Variants in the EMD gene cause Emery-Dreifuss muscular dystrophy type 1 (EDMD1). While the pattern of fat replacement in the legs of patients with EDMD1 is known, the involvement of the trunk and arms remains unclear. This study aimed to characterize the whole-body distribution of fatty replacement in EDMD1 and clarify its relationship with clinical symptoms. Imaging data from eight Japanese EDMD1 patients was analyzed. Fatty replacement in 47 skeletal muscles was scored using the modified Mercuri score (mMS). Hierarchical clustering classified patients according to mMS, and intercluster differences were assessed. Fatty replacement was observed in the soleus and paraspinal muscles in all patients, as well as in the medial gastrocnemius, semimembranosus (Sm), biceps femoris long head (BFL), serratus anterior (SA), and biceps brachii (BB) in seven patients. A significant difference in mMS was observed between the low- and high-score groups in the SA (p = 0.0042), BB (p = 0.0031), semitendinosus (p = 0.0015), Sm (p < 0.0005), and BFL (p = 0.0031). Elbow flexion strength on manual muscle testing strongly correlated with BB mMS (p = 0.03, r = -0.75). The patient with a missense variant had a lower mMS than those with truncating variants. Elbow flexion strength is a potential marker of disease severity. The finding that the patient with a missense variant had a lower mMS supports previous reports that missense variants are associated with milder phenotypes. Genetic variant type should be considered in biomarker development for EDMD1.

While the pathogenic role of autoantibodies targeting the podocyte protein THSD7A in membranous nephropathy (MN) is well described, the consequences of autoantibody binding for podocyte homeostasis and the function of THSD7A remain unclear. Here, we induced an MN model in control and podocyte-specific Thsd7a knockout (Thsd7a-/-) mice using rabbit anti-THSD7A antibodies, followed by transcriptome and proteome analyses. Anti-THSD7A antibodies in WT mice caused significant loss of key slit diaphragm (SD) proteins such as nephrin and NEPH1, without transcriptional downregulation. Glomeruli showed substantial transcriptomic and proteomic reconfiguration indicative of extensive podocyte injury, including disruptions in podocyte adhesion, cytoskeletal dynamics, and marked upregulation of ubiquitin-proteasome system components, cathepsins and ADAM proteases. Notably, experiments in C3-deficient mice revealed that proteolytic activation and SD protein loss are driven by complement-independent pathways. While Thsd7a-/- mice only displayed a mild phenotype under basal conditions, they were completely protected from MN development upon anti-THSD7A antibody transfer. Finally, interactomic analysis identified a protein complex including THSD7A and integrin α3, linking THSD7A complexes to pathogenic regulation of cytoskeleton, adhesion, and membrane signaling in MN. Thus, anti-THSD7A antibodies induce profound molecular reconfiguration, including dysregulated proteolytic systems via a complement-independent pathway, revealing potential therapeutic targets in MN.

