Journal of Medical Genetics

Abstract Purpose: Published clinical outcome data on preconception carrier screening (PCS) in Central Asia are limited. We report the first clinical implementation study from Uzbekistan of a whole-exome sequencing (WES)-based multi-platform PCS program combining exome sequencing with targeted SMA, FMR1, and DMD assays. Methods: We retrospectively analyzed anonymized data from 65 individuals (19 couples, 27 singletons) screened at IMC Genomics, Tashkent, between January 2024 and May 2026. WES covering the protein-coding regions of approximately 20,000 genes was followed by exome-wide bioinformatics filtering and clinical geneticist interpretation. Partly overlapping cohorts underwent SMA carrier screening (n=179), FMR1 CGG-repeat analysis in females (n=155), and DMD deletion/duplication testing in preconception females (n=29). Variants were classified by ACMG/AMP criteria against gnomAD v4.1. Results: Sixty-one of 65 WES-screened individuals (93.8%; 95% CI 85.2 - 97.6%) carried at least one reportable variant (152 instances across 126 genes). Four of 19 couples (21.1%; 95% CI 8.5 - 43.3%) were concordant for pathogenic or likely pathogenic variants in the same autosomal recessive gene; two were referred for preimplantation genetic testing for monogenic disease. SMA screening identified four carriers, including two 2+0 silent carriers; FMR1 analysis identified one intermediate allele; DMD MLPA identified no exonic rearrangements. Conclusion: This first reported WES-based multi-platform PCS program in Uzbekistan was feasible and clinically informative, identifying actionable couple-level reproductive risks and supporting structured implementation of reproductive genetic screening in Central Asia.

Background: Neurological, neuropsychiatric, and neurodevelopmental disorders cluster in ALS families, sharing a common genetic architecture with ALS. Pathogenic variants in genes associated with other neurological, neurodevelopmental, or neuropsychiatric disorders may also co-occur in ALS and modify phenotype. We have sought to determine the prevalence and clinical pattern of likely-pathogenic/pathogenic (LP/P) non-ALS neurological, neurodevelopmental, and neuropsychiatric variants, alone and in combination with ALS-gene variants, in two large ALS cohorts. Methods: Whole-genome sequencing (WGS) of 469 Irish and 774 Answer ALS people with ALS (pwALS) was analysed for ClinVar LP/P variants associated with other neurological (n = 15541), neurodevelopmental (n = 9761), and neuropsychiatric (n = 321) phenotypes. Inheritance patterns for associated genes (autosomal recessive/autosomal dominant) along with the associated phenotype were validated using OMIM. Standardised clinical data included family history, site and age of onset, El Escorial category, survival, motor decline, and cognitive and behavioural assessments. Known ALS-gene variants and C9orf72 repeat expansion status were included for each cohort. Results: Non-ALS neurological variants were identified in 47/469 (10.0%) Irish and 69/774 (8.9%) Answer ALS participants, most frequently in hereditary spastic paraplegia-associated genes (3.2% Irish; 2.8% Answer ALS). Irish neurological variant carriers showed higher frequency of respiratory onset (10.6% vs 1.2%, Fisher's exact p = 0.002, {Phi} = 0.20) and fewer premorbid behavioural symptoms (0.92 +/- 0.56 vs 3.08 +/- 0.97, Cohen's d = -0.40). Neurodevelopmental variants occurred in 12/469 (2.6%) Irish and 20/774 (2.6%) Answer ALS participants. In the Irish cohort, neurodevelopmental variant carriers had significantly shorter survival in Cox proportional hazards model (log-rank p = 0.005), corresponding to a more than two-fold increased hazard of death (HR = 2.25, 95% CI 1.26-4.00), and had significantly increased familial burden of neuropsychiatric disorders among first- and second-degree relatives (negative binomial IRR for carriers = 2.41, 95% CI: 1.12-5.18, p = 0.025). Across combined cohorts, 18 individuals (Irish n = 8; Answer ALS n = 10) carried [≥]2 LP/P variants spanning ALS and non-ALS genes. Conclusion: Rare LP/P variants in genes associated with other neurological and neurodevelopmental disorders occur in up to 12% of pwALS across two independent cohorts. Carriers show distinct phenotypes, shorter survival, and characteristic family history patterns. These findings suggest that extended pleiotropic and oligogenic architectures may contribute to ALS heterogeneity.

