Journal of Medical Genetics

Background. MSH3 and MLH3 are non-canonical DNA mismatch repair genes, involved in repairing insertion-deletion mutations. Colorectal cancer (CRC) and adenomas have been reported in patients with bi-allelic germline MSH3 mutations, and in a very few bi-allelic MLH3 mutation carriers. Objectives. We hypothesised that germline loss-of-function MSH3 and MLH3 mutations were akin to constitutional mismatch repair deficiency (cMMRd) and Lynch syndrome, such that CRC could result from either bi-allelic germline mutations, or heterozygous germline mutations after second hits. Design. Nearly 12,000 CRC and multiple polyp cases and 460,000 controls were studied. 2,023 patients underwent cancer genome sequencing. Results. One CRC/multiple polyp case had bi-allelic MSH3 mutations and another, bi-allelic MLH3 mutations. MSH3 and MLH3 germline heterozygotes had an increased risk of CRC (respectively 2.2-fold, P=6.6x10-5 and 1.6-fold, P=0.028), owing to somatic second hits that inactivated the wildtype allele. Single second hits sometimes inactivated both MSH3 and the nearby APC gene. All CRCs with MSH3 or MLH3 deficiency were microsatellite-stable, but hypermutant. Deletions of 2 or more base pairs were particularly increased (about 12-fold) and signature ID4 was usually present (P<0.0001). CRCs from heterozygotes without second hits showed no hypermutation. Conclusion. The phenotypes of bi-allelic MSH3 and MLH3 mutation carriers resemble some cMMRd patients. Heterozygous germline MSH3 and MLH3 alleles have incomplete penetrance, but increase CRC risk via hypermutation, phenotypically resembling PMS2-mutant Lynch syndrome. A causal association with specific mutations has not previously been reported for ID4 in human tumours. ID4 probably does not have a single aetiology, but can result from MSH3 or MLH3 deficiency. The findings of this manuscript are provisional and should not be used to guide clinical practice, health-related behavior, or policy.

Objective Beckwith-Wiedemann spectrum (BWSp) is an overgrowth and cancer predisposition disorder caused by genetic and epigenetic alterations of chromosome 11p15. The 2018 international consensus produced a clinical scoring system to capture the phenotypic variability of BWSp and guide genetic testing and clinical management, including tumor screening, in patients without molecular confirmation. In this study, we evaluated BWSp predictors to identify the most informative features. Methods Supervised machine learning analyzed 25 phenotypic features in 555 patients with BWSp and 150 controls. Logistic regression, combined with a purposeful stepwise selection algorithm, identified a subset of features that can accurately classify subjects. Model performance was evaluated in a testing set and validated externally. Results The final model included six predictors: macroglossia, lateralized overgrowth, midface flattening, hepatomegaly, omphalocele, and developmental delay. Developmental delay was the only negative predictor; macroglossia (OR 46.10) and lateralized overgrowth (OR 27.87) were the strongest predictors. The proposed model and 2018 system did not differ in classification performance for testing (P = .39) or external (P = .15) sets. Conclusion A simplified diagnostic model, driven by macroglossia and lateralized overgrowth, differentiates between patients with BWSp and controls with performance comparable to the 2018 system. And may help physicians prioritize BWSp evaluation.

Germline pathogenic or likely pathogenic variants (GPVs) in BRCA-1 Associated Protein 1 (BAP1) are associated with a spectrum of tumors, including uveal melanoma (UM). Currently, UM patients with BAP1 GPVs are treated as high-risk class 2 tumors based on mostly empiric data. In the current study, we examined the clinical phenotype of a cohort of 29 UM patients with BAP1 GPVs. We also carried out a systematic review of the literature of UM patients with BAP1 GPVs. We observed that UM patients with BAP1 GPVs have significantly lower median age of diagnosis compared to median age reported in UM patients in the Surveillance, Epidemiology, and End Results Program (SEERS) database. Metastatic risk and overall survival in the UM BAP1 GPVs cohort were statistically significant from those in patients with class 1 tumors, but were comparable to those observed in UM patients with class 2 tumors. In UM BAP1 GPVs treated with radiation (n=12), no secondary cancers were observed in the field of radiation in a median 26.5 months (range, 4-119 months) follow up period. One patient experienced a separate growth of UM at a distinct location within the same eye. These data support managing UM in patients with BAP1 GPVs as aggressive class 2 tumors, following the currently established standard of care for these high-risk tumors.