The risk of increased intracranial pressure (ICP) in metopic synostosis remains poorly defined, leading to uncertainty about the need for routine surgical intervention vs conservative management. To compare head growth trajectories and the prevalence of signs of increased ICP among patients with metopic synostosis managed surgically or conservatively. This prospective cohort study included all 209 new patients with single-suture metopic synostosis presenting to Erasmus Medical Center, Rotterdam, the Netherlands, from January 1, 2017, to December 31, 2024. The current analysis included data collection up to July 31, 2025. Patients underwent annual follow-up with head circumference measurement and fundoscopy. Surgical or conservative management of metopic synostosis determined through shared decision-making between clinicians and parents. The primary outcome was longitudinal head circumference standard deviation (SD), analyzed using linear mixed models. Secondary outcomes were head growth deflection and papilledema, understood as signs of increased ICP, detected on fundoscopy. Among 209 patients (78 surgical and 131 conservative; median age at presentation, 4 months [IQR, 2-7 months]; 154 boys [74%]), the median age at last follow-up was 40 months (IQR, 24-61 months). Head circumference SD increased significantly with age in a nonlinear pattern (age spline df = 1; β = 0.87; 95% CI, 0.54-1.21; P < .001; and age spline df = 2; β = 0.73; 95% CI, 0.29-1.16; P < .001). Female sex was associated with higher SD (β = 0.31; 95% CI, 0.03-0.60; P = .03). Surgical treatment was associated with higher initial SD but a significantly flatter growth trajectory over time compared with conservative treatment (β = -1.02; 95% CI, -1.52 to -0.52; P < .001 for interaction age spline and treatment). Severe deformity phenotype was associated with lower SD values compared with mild deformity phenotype (β = -0.39; 95% CI, -0.75 to -0.04; P = .03). Among 158 patients with 2 or more years of follow-up, head growth deflection occurred among 3 patients (1.9%): 2 of 65 (3.1%) in the surgical group and 1 of 93 (1.1%) in the conservative group (P = .57). Papilledema was observed in 3 patients (1.4%): 2 of 78 (2.6%) in the surgical group and 1 of 131 (0.8%) in the conservative group (P = .56). None of these patients required additional surgery. In this prospective cohort of patients with metopic synostosis, signs of elevated ICP were rare and did not differ between surgical and conservative groups. Although surgery altered head growth trajectories, the low prevalence of ICP-related findings supports close monitoring and selective surgical intervention as safe alternatives to routine surgery.

Polycystic ovary syndrome (PCOS) is a common endocrine–metabolic condition that carries a higher cardiovascular risk than currently reflected by traditional screening tools. Emerging evidence suggests that resting tachycardia and autonomic dysfunction may serve as early, non-invasive indicators of cardiovascular dysregulation in this population. This review synthesizes current data on resting heart rate (RHR), heart rate variability (HRV), and direct autonomic markers in women with PCOS, drawing from human studies published between 2000 and 2025. Across 32 eligible studies, most reported increased sympathetic activity, reduced parasympathetic tone, elevated RHR, and impaired HRV patterns observed even in normal-weight or metabolically mild PCOS phenotypes. These alterations correlate with endothelial dysfunction, arterial stiffness, and subclinical atherosclerosis, underscoring their cardiovascular relevance. Mechanistic insights highlight the contributions of insulin resistance, hyperandrogenism, inflammation, adipokine imbalance, chemoreflex sensitization, and altered cortisol metabolism to autonomic disruption. Despite consistent findings, methodological variability in HRV protocols and inadequate adjustment for major confounders limit definitive interpretation. RHR, due to its simplicity and accessibility, including through wearable devices, holds promise as a supportive early risk signal; however, it should not be used in isolation. Future studies must adopt standardized autonomic measurements, including diverse cohorts, and evaluate whether modifying autonomic markers translates into improved cardiometabolic outcomes. Integrating RHR and HRV with metabolic and endocrine markers may enhance early cardiovascular risk stratification in women with PCOS.

Newborn screening programs are instrumental in the early detection of treatable conditions in the first days of life. By integrating genomic approaches, there is potential to expand the range of conditions included in these programs. As part of a research study, NewbornsInSA, we validated a genomic newborn screening workflow. Analysis of whole-genome sequencing data was restricted to a virtual panel of 613 genes, selected through engagement with local clinical teams. We assessed the workflow's performance using retrospective samples with known variant status. To reduce manual curation time, bioinformatics scripts were developed to auto-classify cases into those with no findings and those requiring manual review. We report on early findings from applying this workflow to a prospectively recruited cohort in which five reportable findings have been made to date. We discuss reporting challenges encountered in genes associated with multiple conditions, with incomplete penetrance, or variants associated with only mild phenotypes.