Polygenic risk scores (PRSs) are emerging as powerful tools for quantifying inherited risk for common diseases and, in some cases, are approaching clinical implementation. A major concern for PRS implementation is their limited accuracy in non-European populations, particularly in those of African ancestry. However, past evaluations have focused on metrics such as relative risk or AUC, which do not capture background risk arising from contextual factors. We introduce a novel measure of variable importance, the conditional average derivative estimator (CADE), to evaluate PRS utility across diverse contexts and populations within absolute risk models that integrate PRSs with other relevant risk factors. We illustrate this framework by integrating PRSs for breast and prostate cancer within age-specific absolute risk models for incidence and mortality fit using individual-level data from the All of Us Research Program with inputs from the National Cancer Institute SEER cancer registry. Our projections show that although the PRSs are known to have the lowest discriminatory accuracy in African Americans (AA), there are contexts in which they provide greater utility, such as for the stratification of prostate cancer risk and mortality, where the CADE values for AA were 2- and 7-fold higher than for European Americans. These findings suggest that conclusions about the limited clinical utility of PRS in non-European populations may be premature and underscore the need to quantify PRS risk-stratification utility at the absolute-risk level, while accounting for disease onset, survival, and broader health and economic factors.

Background: 48,XXYY syndrome is a rare sex chromosome aneuploidy (SCA) characterized by neurodevelopmental deficits and medical comorbidities. The limited information available in the literature is almost exclusively limited to postnatally diagnosed cases. This study aims to describe the early medical and developmental features of prenatally identified 48,XXYY infants, with comparisons to 47,XYY, 47,XXY cohorts, and typical populations, as well as previously reported postnatally diagnosed 48,XXYY cases. Methods: The eXtraordinarY Babies Study prospectively follows children prenatally identified to be at high risk for SCA with annual medical and neurodevelopmental evaluations. Data presented herein include the prevalence of medical conditions, developmental milestones, developmental and adaptive functioning assessment scores, and therapy utilization in participants confirmed to have 48,XXYY. Comparisons were made between this cohort and the typical population, infants with 47,XYY and 47,XXY also enrolled in the eXtraordinarY Babies Study, and a 2008 cohort of individuals postnatally identified 48,XXYY. Results: Infants with 48,XXYY exhibited a range of early medical features, including high rates of feeding and GI disorders (breastfeeding difficulties, gastroesophageal reflux, and eosinophilic esophagitis), allergic disorders (food allergies and environmental allergies), and hypotonia. Developmental and adaptive functioning scores indicated delays in motor, communication, and social domains, with nearly all infants receiving speech therapy, physical and/or occupational therapy. Comparisons with the 47,XYY and 47,XXY cohorts revealed more medical and developmental challenges in the 48,XXYY group, however there was variability and some overlap with both the general population and sex chromosome trisomy conditions. Additionally, comparison to the 2008 postnatally identified 48,XXYY cohort indicated that while prenatal diagnosis allowed for earlier intervention, developmental outcomes in the first years of life were similar between the two groups. Conclusions: 48,XXYY diagnosed prenatally facilitates early monitoring, anticipatory guidance, and proactive referrals for medical evaluations and intervention, given developmental delays and medical challenges are more common in infancy and early childhood compared to the general population and trisomy SCAs. These findings provide valuable insights for genetic counselors and healthcare providers, emphasizing the spectrum of medical and developmental findings and importance of early and proactive care to support individual outcomes. Prospective study of this prenatally identified cohort will provide important natural history and phenotypic variability in XXYY, as well as identification of predictors of health and developmental outcomes.

Objective: ADHD has been associated with obesity indicators, including BMI, across the lifespan. A possible mechanism linking ADHD and BMI is binge eating. Previous research has found associations between ADHD, binge eating and BMI. However, the role of genetic and environmental influences on these associations remains unclear. Method: We utilized data from the Twins Early Development Study (TEDS), comprising 3,675 monozygotic and 7,063 dizygotic twin pairs. ADHD symptoms in childhood and adolescence were assessed using parent-reported questionnaires. Adult ADHD symptoms were measured using both self-report and parent-report questionnaires. Phenotypic mediation models examined whether binge eating mediated the association between ADHD and BMI, without controlling for genetic confounding. Subsequently, the etiological architecture underlying the associations among the three traits across childhood, adolescence, and adulthood were investigated by incorporating genetic and environmental influences into the models. Results: Binge eating significantly mediated the association between ADHD symptoms and BMI in both adolescence and adulthood. However, these mediation effects were no longer present once genetic and environmental influences were incorporated into the models. The best-fitting model in childhood, adolescence and adulthood was Cholesky decomposition models, where covariance between traits was explained by shared aetiology. Conclusions: This twin study reveals shared liability across ADHD, binge eating, and BMI. The mediating role of binge eating in the relationship between ADHD symptoms and BMI was largely confounded by shared genetic influences. Intervention strategies could focus more on common underlying behavioural and self-regulatory mechanisms across these traits, as well as placing more emphasis on symptom patterns within families.