Accurate interpretation of rare germline variants remains a major challenge in developmental disorders (DD). Somatic mutation data represent a largely untapped source of evidence for germline variant classi-fication. Identical or nearby mutations that drive positive selection when present in somatic tissues can cause developmental disorders when present in the germline. We integrated somatic mutation data from the Catalogue Of Somatic Mutations In Cancer (COSMIC), and healthy tissues (sperm and buccal epithelium) with germline variant datasets from ClinVar and large studies of de novo mutations in DD patients. Across 970 dominant DD genes, 195 have evidence of somatic selection, with a majority demonstrating concordant mechanisms between germline and somatic contexts. We benchmark the ability of somatic data to discriminate pathogenic from benign germline missense variation across dominant DD genes, identifying 145 genes in which somatic data are informative. The strongest utility is in altered-function genes where germline and somatic mechanisms are concordant, for example the RASopathy genes. In these genes, codon-level aggregation of somatic missense counts yields predictive performance comparable to computational predictors or MAVE assays (AUC-ROC 0.895 for somatic data, versus 0.893 for REVEL). Combining somatic features with computational scores improves discrimination further. Using likelihood ratios, we map COSMIC missense codon count thresholds onto American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP)-style evidence strengths, showing that somatic data can reach strong levels of evidence in germline variant interpretation in DD and enable reclassification of variants of uncertain significance. Together, these results establish somatic mutation data as a scalable and clinically actionable evidence source for germline variant interpretation in select DD genes. Graphical abstract(Generated using FigureLabs) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/732808v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@150bec9org.highwire.dtl.DTLVardef@1dacf5org.highwire.dtl.DTLVardef@46121dorg.highwire.dtl.DTLVardef@4f5c38_HPS_FORMAT_FIGEXP M_FIG C_FIG

Background: Recurrent constellations of embryonic malformations (RCEMs) comprise multiple malformation conditions with largely unexplained etiologies and no established molecular biomarkers. A shared DNA methylation episignature was recently identified in VACTERL association and oculoauriculovertebral spectrum (OAVS). We sought to validate this episignature in an independent, deeply phenotyped cohort and evaluate its detection across related RCEMs. Methods: Genome-wide DNA methylation profiling was performed on peripheral blood from 38 participants with clinically diagnosed RCEMs, including VACTERL (n=21), partial VACTERL (n=3), OAVS (n=3), and other RCEM-related conditions (n=11). Results: The Episign V5 RCEM episignature demonstrated robust sensitivity for VACTERL (18/21, 85.7% positive), while the remaining three participants showed intermediate positivity. Of three participants with partial VACTERL, one with tracheoesophageal fistula demonstrated intermediate positivity, whereas the other two were negative. Episignature positivity was also identified in oculoauriculofrontonasal dysplasia (1/1, robust) and rhomboencephalosynapsis (1/2, robust) but was limited in OAVS (1/3, intermediate) and absent in frontonasal dysplasia (0/4). Conclusions: Independent validation establishes the Episign V5 RCEM episignature as a reproducible molecular biomarker for VACTERL, a condition that remains a diagnosis of exclusion. Variable detection across related malformation conditions suggests etiologic heterogeneity, whereas overlap among selected phenotypes supports epigenomic convergence across the RCEM spectrum.