Podocytes, epithelial cells of the glomerular filtration barrier, are constantly exposed to biomechanical forces. These include hydrostatic pressure and shear stress, which increase during diseases such as hypertension or diabetes. To sense and respond to such changes in their physical environment, podocytes express mechanosensors and mechanotransducers. To deepen our knowledge about renal mechanotransduction mechanisms, we used Drosophila nephrocytes. Nephrocytes and mammalian podocytes are highly similar in morphology and molecular make-up of the filtration barrier; thus, nephrocytes are considered the homologue cells to podocytes. In addition, nephrocytes also experience biomechanical forces because of haemolymph movement. Here, we investigated the role of the mechanotransducer Piezo in larval garland nephrocytes. Depletion of Piezo produces only a mild functional phenotype, whereas elevated Piezo levels result in a severe phenotype with functional and morphological disturbances. Increased Piezo levels also cause the accumulation of actin stress fibres, increased Cubilin expression, more acidic vesicles, increased mitochondrial mass and/or activity, and elevated superoxide levels.

ADSS1 myopathy is an ultrarare congenital myopathy characterized by progressive cardiac and skeletal muscle degeneration with childhood to adolescent onset. This autosomal recessive disease is caused by mutations in the ADSS1 gene, encoding the enzyme adenylosuccinate synthetase (AdSS1). AdSS1 plays a critical role in the adenine nucleotide cycle, which is important for energy metabolism in muscle cells. Enzymatic defects, engendered by loss-of-function mutations in ADSS1, lead to a bottleneck in the adenine nucleotide cycle, causing metabolic dysfunction that ultimately results in progressive muscle weakness, mobility impairment, and respiratory and cardiac dysfunction, often requiring the use of a ventilator. Despite its debilitating nature, there are currently no cures or targeted treatments available, and little research into possible therapeutic strategies has been done. With a limited patient profile encompassing fewer than 200 known patients worldwide, establishing a mouse model for ADSS1 myopathy is critical to understanding its pathogenesis and for developing future therapies. Here, we present and characterize the first mouse model of ADSS1 myopathy-a constitutive Adss1 knockout model-by (1) defining its natural history, (2) exploring its metabolic pathomechanisms, and (3) characterizing its histopathological features. We find that Adss1KO/KO mice have subtle motor deficits and present with histopathological features consistent with patient phenotypes. Overall, we show that despite a relatively mild phenotype, this novel mouse model has quantifiable pathological features that can be used to develop therapies for, and further probe pathophysiology of, ADSS1 myopathy.