Purpose: To evaluate the incidence and baseline predictors of intraocular pressure (IOP)-lowering treatment following detection of referable glaucoma by teleretinal screening. Design: Retrospective cohort study. Methods: Participants were derived from a safety-net teleretinal diabetic retinopathy screening program (2013-2024). Participants included individuals who screened positive for referable glaucoma (cup-to-disc ratio [CDR] [&ge;]0.6 or CDR asymmetry [&ge;]0.2) and completed in-office diagnostic evaluation. The primary outcome was initiation of IOP-lowering treatment (medication, laser, or surgery) and the secondary outcome was intervention with surgery. Cumulative incidence functions were estimated, accounting for loss to follow-up. Fine-Gray models were used to identify baseline screening predictors to risk stratify each outcome. Glaucoma diagnosis was approximated using diagnostic codes and chart review. Results: 2,367 participants were included. The cumulative incidence of treatment was 19.6% (95% CI: 18.0-21.2) at Year 1 and 45.1% (42.1-48.1) at Year 8. Early treatment occurred primarily in glaucoma cases, whereas treatment accumulated longitudinally in glaucoma suspects, reaching 36.5% (31.6-41.5) by Year 8. Surgery was less common (8-year incidence: 5.3%). Baseline screening data predicted treatment and surgery, enabling risk stratification. At Year 8, cumulative incidence differed substantially between high- and low-risk groups (treatment: 59.9% vs. 31.2%; surgery: 9.7% vs. 1.0%). Older age (sub-distribution hazard ratio [SHR] 1.03 per year, p<0.001), Black race (SHR 1.50, p<0.001), and personal history of glaucoma (SHR 1.90, p<0.001) were associated with treatment; Asian race was protective (0.71, p=0.03). Older age (SHR 1.06, p<0.001), worse visual acuity (SHR 5.11 per logMAR unit, p<0.001), and screening at a hospital-based site (SHR 2.46, p=0.003) were associated with surgical treatment. Conclusion: Nearly half of safety-net diabetic patients screening positive for referable glaucoma initiated IOP-lowering treatment over 8 years, while few received surgery. Baseline screening characteristics enabled risk stratification of treatment and surgery. These findings address an evidence gap about longitudinal consequences of screening and suggest that its impact extends beyond detection of prevalent glaucoma to include identification of high-risk glaucoma suspects who warrant ongoing surveillance.

Objective To determine if it is possible to assess individual patient risk of the development of colorectal cancer (CRC) in people in high-risk groups due to their family history. Design/Method Retrospective observational study of prospectively collected data from consecutive patients referred for a colonoscopy. 2,478 consecutive patients were referred to a single colorectal surgical practice in Sydney, Australia between 1977 and 2018 for a colonoscopy because of a family history of CRC. Of these, 1,963 have been followed for more than 10 years and are the subject of this paper. Histopathological findings categorised as normal (N), non-advanced adenoma (NAA) or advanced neoplasia (AN) with AN proven to be the precursor to CRC. Intervention Colonoscopic screening on the basis of contemporary practice to 2006 and subsequently according to Australian National Health and Medical Research Council guidelines. Results Participants with normal or low-risk findings in the first decade remain at lower risk of CRC for 30 years from the commencement of screening. Conclusion It is possible to stratify individual patients in a high relative risk cohort into those with high or low personal risk of CRC based on colonoscopic findings in the first 10 years of surveillance. Those with no AN in the first ten years have a lower 30-year risk of developing AN than the general community. This offers the possibility of structuring surveillance programs around individual risk rather than group risk, lessening the need for multiple surveillance colonoscopies in the majority of such patients and improving the cost effectiveness of CRC screening at the population level.