Advances in high-throughput sequencing and genetic research have expanded the role of genetics in medicine and society. Population-based screening programs, including neonatal and preconception testing, are increasingly implemented globally, alongside the rise of direct-to-consumer (DTC) genetic testing. The "Genetics and the General Public" Ethics Working Group of the French Federation of Human Genetics (FFGH) assessed knowledge and awareness of genetics within the French population through a nationally representative survey (n=3,013) conducted by the polling firm Ipsos bva. Results indicated that 69% of respondents report an interest in genetics, although their level of knowledge remains limited. Most respondents expressed positive attitudes toward genetics, perceiving it as a major source of hope in healthcare. While a majority indicated willingness to undergo genetic testing for medical purposes, they also reported legitimate concerns regarding the potential results. Despite legal restrictions, 12% reported having ordered a DTC genetic test (5% for genealogical; 5% for medical and 2% for both purposes), and 45% of non-users expressed strong interest in this type of test. Notably, there is a substantial lack of awareness regarding the limitations of these tests and the French legal framework governing their use. These findings highlight critical gaps in public knowledge, emphasizing the need for improved genetic education, including incorporating genetics into school curricula and launching targeted awareness campaigns. These initiatives should help clarify the distinctions between clinically validated genetic tests and DTC genetic testing services, addressing both their benefits and their ethical, legal, and scientific limitations, in order to promote informed decision-making.

Objective: In KCNQ2-related disorders (KCNQ2-RD), neurodevelopmental outcome remains variable despite established genotype-phenotype correlations. Our aim is to improve counselling, by developing and internally validating models predicting neurodevelopmental outcomes based on early clinical and genetic features, universally available to clinicians. Methods: We conducted a multicentric retrospective cohort study including 277 individuals carrying a (likely) pathogenic variant in the KCNQ2 gene, with a minimum follow-up age of three years. Mosaic variants were excluded. The cohort was randomly split into training (70%) and validation (30%) sets. Ten expert selected parameters with minimal missing data were used to train random forest models to predict (i) dichotomous outcomes and (ii) three-category outcomes for cognition, language, and gross motor milestones. Results: Models incorporated seven clinical (neonatal hypotonia, EEG characteristics, age at seizure onset, seizure type, and seizure frequency at onset, prematurity, and sex) and three genetic variables (de novo status, exon localisation, and position within known KCNQ2-developmental and epileptic encephalopathy (DEE) hotspot regions). Dichotomous models showed the highest predictive performance, with accuracies of 0.83 for normal vs. mild-profound intellectual disability (ID), 0.83 for achievement of first words, and 0.86 for achievement of independent walking. Three category models remained clinically informative: accuracies were 0.79 for normal vs. mild vs. moderate-profound ID, 0.70 for first words [&le;]16 months vs. >16 months vs. never, and 0.71 for independent walking [&le;]18 months vs. >18 months vs. never. The strongest predictors for adverse neurodevelopmental outcomes were presence of hypotonia at birth, seizure onset within the first day of life, multiple seizures per day at onset, tonic seizures at onset, a burst-suppression pattern on EEG at onset, the presence of a de novo variant, and variant location within exons 6-7. Significance: These prediction models demonstrate the feasibility of early prognostication in KCNQ2-RD and support future prospective external validation. They enable more accurate individualised counselling by integrating clinical and genetic information readily available at time of genetic diagnosis and provide an objective foundation for early intervention planning and future precision medicine trial stratification.