Introduction. Loss-of-function (LOF) variants of the LRP5 gene are associated with primary osteoporosis. Heterozygous carriers typically have a milder phenotype, manifested primarily by decreased bone mass in childhood. Homozygotes and compound heterozygotes for the LRP5 gene may also exhibit the phenotype of familial exudative vitreoretinopathy, which disrupts the growth and development of retinal blood vessels, and osteoporosis-pseudoglioma syndrome. Furthermore, LRP5 is essential for normal cholesterol and glucose metabolism. The impact of LRP5 gene variants on the development of atherosclerosis and its complications is controversial. On the one hand, impaired function contributes to elevated blood cholesterol levels, lipid and macrophage retention in the vascular wall, increased systemic inflammation, and osteoporosis, which itself is a risk factor for atherosclerosis. On the other hand, this pathology is characterized by the absence of plaque and aortic leaflet calcification. Brief description. This article presents a case of a patient with osteoporosis complicated by a right tibia fracture. Genetic testing revealed a previously undescribed, likely pathogenic LOF variant in the LRP5 gene (p.Leu17ArgfsTer128). At the time of examination (at age 64), the patient had no subclinical manifestations of carotid atherosclerosis, except for increased intima-media thickness, and total coronary calcium score was 0. Six years after visit, it was learned that at age 65, she had an acute myocardial infarction and underwent transluminal balloon angioplasty with stenting of the anterior descending artery. Conclusion. This case presents with a combination of osteoporosis complicated by a right tibia fracture and severe hypercholesterolemia, with progressive coronary atherosclerosis without plaque calcification, ultimately resulting in myocardial infarction. This patient carried a previously undescribed, likely pathogenic, LOF variant in the LRP5 gene.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) represents the most common inherited disorder of adrenal steroid biosynthesis worldwide. Over the past 25 years, advances in newborn screening, molecular diagnostics, and genotype–phenotype characterization have produced large shifts in the global epidemiological landscape. However, marked disparities persist between countries and ethnic groups, reflecting founder mutations, consanguinity, migration patterns, and differences in healthcare coverage. Exclusion criteria included mixed-etiology CAH without subtype separation and cohorts lacking validated genetic testing. Quality assessment relied on established criteria for observational epidemiology and registry-based studies. Birth prevalence showed extreme global heterogeneity, ranging from 1:23,000 in New Zealand to 1:1,200 in Egypt and as high as 1:282 among Arctic Indigenous founder populations. Ethnicity strongly influenced incidence, with Asian, Hispanic/Latino, and European populations generally displaying moderate rates (5–10 per 100,000 births), while Middle Eastern and North African populations demonstrated markedly higher incidence due to elevated consanguinity rates and clustering of severe CYP21A2 alleles. Cross-country phenotype analysis revealed that salt-wasting predominated in Egypt, China, India, Turkey, Argentina, and several Eastern European cohorts, whereas European cohorts—especially Portugal and the UK—showed higher proportions of nonclassic or milder phenotypes. Genotype–phenotype mapping demonstrated consistent associations: null and severe Group A mutations with the SW phenotype, I2 splice and I172N variants with SV presentations, and V281L with NC disease. Sex differences were notable: females more commonly presented in infancy due to virilization, while males frequently remained undetected until adrenal crises or testicular adrenal rest tumors. National screening programs significantly shifted age of diagnosis and reduced infant morbidity and mortality. Global epidemiology of CAH continues to display substantial geographic and ethnic variability, driven by population genetics, healthcare disparities, and screening strategies. Understanding these differences is essential for improving early detection, tailoring genotype-informed care, guiding newborn screening expansion, and reducing long-term complications

This study investigates the clinical course and long-term outcomes of adults with subvalvular aortic stenosis (SAS). Adults with SAS, prospectively registered in the Dutch Congenital Cor Vitia (CONCOR) registry between 2001-2019, were included. All-cause mortality, SAS (re-) operation, and cardiovascular events, including arrhythmias, heart failure, (re-)operation for aortic regurgitation (AR), were assessed. Longitudinal changes in echocardiographic peak velocity, interventricular septal thickness (IVST), and left ventricular posterior wall thickness (LVPW) were analysed using linear mixed-effects models. Differences in the history of SAS repair (operated/unoperated patients), isolated/non-isolated SAS, and sex were explored. Overall, 312 patients were included [age: 26.0 (interquartile range, IQR: 20.0-35.3) years, 68.3% history of SAS repair] with a median follow-up of 16 (IQR: 10-20) years (4423 patient-years). Unadjusted survival at 15 years was lower in the operated group compared to the unoperated group (P = .009) and no significant differences were observed between sexes (P = .083) or isolated/non-isolated SAS (P = .810). The cumulative incidence of (re-)operation for AR at 15 years was 7.6% (95% CI 4.7%-11.0%). The hazard of SAS repair during follow-up was higher in the unoperated group compared to the operated group [HR 0.2 (95% CI 0.1-0.5), P < .001], after correction for covariates. Peak velocity progression was 0.1 m/s (P = .357) during the first period and 0.3 m/s (P = .032) during the second (after ±10 years). No patient showed fast progression (≥0.3 m/s/year) in peak velocity. At baseline no evidence of left ventricular hypertrophy was observed, following IVST/LVPW criteria. Survival of adult SAS patients with a history of SAS repair was substantially lower compared to the unoperated group, reflecting a potentially more severe SAS phenotype. Nevertheless, long-term clinical event rates were considerable. SAS remained stable, suggesting less echocardiographic follow-up may suffice, particularly in mild phenotypes without AR. Additionally, follow-up should focus on the clinical sequelae of SAS.

Genotype-first assessment of presentation and penetrance of neurofibromatosis type 1, autosomal dominant polycystic kidney disease, and Marfan syndrome within the All of Us research program cohort.