Although the Y chromosome represents roughly 2% of the male genome, it is often ignored in genome-wide association studies (GWAS). Subsequently, the potential health impacts of Y-chromosomal genetic variation remain incompletely understood. To fill this gap, we performed a phenome-wide association study (PheWAS) in FinnGen across 1,426 binary and quantitative traits using Y-chromosomal variation (frequency [&ge;] 1%) in 104,334 genotyped men. As Y chromosome variation is prone to population stratification, we performed carefully adjusted association analyses and further examined these through kin-based validation in 19,275 female and 24,712 male 1st degree relatives. We found 121 suggestive (p < 5.6x10-3) phenotypic associations in the Y chromosome, yet none of these were strong enough to reach phenome-wide significance (p < 3.9x10-6). While only 38 associations were supported in the kin-based validation, intriguingly we found support for a previously suggested link between haplogroup I1 and coronary heart disease (CHD; OR=1.06, 95%CI=1.02-1.11, p=3.7x10-3; male validation OR=1.05; female validation OR=0.97). The I1-CHD association was detected across distinct geographical areas within Finland and was independent from Loss of Y (LOY) and the autosomal risk to CHD, proposing a link between germline Y-chromosomal variation and heart disease risk. Overall, this study presents a comprehensive phenome-wide analysis of Y-chromosomal associations, highlighting the potential relevance of Y-chromosomal variation beyond sex determination. Our findings further emphasize the need for improved capture of Y-chromosomal variants and further analyses in biobank-scale data to allow for deeper exploration of male-specific genetic architecture of complex diseases.

Objectives To explore caregiver and clinicians perspectives on implementing mental health conversations and supports for caregivers of children with chronic conditions in paediatric outpatient clinics. Specifically, views were sought on (a) screening approaches and measures (phase 1) and (b) how feedback and support could be provided to caregivers experiencing mental health difficulties (phase 2). Methods Caregivers and clinicians from two outpatient clinics (neuromuscular and diabetes) at a tertiary paediatric hospital in Melbourne, Australia participated in online focus groups in July and August 2024. Caregivers were recruited from outpatient clinics and clinicians were recruited via email. Both groups were combined for phase 1 before separating into breakout rooms for phase 2. Two authors conducted reflexive thematic analysis of transcripts using NVivo. Results Sixteen participants (caregivers n = 8; and clinicians n = 8) took part in in two semi-structured focus groups. Analysis generated two overarching domains, each comprising multiple themes. Domain 1, Addressing caregiver mental health, captured themes of overwhelm and invisibility, diverse caregiving roles, and the need for time and resources to support wellbeing conversations. Domain 2, Housing the mental health conversation, encompassed themes of screening preferences, caregiver agency in confidentiality, delivery of feedback, and access to tailored supports. Conclusions Caregivers and clinicians support routine caregiver mental health discussions in paediatric outpatient settings. Caregivers favour screening at diagnosis and key transitions, with clear, and actionable feedback delivered away from the child. Questions about record-keeping warrant further exploration, as do the perspectives of fathers.

Educational attainment-related polygenic scores have been implicated in autism spectrum disorder (ASD), but how parental polygenic scores shape offspring phenotypes remains unclear. Using genotyping and exome-sequencing data from 142,357 individuals (55,252 ASD cases) in a large ASD cohort, we dissected the direct and indirect genetic effects of educational attainment-related polygenic scores on ASD phenotypes. Trio-model analyses showed that parental polygenic scores for educational attainment (PGSEA ) were associated with milder core ASD symptoms, including social deficits and repetitive behaviors, predominantly through indirect genetic effects, whereas their associations with comorbidities were driven predominantly by direct genetic effects. PGSEA was also significantly negatively associated with rare variant burden and prenatal factors, although these factors contributed largely independently to most phenotypes. Adjustment for full-scale intelligence quotient (FSIQ) and socioeconomic status (SES) partially attenuated the indirect effects of PGSEA on offspring phenotypes. Finally, higher parental PGSEA was associated with later age at diagnosis in offspring, partly through its protective effects on ASD phenotypes. These findings indicate that indirect genetic effects of parentalPGSEA contribute substantially to phenotypic variation in ASD and highlight family-mediated pathways as an important component of ASD heterogeneity.