Early glaucoma detection and treatment are critical to prevent irreversible blindness. Glaucoma polygenic risk scores (PRS) offer an effective approach for stratifying disease risk and are increasingly available in clinical practice. However, the psychosocial impact of receiving glaucoma PRS results is currently unknown. As such, this study investigated short-term psychosocial outcomes of disclosing glaucoma PRS to individuals over 50 years from the general population. Individuals from the bottom 10%, middle 45 to 55%, and top 10% of PRS scores were invited to receive their results and complete surveys before and 2 weeks after receiving results to assess anxiety, test-related distress, decisional regret, recall and understanding. Of invited participants, 51.7% (136/263) enrolled with 133 completing both surveys. Two weeks after disclosure, PRS recall was high (78.2%), although PRS knowledge remained limited. Privacy concerns were moderate, not differing across PRS groups (X^2 = 4.17, p = .124). Small reductions in glaucoma-related anxiety (z = -2.93, p = .003), generalised anxiety (z = -3.75, p < .001) and stress (z = -2.49, p = .013) were observed following disclosure. While scores remained within normal ranges, higher glaucoma-related anxiety (t = -2.36, p = .020), higher negative emotions (X^2 = 20.80, p < .001), and lower positive experience (F = 5.70, p = .004) were seen for high-risk participants compared to lower-risk participants. Decisional regret was low and did not differ across PRS groups (X^2 = 0.28, p = .869). These findings support the psychosocial safety of glaucoma PRS testing while highlighting the need for improved education and longer-term follow-up to support clinical implementation.

Pathogenic variants in the myocilin (MYOC) gene are the most common cause of Mendelian open-angle glaucoma. In 2022, the Clinical Genome Resource (ClinGen) Glaucoma Variant Curation Expert Panel (VCEP) published rule specifications for MYOC variant interpretation, including a pilot study of 81 variants. Here, we present the results of curating 271 MYOC variants reported in people with open-angle glaucoma using updated specification rules. Of all the variants, 11 were classified as benign (B), 45 as likely benign (LB), 166 as variants of uncertain significance (VUS), 35 as likely pathogenic (LP), and 14 as pathogenic (P). All LP/P variants were located within the conserved olfactomedin domain encoded by exon 3. The updated variant curation guidelines from the Glaucoma VCEP increased the number of clinically definitive classifications from 28% (74/265) to 39% (105/271), with 95% (41/43) of reclassified variants moving to greater clinical relevance. Functional evidence was lacking for 93% (154/166) of VUS. Additional functional evidence could further enhance classification by halving (85/166) the proportion of those classified as VUS. These findings highlight the role of rule calibration and rigorous functional evidence assessment toward improving variant classification with clinical utility for patients.

Background: Interocular asymmetry of axial elongation predicts accelerated myopia progression in adults, but childhood prevalence and dynamics are uncharacterised, with no standardised metric. A scale-invariant metric is proposed and characterised in a paediatric cohort with progressive myopia. Methods: A retrospective cohort of 267 children (5-16 years; 913 follow-up intervals) with progressive myopia and routine optical biometry collected during 2015-2026 was analysed. The Relative Asymmetry Index was defined per interval as the absolute interocular axial length difference normalised to the larger eye's change; its patient-level median defined the Cumulative Relative Asymmetry Index (CRAI). An annualised Absolute Asymmetry Index (AAI) was introduced as a complementary rate metric. Results: Median CRAI was 22.7 % [interquartile range 12.8-38.8]; median AAI 0.073 mm/year. Statistically detectable asymmetry (AAI > minimal detectable change at 95 % confidence) was present in 15 % of patients; 13.9 % showed pronounced asymmetry (CRAI > 50 %; AAI 0.218 mm/year). CRAI rose with age (Spearman rho = +0.28; partial rho = +0.25 after adjustment for net axial length change rate, both p < 0.001), and was independent of the overall rate after age adjustment (partial rho = -0.08, p = 0.20), consistent with scale invariance. The overall net axial length change rate decreased approximately three-fold across age strata (rho = -0.23, p < 0.001). Conclusions: CRAI and AAI provide complementary approximately scale-invariant and absolute metrics of interocular asymmetry. Interocular asymmetry appears common in this cohort and shows a marked age-related rise independent of overall progression rate.

