH1. CASE PRESENTATION: The proband presented with a ventricular septal defect, pulmonic stenosis, and ocular findings consistent with familial exudative vitreoretinopathy (FEVR), which NOTCH1 has not been associated with to date. Trio exome sequencing identified a paternally inherited variant of uncertain significance in NOTCH1:c.2153 A > G. We assessed the variant's effect using RT-PCR, finding an increased use of a cryptic donor compared to the control. On this basis, we were able to re-classify this variant as pathogenic. CONCLUSIONS: We expand the phenotypic spectrum of NOTCH1 and contribute to the building evidence that variants in NOTCH1 cause a spectrum of disorders of vascular development.

Humans↗

PubMed2025

The CTDP1 Founder Variant in CCFDN: Insights into Pathogenesis, Phenotypic Spectrum and Therapeutic Approaches.

Congenital Cataracts, Facial Dysmorphism, and Neuropathy (CCFDN) syndrome is a rare autosomal recessive disorder predominantly found among Vlax Roma populations, caused by a deep intronic founder variant in the CTDP1 gene. This review synthesizes recent advances in understanding the molecular mechanisms of CTDP1 dysfunction, highlighting its central role in transcriptional regulation, RNA splicing, DNA repair, and genome integrity. The unique splicing defect caused by the founder disease-causing variant in the Roma population results in a multisystem phenotype with early-onset neuropathy, congenital cataracts, and characteristic facial dysmorphism. Beyond its genetic homogeneity, CCFDN displays variable clinical severity and presents diagnostic challenges due to overlapping syndromic features. We discuss the emerging therapeutic landscape, focusing on antisense oligonucleotides, small molecule modulators, gene replacement, and genome or transcriptome editing strategies, while emphasizing the challenges in targeted delivery and efficacy. Ongoing insights into CTDP1's broader biological functions and population genetics inform new directions for diagnosis, genetic counselling, and the development of effective therapies for this severe yet underrecognized disorder.

Humans↗

PubMed2025

VarPPUD: Pinpointing diagnostic variants from sets of prioritized, strong candidate variants.

Rare and ultra-rare genetic conditions are estimated to impact nearly 1 in 17 people worldwide, yet accurately pinpointing the diagnostic variants underlying each of these conditions remains a formidable challenge. Because comprehensive, in vivo functional assessment of all possible genetic variants is infeasible, clinicians instead consider in silico variant pathogenicity predictions to distinguish plausibly disease-causing from benign variants across the genome. However, in the most difficult undiagnosed cases, such as those accepted to the Undiagnosed Diseases Network (UDN), existing pathogenicity predictions cannot reliably discern true etiological variant(s) from other deleterious candidate variants that were prioritized through case- or family-level analyses. Pinpointing the disease-causing variant from a small pool of plausible candidates remains a largely manual effort requiring extensive clinical workups, functional and experimental assays, and eventual identification of genotype- and phenotype-matched individuals. Here, we introduce VarPPUD, a tool trained on prioritized variants from UDN cases, that leverages gene-, amino acid-, and nucleotide-level features to discern pathogenic (disease causative) variants from other damaging or deleterious variants that are unlikely to be confirmed as relevant to the disease. VarPPUD achieves a cross-validated accuracy of 79.3% and precision of 77.5% on a held-out subset of uniquely challenging UDN cases, respectively representing an average 18.6% and 23.4% improvement over nine existing state-of-the-art pathogenicity prediction tools on this task. We validate VarPPUD's ability to discriminate likely from unlikely pathogenic variants using both synthetic data generated via a GAN-based framework and a temporally held-out set of UDN patients evaluated between 2022 and 2024. The model was trained exclusively on data available through 2021 and applied without retraining to the post-2021 cohort, demonstrating strong generalizability to newly accrued cases. Finally, we show how VarPPUD can be probed to evaluate each input feature's importance and contribution toward prediction-an essential step toward understanding the distinct characteristics of newly-uncovered disease-causing variants.