Lessons from late-onset Pompe disease identified by Newborn screening: A systematic review.

From genotype to outcome: Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease.

Radio-Tartaglia Syndrome (RATARS) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function (LoF) variants in SPEN. It is characterized by global developmental delay, intellectual disability, distinctive craniofacial features and multisystem involvement. To date, only a limited number of postnatal cases have been reported, and no prenatal case has been documented. The clinical data of a 17-week pregnant woman and her affected mother who were suspected with a congenital disorder was comprehensively assessed. To investigate the genetic aetiology, whole-exome sequencing (WES) was performed to detect candidate pathogenic variants, which were subsequently validated using Sanger sequencing within the family. The proband underwent amniocentesis for prenatal genetic diagnosis of the foetus. The 22-year-old pregnant woman presented with neurodevelopmental defects including moderate intellectual disability (ID) and hypotonia, gait abnormalities, behavioural problems, kyphosis and dysmorphic facial features. WES identified a previously unreported heterozygous frameshift variant (c.2417_2418dup, p.Arg807Aspfs*3) in the SPEN gene. Sanger sequencing confirmed the authenticity of the variant and revealed that it was inherited from the mother of the pregnant woman. Compared to the proband, the mother has a milder phenotype, mainly manifested as mild ID. Prenatal ultrasonography during pregnancy revealed no obvious structural abnormalities. However, prenatal genetic testing revealed the foetus harboured the same SPEN pathogenic variant. This family has been diagnosed with RATARS caused by a SPEN variant. Our findings broaden the mutational and phenotypic spectrum of SPEN and characterize the first documented prenatal diagnosis of RATARS. The identification of intrafamilial phenotypic variability highlights the heterogeneous expressivity of RATARS, even among carriers of identical variants.

NR5A nuclear receptors coordinately regulate locust metamorphic transition and fecundity.

The D2.B10-Dmdmdx/J Mouse Model of Duchenne Muscular Dystrophy Exhibits a Severe Mitochondrial Deficiency Not Observed in the C57BL/10ScSn-Dmdmdx/J Mouse.

Pathogenic variants in the HADHA and HADHB genes are associated with impairment of mitochondrial trifunctional protein. Mitochondrial trifunctional protein deficiency is a disorder of long-chain fatty acid oxidation with different clinical presentations: the neonatal-onset form expressing with severe cardiac phenotype, the infantile-onset form with intermediate hepatic phenotype with metabolic crises, and the late-onset form with mild neuromyopathic phenotype. Long-term complications in patients with the intermediate and late-onset phenotypes include peripheral neuropathy and retinopathy. We report a patient harboring 2 compound heterozygous variants in the HADHA gene (p.Tyr724* and p.Gly319Ser) and presenting with an early-onset, progressive sensorimotor axonal polyneuropathy, without any other systemic manifestations typical of mitochondrial trifunctional protein deficiency. We also provide a literature review of HADHA mutated patients presenting with early-onset isolated neuropathy phenotype.

Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis, caused by biallelic mutations in the DHCR7 gene. Genotype-phenotype correlations regarding DHCR7 variants could explain the variation in severity, ranging from in utero demise or severe SLOS to a mild phenotype. Clinical recognition can be challenging. This study aimed to determine the frequency of SLOS carriers in the Central European population, as well as the mutational spectrum of DHCR7 in these carriers. A retrospective analysis of DHCR7 variants was conducted using next-generation sequencing data from 55,289 individuals in Czech and Hungarian genetic laboratories. The SLOS carrier frequency and the mutational spectrum of the DHCR7 gene in its carriers were established in the Czech and Hungarian sub-cohorts. In the combined dataset, we identified causative DHCR7 variants on 1567 alleles among 55,289 tested individuals, contributing to an SLOS carrier frequency of 2.83%. Of the 31 DHCR7 variants detected, the c.452G>A variant was the most prevalent, accounting for 1.8% of all detected alleles in our cohorts. In contrast, the c.964-1G>C variant was more frequent in non-Finnish Europeans, as indicated by the gnomAD 4.1.0 database. The DHCR7 mutational spectra of patients and carriers were comparable in terms of the most common variants. The high SLOS carrier frequency (2.83%) underscores the importance of SLOS carrier screening in Central European populations. The prevalent DHCR7 null mutations and their potential combinations may explain the lower-than-expected prevalence of SLOS, whilst Central and Eastern European populations remain likely underrepresented in the current gnomAD database.