Importance: Hereditary breast and ovarian cancer (HBOC) variant carriers benefit from risk-reducing interventions, but only if identified. The extent to which carriers are clinically recognized, and whether recognition is equitable across diverse populations, is poorly characterized in a single large U.S. cohort. Objective: To estimate P/LP HBOC carrier prevalence across genetic ancestry groups, quantify documented clinical genetic testing among carriers, and evaluate ancestry and socioeconomic disparities in testing. Design, Setting, and Participants: Cross-sectional analysis of the All of Us Research Program Controlled Tier (Curated Data Repository v8/C2024Q3R9), comprising participants with short-read whole genome sequencing and linked electronic health record (EHR) and survey data. Carriers were ascertained from research genomic data independent of clinical testing. Exposures: Genetically inferred ancestry (African [AFR], Admixed American [AMR], East Asian [EAS], European [EUR], Middle Eastern [MID], South Asian [SAS]); self-reported household income and educational attainment. Main Outcomes and Measures: (1) Carrier prevalence with Wilson 95% CIs; (2) documented clinical genetic testing (procedure codes) among carriers; (3) adjusted odds of documented testing among women, by ancestry, before and after socioeconomic adjustment, using multivariable logistic regression. Results: Among 414,830 participants, P/LP HBOC carrier prevalence was 1.42% (95% CI, 1.38-1.45) overall and similar across ancestry groups (AFR 1.24%, AMR 1.32%, EAS 1.19%, EUR 1.52%, MID 1.68%, SAS 1.33%; overlapping CIs). Among 250,071 women in the testing analysis, documented clinical genetic testing was rare: only 74 of 5,878 carriers overall (1.3%) and 59 of 3,572 European-ancestry carriers (1.7%) had a documented test, with counts below reportable thresholds in all other ancestry groups. African-ancestry women had lower adjusted odds of documented testing than European-ancestry women (Model 1 adjusted odds ratio [aOR], 0.32; 95% CI, 0.27-0.39), an association that attenuated but persisted after adjustment for income and education (Model 2 aOR, 0.48; 95% CI, 0.40-0.58; P < 0.001); Admixed American women also had reduced adjusted odds (aOR, 0.71; 95% CI, 0.61-0.84). Lower income and lower education were independently and dose-dependently associated with lower testing odds (income <$25,000 aOR, 0.46; high-school education aOR, 0.54). Conclusions and Relevance: High-risk HBOC variant carriers are present across all ancestry groups at similar frequencies, yet documented clinical genetic testing was disparate in the different ancestry groups. African-ancestry women experience a testing gap that is not fully explained by socioeconomic position, implicating structural barriers in access and referral. Population-level strategies that decouple carrier identification from current referral pathways may be required to close this gap.

Consanguinity is a reproductive union between individuals who share a recent common ancestor. These unions are common in many regions of the world and increase the burden of rare recessive disorders by elevating autozygosity in offspring. Current reproductive genetic screening focuses on a limited set of known pathogenic variants, leaving most recessive risk unaddressed. Here we argue that embryo-level autozygosity, quantified as the fraction of the genome in long runs of homozygosity (FROH), is a potentially actionable genomic biomarker that can be integrated into routine preimplantation genetic testing as a homozygosity-informed embryo-prioritization framework (PGT-H) that can be layered onto existing embryo biopsy workflows when couples are already undergoing IVF with PGT-A or PGT-M. Using forward simulations of first-cousin and double-first-cousin couples, we show that siblings conceived by the same couple span a wide range of FROH; selecting the lowest-FROH candidate from a cohort of five embryos reduces FROH by approximately 40% on average. Combining these reductions with empirical effect-size estimates, we estimate that for first-cousin couples this strategy could reduce risk of intellectual disability by roughly 35-45% (corresponding to an absolute risk reduction of about 1.8-2.2%) and potentially reduce excess recessive disease burden, while also modestly reducing risk of common diseases such as type 2 diabetes. We outline how existing PGT-A and PGT-M workflows could potentially be extended to report embryo-level FROH and discuss ethical and counseling considerations. Autozygosity-based embryo prioritization offers a principled way to address a component of recessive risk that current variant-centric approaches miss.

Background: Polygenic risk scores (PRS) for breast cancer are increasingly used for risk stratification to inform screening and prevention. However, for PRSs to be equitable and clinically useful, they need to perform well across diverse populations. While PRS performance is known to be ancestry-dependent, it is not well understood how environmental context, such as that of socioeconomic status (SES), affects PRS transferability. Here, we assess whether SES, measured via self-reported household income, modifies breast cancer PRS performance and, if so, whether socioeconomic context contributes predictive information beyond genetic risk alone. Methods: We used the US-based All of Us biobank to evaluate how SES impacts breast cancer PRS performance. First, we quantified changes in breast cancer PRS performance by modeling a commonly-cited polygenic score for breast cancer previously described by Mavaddat et al. with SES. We then reestimated the genetic effect sizes of the 3,820 variants from Mavaddat et al. in All of Us with and without income as a covariate. Because social determinants of health affect breast cancer detection and outcomes, we stratified analyses by socially defined populations on the basis of self-identified race and ethnicity. We further stratified individuals whose self-identified race is White (''White'') into three SES groups (high, middle, low) based on self-reported income and re-estimated genetic effect sizes to create SES-specific PRSs. We then applied these PRSs to White participants, the largest group in the study, and to Black or African American (''Black'') and Hispanic or Latino (''Hispanic'') participants, groups underrepresented in breast cancer research. Model discrimination between cases and controls was measured by area under the curve (AUC). Results: We analyzed 163,715 women from the All of Us biobank, which included 8,833 breast cancer cases (6,619 White, 1,178 Black, and 1,036 Hispanic), with relative income available for a subset of these cases (5,525 White, 848 Black, and 566 Hispanic). The ancestry-dependent performance of the breast cancer PRS described in Mavaddat et al. was replicated in All of Us. In Black individuals, this PRS (AUC and 95% CI: 0.576 [0.571, 0.582]) produced a similar increase in AUC as relative income (AUC: 0.573 [0.568, 0.577]) when added to an age-only model. Incorporating income with PRS, age, and genetic PCs 1-3 improved AUC by 0.007 in White Americans and 0.018 in Black Americans (both p < 10-11), while attenuating the contribution of PRS in the full model. PRS performance also varied among SES categories. Notably, PRSs with variant effect sizes that were recalibrated in low-SES White participants performed best in low-SES White participants (AUC: 0.605 [0.583, 0.628]) and Black Americans (AUC: 0.588 [0.586, 0.591]), both better than performance in high-SES White Americans (AUC: 0.579 [0.577, 0.580]) and middle-SES White Americans (AUC: 0.578 [0.569, 0.586]). Conclusion: Socioeconomic context, measured by income, significantly impacts the transferability of a PRS for breast cancer within and among groups defined by self-identified race and ethnicity. Accounting for SES improves PRS performance, most notably in Black Americans and low-SES White individuals.