Humans↗

PubMed2026

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

Congenital muscular dystrophies (CMDs) are a genetically heterogeneous group of disorders. Variants in the INPP5K gene, which encodes a phosphoinositide phosphatase, are a rare cause of CMD. The condition is commonly associated with muscle weakness, early-onset cataracts, and intellectual disability, and prior reports have primarily identified missense, frameshift, or deletion variants. We describe the first Chinese case of INPP5K-related muscular dystrophy in a 28-year-old male with a mild phenotype, notably lacking intellectual disability. His presentation included bilateral cataracts at age 5 and adolescent onset limb girdle weakness. Muscle magnetic resonance imaging (MRI) revealed a characteristic pattern of selective fatty infiltration, with severe involvement of gluteal and thigh muscles and striking sparing of the rectus femoris, sartorius, and gracilis. Genetic analysis identified compound heterozygous novel INPP5K variants: a missense c.274C>T, p.(Arg92Cys) and a synonymous c.261G>A, p.(Lys87=) change. Functional studies confirmed the synonymous variant causes aberrant splicing (exon 3 skipping), leading to a frameshift and premature termination p.(Leu52SerfsTer49). According to American College of Medical Genetics and Genomics guidelines, the c.274C>T and c.261G>A variants were classified as likely pathogenic and pathogenic, respectively. This first report of a Chinese patient with INPP5K-related muscular dystrophy broadens both the genetic and clinical spectrum of the disorder. We identify the first disease-causing synonymous variant (via aberrant splicing) and a novel hypomorphic missense variant p.(Arg92Cys), the combination of which explains the attenuated phenotype lacking intellectual disability. Our case highlights the critical role of RNA analysis in diagnosing non-canonical variants and confirms the universal diagnostic relevance of the characteristic muscle MRI pattern.

Adult↗

PubMed2026

Fractures are highly correlated with bone density and inversely correlated with bone turnover markers in autosomal dominant osteopetrosis.

Autosomal dominant osteopetrosis (ADO) is a rare osteosclerotic disorder usually caused by missense variants in the CLCN7 gene, which results in impaired osteoclastic bone resorption. Penetrance is incomplete, and disease severity varies widely, even among relatives within the same family. Although ADO can cause visual loss, osteonecrosis, osteomyelitis, and bone marrow failure, the most common complication of ADO is fracture. We are conducting a natural history study to characterize disease progression and determinants of disease severity. We hypothesized that baseline BMD and bone turnover markers would correlate with self-reported fracture history. We report cross-sectional analysis of baseline data from the natural history study in 54 individuals (42 adults, 12 children). In adults, Z-scores for both volumetric (r = 0.87, p < .001) and areal BMD (aBMD) of the LS, and Z-scores for FN, and TH aBMD (r = 0.77 to 0.78; p < .001) were correlated with lifetime fracture number. Tartrate resistant acid phosphatase, a marker of osteoclast number, correlated positively with fracture (r = 0.52, p = .004) consistent with an adaptive response of higher numbers of osteoclasts among more severely affected individuals. However, fracture number correlated inversely with the bone resorption markers serum C-telopeptide (r = -0.60, p < .001) and urine N-telopeptide/creatinine ratio (r = -0.35, p = .047), suggesting that ADO subjects who have the most reduced osteoclast activity have a greater tendency to fracture. Correlation coefficients between fractures, BMD, and bone turnover markers were similar when limited to the 37 adults with disease-causing CLCN7 variants. There were no statistically significant differences between subjects with the most common CLCN7 variant (G215R), the most common variant in our cohort, compared to other CLCN7 variants with respect to fracture, bone density measures, or biochemical markers of bone turnover. These data demonstrate that bone density and biochemical bone turnover markers are indicators of ADO severity as defined by fracture number.

Humans↗

PubMed2026

No Correlation Between Interferon Signaling and Cytosolic Mitochondrial DNA/RNA Leakage in Cultured Skin Fibroblasts of Patients With Mitochondrial Diseases.

Mitochondria have long been known to be involved in the regulation of innate immune response. We questioned whether cultured skin fibroblasts of patients suffering from mitochondrial diseases are valuable biological resources for the study of interferon signaling. Expression of interferon-stimulated genes was measured in control cells supplemented with interferon and in cultured fibroblasts of patients carrying pathogenic variants in mitochondrial disease-causing genes. Control fibroblasts showed a strong expression of interferon-stimulated genes in response to interferon, but only 43% of patients' fibroblasts displayed increased interferon stimulated genes scores. Cytosolic mitochondrial DNA and RNA were quantified by immunofluorescence and confocal microscopy. No correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA release could be established. We found that cultured skin fibroblasts represent a valuable biological resource for the investigation of interferon signaling, but that abnormal interferon signaling is not always observed in patients with mitochondrial diseases. At variance to gene silencing in control fibroblasts, the lack of correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA leakage in patients' fibroblasts questions the relevance of cellular models as illustrators of pathological situations in humans.

Humans↗

PubMed2026

Phenotypes of Hereditary Diseases Associated With Rauch-Steindl Syndrome.