Sorting Nexin 27 (SNX27), a key regulator of synaptic receptor trafficking and endosomal recycling, has been implicated in maintaining synaptic homeostasis and cognitive function. To date, variants in SNX27 have been reported in a small number of patients across three publications with severe neurodevelopmental phenotypes. However, the genetic and functional landscape of SNX27-related disorders remains poorly understood, and further evidence is needed to confirm its association with disease and to better delineate the associated phenotype. Two unrelated Pakistani families with a total of five affected individuals segregating a neurodevelopmental disorder were investigated via exome or genome sequencing. This revealed a novel homozygous frameshift variant in family I [NM_001330723.2: c.75dup; p. (Ser26Valfs*85)], predicted to be targeted by nonsense-mediated decay. In family II, a novel homozygous missense variant [NM_001330723.2: c.929 T>C; p. (Met310Thr)] was found within the FERM-like region of the SNX27 protein, which is critical for retromer complex interaction. Comparison of five cases described in this study with previously reported six cases reinforces the presence of consistent "core" clinical features-global developmental delay, intellectual disability, speech delay, behavioral abnormalities, seizures, and motor dysfunction in all assessed cases. Other features such as dental anomalies, failure to thrive, and dysmorphisms occurred variably in few. Affected individuals with predicted loss-of-function variants typically presented with a more severe phenotype. Thus, core features of SNX27-related neurodevelopmental disorders (NDDs) are intellectual disability, developmental, and speech delays. This study, alongside prior reports, augments the genetic and phenotypic spectrum of SNX27-associated NDDs. The novel frameshift variant p.(Ser26Valfs*85) is predicted to severely disrupt SNX27 function, causing profound neurodevelopmental impairment, whereas the missense p.(Met310Thr) in the FERM-like region is associated with a milder phenotype. Comparative analyses with previous reports reveal a spectrum from early lethality to long-term survival with intellectual disability in SNX27-linked families. These findings underscore the importance of SNX27 in neurodevelopment and further validate its link to a neurodevelopmental disorder.

The inflammatory bowel disease (IBD) ulcerative colitis (UC) is characterized by colonic mucosal inflammation and barrier dysfunction. We hypothesized that UC causes persistent defects in mucosal homeostasis, evident even in the absence of active inflammation, contributing to disease chronicity. To test our hypothesis, we grew patient biopsy-derived sigmoid colonoids into air-liquid interface (ALI) monolayers, characterizing them through microscopy, proteomics, bulk RNA Sequencing (RNAseq), and their susceptibility to UC patient-isolated Escherichia coli pathobiont p19A. Non-IBD ALI monolayers formed uniform crypt-like structures and a thick mucus layer containing all epithelial-derived proteins previously identified in human colonic mucus. In contrast, ALI monolayers from UC patients displayed a range of impairments, with classification ranging from a mild phenotype with distorted architecture and a thinner, more permeable mucus layer to a severe phenotype with defects in cellular differentiation and an inability to produce a mucus layer. With the use of transcriptome analysis, we identified activated pathways associated with extracellular matrix formation and cell signaling, including numerous cancer-associated genes in UC ALI monolayers, which also proved significantly more susceptible to E. coli p19A. Taken together, the culturing of patient biopsies into ALI colonoid monolayers provides a powerful model to assess human colonic mucosal development, healing, homeostasis, and mucus barrier function, revealing that UC-derived colonoid monolayers display a range of developmental and functional defects that persist in the absence of inflammation.