Purpose: Pathogenic variants in NFIX cause Marshall-Smith syndrome and Malan syndrome (MALNS). We identified a severe subtype of MALNS characterized by adolescent-onset musculoskeletal deterioration and investigated functional consequences of underlying variants. Methods: Clinical data were collected from seven individuals with pathogenic NFIX variants. Wild-type and mutated recombinant NFIX DNA-binding domains (DBDs) were evaluated using biochemical, structural, and DNA-binding assays. Results: Six individuals carrying R116W, R116P, K125E, or G147E NFIX substitutions developed progressive muscle wasting, markedly reduced body mass index, and rapidly progressive scoliosis after the typical childhood features of MALNS; two died from disease-related complications. A seventh individual with R116G did not develop this severe phenotype. Functional studies on recombinant NFIX DBDs showed complete or near-complete loss of DNA-binding activity for R116W, R116P, K125E, and G147E despite preserved protein folding, consistent with disrupted DNA recognition and a potential dominant-negative mechanism. In contrast, R116G exhibited a 7.7{degrees}C decrease in thermal stability, which may support haploinsufficiency mediated by protein degradation. Conclusion: Specific NFIX missense variants define a severe subtype of MALNS associated with progressive musculoskeletal deterioration. In vitro functional studies support variant-specific disruption of DNA binding, providing a mechanistic basis of genotype-phenotype correlations and informing prognosis, clinical surveillance, and therapy development.

Individuals with inherited retinal dystrophies (IRDs) undergo a slow, genetically heterogeneous loss of vision, yet how the visual cortex and non-visual sensory, motor, and psychological systems adapt to this deprivation remains poorly characterized. Existing evidence comes mainly from single-modality, cross-sectional studies that rarely account for genetic heterogeneity, making it hard to distinguish adaptive change from a direct, non-retinal mutation effect, since several IRD genes are not retina-specific. To address this gap, we designed an observational, longitudinal, multimodal protocol that combines ophthalmological, genetic, and in silico characterization with electrophysiological (steady-state visual evoked potentials and TMS-EEG), chemosensory, sensorimotor, and psycho-personological assessments. Patients aged 18 to 75 years with rod-cone (retinitis pigmentosa, Usher syndrome) or cone and cone-rod dystrophies will be assessed at baseline (T0) and at an 18-month follow-up (T1); sighted controls, matched for age, sex, and handedness, will complete the same battery once. Importantly, pairing genotypic with phenotypic data allows changes in non-visual domains to be interpreted against, rather than independently of, each patient's molecular background. We expect individuals with IRDs to differ from controls in visual cortical responsiveness and in selected non-visual sensory and sensorimotor measures, with genotype-related differences explored where sample size permits. Given the rarity of IRDs, the design is exploratory and emphasizes effect sizes and individual variability over large-sample inference. The protocol was approved by the Ethics Committee of the University of Verona (CARP 08.R1/2024) and follows the Declaration of Helsinki and the GDPR; findings will be disseminated through peer-reviewed publications and shared with patients and IRD patient associations.

Consanguinity increases the risk of autosomal recessive disorders and may result in the co-segregation of multiple pathogenic variants within the same family. Although most affected families are explained by a single genetic diagnosis, multilocus pathogenic variation can produce complex and overlapping clinical phenotypes. We investigated a consanguineous Pakistani family with three affected siblings, including dizygotic twins presenting with neurodevelopmental disorder and hearing loss, using detailed clinical evaluation, long-read whole-genome sequencing, bulk transcriptomics, protein profiling, and segregation analysis to determine the underlying molecular diagnoses. One sibling presented with isolated non-syndromic hearing loss, whereas the dizygotic twins exhibited severe neurodevelopmental impairment characterized by global developmental delay, spastic quadriplegic cerebral palsy, microcephaly, and white matter abnormalities. Long-read whole-genome sequencing identified a homozygous start-loss variant in HPDL (c.3G>C) in both twins, consistent with HPDL-related neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA). In addition, a novel homozygous nonsense variant in EPS8 (c.1294C>T) was identified in one twin and the sibling with isolated hearing loss, explaining the auditory phenotype. Long-read transcriptomic analysis demonstrated absence of detectable EPS8 transcripts in both individuals homozygous for the nonsense variant, providing transcript-level evidence consistent with a loss-of-function mechanism. Genome-wide comprehensive proteomic profiling (SomaScan) identified distinct protein abundance profiles across family members, with the most pronounced alterations observed in the twins affected by HPDL-related neurodevelopmental disease, particularly the individual harboring pathogenic variants in both EPS8 and HPDL. This study expands the mutational spectrum of EPS8 and highlights the independent segregation of two autosomal recessive disorders within the complex consanguineous family, resulting in distinct and blended phenotypes.