Purpose: Pathogenic or likely pathogenic (P/LP) variants are increasingly identified in genes more commonly associated with adult-onset cancer predisposition, but their prevalence and relevance to children who present with cancer remain unclear. Methods: We retrospectively analyzed 1,280 consecutive pediatric patients with cancer who underwent clinical germline sequencing, using a virtual panel, from 2021 to 2024. Genes with P/LP variants were categorized as aoCPG or pediatric-onset cancer predisposition genes (poCPG) according to cancer risk before age 18 years and pediatric surveillance recommendations. Variant relevance was adjudicated using tumor diagnosis/histopathology, immunohistochemistry, and tumor molecular features and classified as primary, secondary, or indeterminate. Results: Among 1,280 patients, 197 (15.4%) harbored 211 P/LP variants across 54 genes. Sixty-six variants (31.3%) occurred in aoCPG, 87 (41.2%) in poCPG, and 58 (27.5%) were heterozygous variants in autosomal recessive genes. Among adult-onset variants, 7 (10.6%) were primary, 54 (81.8%) secondary, and 5 (7.6%) indeterminate. Among pediatric-onset variants, 77 (88.5%) were primary and 10 (11.5%) secondary. Six patients (3 adult-onset variants; 3 pediatric-onset variants) received targeted therapy informed by germline/somatic sequencing results. Conclusion: In pediatric oncology, most variants in aoCPG are secondary rather than tumor-related findings. Tumor-informed interpretation, beyond variant classification, may improve reporting, counseling, and therapeutic decision-making

Background. Tethered cord syndrome (TCS) is classically associated with a low-lying conus medullaris, yet many surgically treated children have a normally positioned conus (occult TCS). Large-scale normative data on conus position in children, and the diagnostic value of quantitative conus assessment, are limited. Purpose. To establish a large-cohort reference distribution for conus medullaris termination level in children, to quantify conus position in children surgically treated for presumed (occult) TCS, and to test whether automated conus segmentation and radiomics can distinguish TCS from normal. Materials and Methods. In this retrospective single-center study, conus termination level was extracted from structured radiology reports of consecutive pediatric lumbosacral MRI examinations and encoded numerically (L1 = 1, L2 = 2, etc.). Children surgically treated for tethered cord were identified by linkage to an operative registry (name and date of birth) and restricted to preoperative examinations. A deep-learning model (nnU-Net) was trained for conus segmentation on axial T2-weighted images. IBSI-compliant radiomic features were extracted; reproducibility was assessed by intra- and inter-observer intraclass correlation (ICC). A case-control radiomics analysis used batch-only ComBat harmonization and cross-validated L1-penalized logistic regression; discrimination was compared with conus level by paired bootstrap. Results. Among 9,808 examinations with a parseable conus level (98.5% of reports; parser validated against dual blinded annotation, 99.4% agreement, weighted kappa 0.946), the conus terminated in the L1 region in 85.7% and the L2 region in 14.3% of the reference cohort (postoperative examinations excluded, n = 9,655); a low-lying conus (>=L3) occurred in only 0.05% (5/9,655), and remained rare (0.14%, 14/9,808) including operated examinations (median L1; mean 1.13 +/- 0.33). A slightly more cephalad position was seen with increasing age (negligible correlation). Among 475 preoperative children surgically treated for tethered cord, 99.6% had a normally positioned conus (<=L2) and only 0.4% were low-lying. Automated conus segmentation achieved a held-out Dice of 0.85. Conus radiomics likewise did not distinguish TCS from controls (equivalence-tested null; full segmentation/radiomics pipeline reported in the companion methodological paper). Conclusion. In children, the conus medullaris terminates at L1-L2 in more than 99% of cases and is normally positioned in virtually all children surgically treated for TCS. Within the conus, neither position nor texture (radiomics) identifies tethered cord; whether the filum terminale carries a diagnostic signal was not tested here.