PURPOSE: Prenatal phenotypic manifestations of genetic disorders associated with NSD2 variants remain poorly characterized. This study presents our institutional experience with the prenatal diagnosis of NSD2-associated genetic disorders, specifically Rauch-Steindl syndrome (RAUST), aiming to improve understanding of both the molecular and clinical features of RAUST. METHODS: We performed a retrospective analysis of six fetuses and one adult diagnosed with RAUST at our institution and thoroughly reviewed the prenatal ultrasound reports of six fetuses. Prenatal and postnatal phenotypes of RAUST cases were summarized alongside findings from previously published literature. Correlations between NSD2 variant locations, variant types, and phenotypes were analyzed. Additionally, protein modeling was used to visualize structural changes in NSD2 protein before and after C-terminal variants. We integrated single-cell transcriptomic and gene expression data from multiple public databases to investigate spatiotemporal expression patterns of NSD2 during human fetal development. RESULTS: Fetal growth restriction (FGR) was the most prevalent prenatal manifestation in RAUST fetuses, followed by microcephaly. Bilateral renal hypoplasia emerged as a novel prenatal ultrasonographic feature. Postnatally, speech and motor developmental delays were the most commonly reported phenotypes, followed by physical developmental delays and intellectual disability. Genotype-phenotype correlation analysis revealed an association between N-terminal truncating variants in NSD2 and impaired fetal growth parameters. Notably, C-terminal truncating variants-predicted not to directly impact NSD2 functional domains-also exerted disease-causing effects. CONCLUSION: This study provides a comprehensive analysis of prenatal phenotypes in RAUST cases, enriching the prenatal phenotypic spectrum of the disease and facilitating early diagnosis and clinical management of RAUST. Furthermore, our genotype-phenotype correlation findings lay a foundational basis for future research into the complex molecular mechanisms underlying NSD2-associated genetic disorders.

Humans↗

PubMed2025

Whole-genome sequencing, as a powerful diagnostic tool in hearing loss, reveals novel variants in PTPRQ missed by whole-exome sequencing.

BACKGROUND/OBJECTIVES: Hearing loss (HL) is one of the most common congenital disorders, affecting 1-2 in 1,000 newborns. Modern genetic diagnostics using large gene panels and/or whole exome analysis (WES) can identify disease-causing mutations in 25-50 % of patients, with higher solve rates in individuals with earlier onset. RESULTS: Here, we used whole-genome sequencing (WGS) to reanalyze 14 index patients/families who remained without genetic diagnosis by WES. We were able to identify the genetic cause of HL in 6 families (43 %). Two families were diagnosed with DFNB84A caused by compound heterozygous recessive mutations in PTPRQ. Three of the four underlying variants, including a structural variant, a deep intronic variant, and a splice variant, escaped detection by WES. Minigene assays confirmed the pathogenicity of the intronic and the splice variants. In addition, we used protein 3D structure prediction and rigid ligand docking to study the pathogenicity of variants that escape nonsense-mediated decay. CONCLUSION: In our study, we present four novel variants in PTPRQ, three of which were detected only by WGS. To our knowledge, we report here the first pathogenic deep intronic PTPRQ variant causing HL. Our results suggest that the mutational spectrum of PTPRQ is not well covered by standard WES and that PTPRQ-associated hearing loss may be more frequent than previously thought. WGS provides an additional layer of information in the diagnostics of HL.

Humans↗

PubMed2026

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

SLC25A4, solute carrier family 25 member 4, gene is a member of the mitochondrial carrier subfamily within the solute carrier protein family. Pathogenic variants in SLC25A4 are associated with a spectrum of mitochondrial disorders that exhibit variable inheritance patterns and clinical manifestations. Specifically, dominantly inherited variants are typically associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, recessively inherited variants are linked to myopathy and cardiomyopathy, and de novo variants can result in early-onset fatal disease presentations. In this study, we aimed to identify and characterize the disease-causing mutation(s) in a nine-year-old female patient from a consanguineous Saudi family. The patient was asymptomatic until the age of 3 years, when she presented with cardiomyopathy and myopathy. Comprehensive genetic analysis inclusive of whole exome sequencing and segregation analysis using Sanger sequencing identified an SLC25A4 variant (NM_001151.4: exon 2: c.112-1G>C) as the most likely cause of the disease. To assess transcript-level effects, we performed RT-PCR on RNA extracted from the patient's cultured lymphoblast cell lines (LCLs) and fibroblast cell lines (FCLs). RT-PCR analysis demonstrated that the variant causes aberrant splicing, resulting in a 6 bp in-frame deletion (p.Gln37_Val38del) in the ANT1 protein. Quantitative RT-PCR demonstrated reduced SLC25A4 transcript levels in both FCLs and LCLs. Quantitative PCR analysis of mitochondrial DNA demonstrated a trend toward increased mtDNA copy number in patient-derived FCLs compared with controls, suggesting a possible compensatory response to mitochondrial dysfunction. Furthermore, Seahorse assays revealed marked reductions in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in patient-derived FCLs compared with controls. These findings expand the molecular and functional spectrum of SLC25A4-associated disease 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.

Humans↗