Background: Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is a rare autosomal recessive disorder caused by biallelic variants in ADPRHL2, which encodes ADP-ribosylhydrolase 3 (ARH3), a key enzyme involved in poly (ADP-ribose) (PAR) metabolism. Although Minocycline has been reported to attenuate PAR-mediated neurotoxicity primarily through modulation of PARP-dependent pathways, whether it may also interact with ARH3 or influence the structural behavior of pathogenic ARH3 variants remains unknown. This study was designed to explore this possibility by integrating clinical observation with computational structural analyses. Methods: Comprehensive clinical evaluation, targeted Sanger sequencing, and in silico pathogenicity analyses were performed. Protein modeling, molecular docking, and 100-ns molecular dynamics simulations were conducted to evaluate the predicted structural consequences of the p.Thr79Pro variant and to explore potential interactions between ARH3 and Minocycline. Results: A homozygous ADPRHL2 variant (NM_017825.3:c.235A>C; p.Thr79Pro) was identified in a child with CONDSIAS. Computational analyses predicted reduced structural stability and increased conformational flexibility of the mutant ARH3 protein relative to the wild-type structure. MM-GBSA calculations estimated differences in binding free energies between the wild-type (-34.51 kcal/mol) and mutant (-39.76 kcal/mol) ARH3-Minocycline complexes, suggesting subtle differences in their predicted energetic profiles. Clinically, neurological progression appeared stable, with improved motor function observed during approximately one year of follow-up and no notable treatment-related adverse effects. Conclusions: By integrating clinical observations with computational structural analyses, this study provides preliminary computational support for the hypothesis that Minocycline may influence ARH3 conformational behavior in addition to its proposed effects on PARP-dependent pathways. Although these findings do not demonstrate direct molecular binding or therapeutic efficacy, they provide a biologically plausible framework for future biochemical, cellular, and functional investigations. Keywords: CONDSIAS; ADPRHL2; ARH3; Minocycline; molecular docking; molecular dynamics simulation; structural bioinformatics; translational medicine

Importance: Family history (FH) and age are the primary criteria employed for early colorectal cancer (CRC) risk stratification. We evaluated how well these criteria identify individuals diagnosed with CRC across age and racial groups. Objective: To evaluate the performance of FH and age based screening criteria for identifying individuals with CRC, with attention to differences by race and age at diagnosis. Design, Setting, and Participants: This case control and case only analysis used data from the Disparities and Cancer Epidemiology (DANCE) cohort, a population based study of invasive CRC cases diagnosed from 2013 to 2022, recruited through the Metropolitan Detroit Cancer Surveillance System and the Louisiana Tumor Registry. Analyses included 1,158 non-Hispanic Black (NHB) and non-Hispanic White (NHW) CRC cases and 1,434 cancer-free controls from the Inflammation Health and Lung Epidemiology (INHALE) study, enrolled from the same Detroit catchment area. Data were analyzed in 2025. Exposures: Self reported cancer FH among first-degree (FD) relatives and grandparents, summarized into three FH-based screening criteria: at least one FD relative with CRC (colon early-screening criterion), any FH of Lynch syndrome related cancers, and meeting NCCN criteria for Lynch syndrome genetic testing. Main Outcomes and Measures: Proportion of cases meeting each FH based screening criterion stratified by race and age at diagnosis (<45, 45 - 49, 50 - 64, and <65 years); case only odds ratios for younger age at diagnosis; and case control odds ratios for CRC associated with each criterion, with race-by-age interaction tested. Results: Cancer FH burden differed by age at diagnosis across both racial groups. First degree (FD) CRC FH was highest among NHB CRC cases diagnosed before age 45 (22.6%) and lowest in those diagnosed at ages 45-49 (8.2%), while NHW participants reported more CRC FH with older age at diagnosis (p interaction=0.011). In case control analyses, having at least one FD relative with CRC was associated with higher odds of CRC before age 45 among NHB (OR=1.44, 95% CI 1.09 - 1.89) but not NHW individuals. The proportion of cases diagnosed before age 45 with a FD CRC FH was low, though markedly higher in NHB than NHW individuals (22.6% vs. 4.0%). While the proportion was slightly higher when including FH of any Lynch syndrome-related cancers (NHB: 24.5%, NHW: 10.0%), the proportion of controls with a FD FH of these cancers also increased. Conclusions and Relevance: Current family history-based criteria fail to identify the majority of individuals diagnosed with CRC before age 45, with performance varying substantially by race, highlighting the urgent need for more equitable and effective approaches to early-onset CRC risk stratification.