Background Little is known about the provision of diagnoses to young people with mental health disorders. We investigated diagnosis provision by NHS mental health services, focusing on 17-year-olds in South London between 2009-2024, and compared with estimated disorder prevalence. Methods To examine diagnosis provision in the population, we extracted diagnosis data from records of the NHS mental healthcare provider serving South London, using the Maudsley Biomedical Research Centre Clinical Record Interactive Search application; we then compared these data with the corresponding population size, obtained from the Office for National Statistics. To assess diagnosis provision in those with mental health disorders, we compared diagnosis data with the number of young people estimated to have met criteria for a disorder, derived from epidemiological interview data collected in the Environmental Risk (E-Risk) Longitudinal Twin Study and weighted according to characteristics of 17-year-old South Londoners. To assess diagnosis provision in those with mental health disorders within health services, we compared diagnosis data with the number estimated to have met criteria for a disorder and used any health service for their mental health, again derived from weighted E-Risk Study data. Findings Of 17-year-olds from South London in 2009-2024, 4.0% (n=8,958/223,404) had a diagnosis in mental health records during the previous year. This diagnosis provision covered <1 in 16 of those estimated to have had a mental health disorder, and <1 in 4 of those estimated to have also used health services. Diagnosis provision was lower in girls than boys and in young people with Black/Asian/Mixed/Other ethnicity than those with White ethnicity, in those estimated to have had a mental health disorder and used health services. Interpretation These findings demonstrate gaps and biases in mental health diagnosis provision for young people, including within health services, and reveal the imperative need to strengthen young people's mental healthcare.

Caveolinopathies caused by CAV3 mutations present with heterogeneous clinical phenotypes ranging from asymptomatic hyperCKemia to limb-girdle-type muscular dystrophy. Although prior imaging studies have described commonly affected muscles, structured modeling of muscle involvement patterns in caveolinopathy has not been established. We analyzed whole-body skeletal muscle computed tomography imaging in eight patients with pathogenic or likely pathogenic CAV3 variants, comprising 14 imaging study samples. Fat infiltration across 43 muscles was graded using modified Mercuri scores. Computational multivariate analysis,including principal component analysis, clustering, and pseudotime modeling,was applied to characterize severity staging and distribution patterns. A statistically supported, stage-dependent continuum of muscle involvement was identified. Most samples demonstrated a distributed limb-girdle-predominant pattern with coordinated progression across muscle clusters. In contrast, one patient (three samples in longitudinal series) exhibited a compartment-restricted thigh-dominant pattern characterized by early posterior and medial thigh involvement. Rectus femoris showed consistent stage-dependent progression, while greater medial gastrocnemius involvement was associated with advanced severity. None of the patients exhibited clinical evidence of rippling muscle disease. These findings suggest that integrating semi-quantitative imaging with computational modeling may provide an objective framework for characterizing muscle involvement patterns in CAV3-related myopathy.