Objective: The objective of this study was to detect genetic factors associated with dermatochalasis using a genome-wide association study (GWAS) across three large cohorts. Design: GWAS meta-analysis Participants: A total of 13,200 dermatochalasis cases and 962,513 controls were included. Methods: A GWAS meta-analysis of dermatochalasis combining data from the FinnGen, the Estonian Biobank and the UK Biobank was conducted. We also performed colocalization analyses, a phenome-wide association study and age-at-onset analysis, and assessed genetic correlations with various diseases and traits. Main outcome measures: Identification of genetic variants associated with dermatochalasis. Results: We identified 18 loci associated with dermatochalasis at genome-wide significance, 16 of which were novel. Most of these loci had genes involved in skin biology and cutaneous diseases, such as the genes encoding elastin (ELN) and Latent TGF-{beta} binding protein 1 (LTBP1). Phenome-wide association study revealed previous associations with morphology-related traits, while genetic correlation analysis highlighted multiple genetic correlations, especially with smoking and pain. Conclusions: We detected 18 genetic loci associated with dermatochalasis, characterized these loci in detail and demonstrated their relevance in skin biology and related processes. These findings give novel information on the genetic background of dermatochalasis and provide a solid basis for further research.

Objective. This systematic review and meta-analysis synthesised the global prevalence of overweight and obesity in people with Down syndrome (DS) across the lifespan, characterised determinants of excess adiposity, and examined associations with adverse cardiometabolic outcomes. Methods. Six databases were searched without date or language restriction. Two independent reviewers screened studies, extracted data, and assessed quality using the Joanna Briggs Institute Critical Appraisal Checklist for Prevalence Studies. Prevalence was pooled using a random-effects logit model. A pre-specified subgroup analysis by age band was conducted. Publication bias was assessed with Egger's test and certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results. Twenty-six studies (7,840 individuals; 14 countries) were included. The pooled prevalence was 18% (95% CI 15-22%) in children and adolescents, 36% (95% CI 26-47%) in adults, and 30% (95% CI 20-43%) in mixed-age cohorts; the test for subgroup differences was significant. The overall pooled prevalence was 22% (95% CI 18-26%; prediction interval 7-53%; I^2 = 95.3%). No publication bias was detected (Egger's t = 0.39, p = 0.6964). DS-specific growth charts yielded estimates 14-37 percentage points lower than general-population references applied to the same cohorts. Obesity more than doubled obstructive sleep apnea risk (RR 2.4; 95% CI 1.34-4.34) and non-alcoholic fatty liver disease was present in 82% of obese versus 45% of non-obese children with DS. GRADE certainty was Moderate for prevalence estimates. Conclusions. Overweight and obesity in DS are highly prevalent, age-progressive, and substantially exceed general-population rates at every life stage. Roughly one in five people with DS is affected overall, rising to more than one in three adults. The reference chart applied is the single largest source of heterogeneity in reported estimates. Cardiometabolic surveillance, adapted lifestyle interventions, and primary prevalence research from low- and middle-income countries are the highest-priority gaps.

Clinical relevance: Validated virtual control arms may provide population-level estimates of treatment effect and reduce reliance on untreated control allocations in myopia trials. Background: Untreated single-vision control arms in paediatric myopia efficacy trials are increasingly difficult to justify and retain. Several published models predict untreated childhood axial elongation by region or ethnicity. Here they are implemented unchanged in an open-source tool and validated against an untreated multi-ethnic cohort. Methods: Five published models predicted untreated elongation from baseline age, cycloplegic spherical equivalent, sex, and ethnicity, anchored at baseline axial length (AL) and evaluated at actual follow-up. Predictions were compared with 242 untreated myopic children (Chinese, Vietnamese, Indian) with AL measured at approximately 6 and 12 months, assessing bias, root-mean-square error, and prediction-interval coverage against pre-specified thresholds (bias <0.03 mm; coverage greater than or equal to 0.90). Results: The regional generalised estimating equation (GEE) and meta-regression models reproduced mean East Asian elongation without meaningful bias at 6 months (GEE bias -0.013 mm; equivalence to plus-or-minus 0.03 mm, p = 0.014) and at 12 months (-0.004 mm), although equivalence was not established at 12 months in an underpowered subgroup (n = 71, all Vietnamese; p = 0.068). Older age-only models under-predicted by 0.07 to 0.12 mm. Published individual prediction intervals were too narrow (coverage 0.77): the means were accurate, the individual uncertainty was not. Indian elongation fell between strata and was matched by no existing model. Conclusions: The models reproduce mean untreated East Asian elongation at 6 months, conditional on cohort independence; South Asian children remain unserved by any existing stratum. The tool is a group-level instrument, not an individual predictor, and a transparent unification of published models in open-source code. Its value for estimating treatment effect awaits back-testing against a trial with a known untreated arm, ideally over 24 to 36 months.

There are no published data on cancer screening by women using medically assisted reproduction (MAR). Such data would aid interpretation of the cancer incidence and risk profiles for this group. Using linked population-based Australian health registries and administrative datasets, we compared organised publicly funded cervical and breast screening episodes for women who received one of three types of MAR and matched women who did not between 1991 and 2016. We modelled the proportion of women screened in the three years before and after first MAR treatment, adjusting for age, remoteness, parity, socio-economic disadvantage, cancer history, and uptake of the other screening program. After adjustment, a greater proportion of women who received MAR than women who did not had cervical screening before MAR (77.3%-84.1% vs 57.5%-62.0%, depending on treatment) and after MAR (77.0%-78.5% vs 68.1%-68.3%). Contrastingly, breast screening estimates were 7.6%-9.6% vs 9.3%-10.5% before MAR and 11.0%-15.0% vs 12.8%-14.9% after MAR.

Orofacial clefts (OFCs), including cleft lip (CL), cleft palate (CP), and cleft lip with cleft palate (CLP), are among the most common craniofacial malformations in humans, with a birth prevalence of approximately 1 in 1,000 live births globally. Non-syndromic forms of OFC are predominantly genetic, with significant variability in prevalence across populations. Understanding the genetic underpinnings of OFCs remains a key public health priority, given the substantial medical and societal burden of these conditions. Recent genome-wide association studies (GWAS) have implicated numerous genetic loci, but challenges remain due to genetic heterogeneity and complex gene-environment interactions. This study aimed to identify sex-specific genetic risk factors for cleft lip with or without cleft palate (CL/P) through a meta-analysis of whole genome sequencing (WGS) data from 1,922 case-parent trios across eight diverse cohorts. Our approach revealed four SNPs in three distinct regions that showed genome-wide significant sex-specific effects. However, despite each of these SNPs passing standard quality control filters, follow-up analyses showed that these signals most likely were technical artifacts caused by sequencing errors, in particular mis-mapped reads due to sequence similarities with the sex chromosomes. These findings highlight the necessity for careful scrutiny when studying differences between the sexes in genetic association studies.