Introduction Dysmenorrhoea is highly prevalent globally and interferes with engagement in education, work, social participation, and quality of life. Although evidence suggests that sociocultural beliefs influence how menstrual pain is understood and managed, relatively little research has explored dysmenorrhoea-related knowledge and beliefs within South Africa. This study aimed to (1) determine the frequency of dysmenorrhoea, (2) assess dysmenorrhoea-related knowledge and compare knowledge between menstruating and non-menstruating individuals, and (3) explore commonly held generational, cultural, and religious beliefs related to dysmenorrhoea in a South African university cohort. Methods We analysed data collected as part of a cross-sectional survey conducted among staff and students at a South African university. Participants completed demographic questions, items assessing dysmenorrhoea-related knowledge, and an adapted Working Ability, Location, Intensity, Days of Pain, Dysmenorrhoea (WaLIDD) questionnaire. Participants were also invited to provide free-text responses describing generational, cultural, and religious beliefs about dysmenorrhoea. Quantitative data were analysed descriptively and compared between menstruating and non-menstruating participants. Free-text responses were analysed using reflexive thematic analysis. Results A total of 863 participants completed the survey, including 578 current or past menstruators. The frequency (95%CI) of dysmenorrhoea was 75.4% (71.7-78.9). Most participants were classified as having moderate (53%) or severe (31%) dysmenorrhoea on the WaLIDD scale. Awareness of dysmenorrhoea was higher among participants who had menstruated than among those who had never menstruated (80.4% vs 55.3%, p<0.001). Most participants (85.1%) reported wanting more education about dysmenorrhoea and its impact. Reflexive thematic analysis of 246 free-text responses identified five themes: (1) menstrual pain is normalised, dismissed, and expected to endure, (2) reproductive meanings attached to menstrual pain, (3) moral, spiritual, and cultural interpretations of menstrual pain, (4) negotiating competing explanations for menstrual pain, and (5) managing and controlling menstrual pain symptoms. Across themes, dysmenorrhoea was interpreted through social, cultural, reproductive, spiritual, and biomedical frameworks that shaped how pain was understood, communicated, and managed. Conclusion Dysmenorrhoea is common in this South African university cohort, and is rarely understood as a purely biological symptom. Instead, menstrual pain is understood and managed through broader social, cultural, reproductive, moral, and biomedical narratives, which shape how pain is recognised, disclosed, legitimised, and treated. These findings highlight the importance of considering sociocultural beliefs alongside clinical factors when developing menstrual health education, support strategies, and healthcare services.

Background: Olfactory dysfunction (OD) in children remains underdiagnosed and poorly characterised. Despite its known impacts on nutrition, quality of life, safety awareness, and psychosocial development, no standardised diagnostic or management pathway currently exists for paediatric OD. This study aimed to characterise global practice patterns and identify diagnostic and therapeutic challenges unique to paediatric care. Methodology/Principal: A 44-item cross-sectional online survey was distributed to a verified international network of paediatric otolaryngologists across 36 countries via a closed professional platform. The survey assessed five domains: diagnostic practices, management protocols, technology and innovation, education and training, and barriers to effective care. Regional grouping was used to facilitate meaningful statistical comparisons. Categorical variables were evaluated using chi-square tests, with odds ratios and 95% confidence intervals reported for significant findings. Results: Of 351 potential participants, 167 responded (47.6% response rate). Most respondents (83%) reported seeing children with OD, yet 95% saw fewer than ten such patients annually. Psychophysical testing was never performed by 54.8% of respondents, while 88.4% routinely ordered cross-sectional imaging. Testing frequency increased significantly with patient age (Cochran's Q p<0.001). The most common barriers to objective testing were insufficient training (44.3%), time constraints (29.9%), and funding limitations (28.1%). Multidisciplinary collaboration was negligible. Significant regional variation was observed across most practice domains. Conclusions: Paediatric OD care is characterised by functional underinvestigation, fragmented multidisciplinary collaboration, and systemic educational gaps. These findings support urgent development of standardised clinical guidelines, age-appropriate validated assessment tools, and formal interdisciplinary care pathways.

Background: Mucopolysaccharidosis type IIIB (MPS IIIB) is a devastating neurodegenerative lysosomal storage disorder caused by alpha-N-acetylglucosaminidase (NAGLU) deficiency. There is currently no approved therapy. We report the 3-month outcomes of a novel intracerebroventricular (ICV) gene therapy in a child with MPS IIIB. Methods: In an open-label, single-center, investigator-initiated trial (ChiCTR2600121466), a single dose of RDGT-101 (2.0E14; vg of an AAV9 vector encoding human NAGLU) was administered via ICV infusion. Primary outcomes were safety and tolerability. Secondary outcomes included serum NAGLU activity, urinary heparan sulfate (HS) excretion, and neurocognitive function. Exploratory analyses included hematological parameters. Results: The patient achieved serum NAGLU activity (17.06 nmol/mL/hour) approaching that of healthy controls (17.75 {+/-} 1.37 nmol/mL/hour) by Month 3, accompanied by a 58.4% reduction in urinary HS. Clinically, previously severe hand and toe contractures resolved, allowing for full extension. Neurocognitive improvements were observed, including clear articulation, logical conversation, and sustained eye contact. Hematological analyses revealed normalized red blood cell indices and improved iron utilization. No dose-limiting toxicities, serious adverse events, or clinically significant laboratory abnormalities were observed. Conclusions: A single ICV infusion of RDGT-101 was safe and well-tolerated in this patient with MPS IIIB. Early biochemical correction was accompanied by marked improvements in somatic, neurocognitive, and hematological parameters. These findings support further investigation of ICV AAV9 gene therapy for MPS IIIB.