European Journal of Human Genetics

Heterozygous FOXL2 (non-)coding sequence and structural variants (SVs) lead to blepharophimosis, ptosis and epicanthus inversus syndrome (BPES), a rare, autosomal dominant developmental disorder characterized by a completely penetrant eyelid malformation and incompletely penetrant primary ovarian insufficiency (POI). We collected variants from our in-house database, generated via clinical genetic testing and downstream research testing in the Center for Medical Genetics Ghent, Belgium (2001-2024), and via literature and other resources in the same period. All retrieved variants were categorized using ACMG/AMP classifications to increase the knowledge of pathogenicity. We collected 413 unique genetic defects of the FOXL2 region, including 76 novel variants, in 864 index patients. Of these, 87% of patients were identified with a coding FOXL2 sequence variant. The polyalanine tract is a known mutational hotspot of FOXL2, illustrated here by the high percentage of pathogenic polyalanine expansions (24%). Furthermore, the molecular spectrum in typical BPES index patients is characterized by 8% coding deletions and 3% deletions located up- and downstream of FOXL2. The remaining 2% carry translocations along with chromosomal rearrangements of 3q23. This uniform and structured reclassification, incorporating the largest dataset of variants implicated in FOXL2-associated disease so far, will improve both the diagnosis as well as genetic counselling for individuals with BPES.

Background As part of Singapore's effort towards precision medicine tailored to Asian diversity, we describe the implementation of a nationwide reproductive carrier screening program. Using a customised 112-gene panel, incorporating population-specific recessive genetic diseases, we outline the overall program design, and initial efforts of community and stakeholder engagement, to inform culturally appropriate implementation. Methods Participants receive culturally tailored online education regarding our reproductive screening program and are provided results with genetic counselling and reproductive options. Community and stakeholder perspectives were assessed through questionnaires and consultations with religious leaders. Results Recruitment is nation-wide, and since initiation of our pilot phase in September 2024, 1,619 couples have registered interest, with 60% uptake of those deemed eligible. Among the 456 couples that have received results to date, four couples (0.9%) were identified to be at increased risk. Community questionnaire responses (n=1002), involving couples who participated in the program as well as the general public, indicated interest is high (59%) across the cohort but awareness, intent to participate and implications for reproductive options differed by sociodemographic factors such as ancestry and religion. Healthcare professional respondents (n=113) acknowledged carrier screening will be routine in medical care, but report limited confidence and resources. Engagement with religious leaders indicated support for the program. Conclusion These early program outcomes and community engagement are guiding the implementation of expanding population-based carrier screening in Singapore, contingent on addressing practical challenges through equitable outreach and professional training.

Purpose To systematically review population preferences for expanded carrier screening programmes to inform service delivery and health policy. Methods PubMed, CINAHL, and Scopus were searched from 1995 to 2025 on carrier screening for autosomal or X-linked recessive genetic conditions across adult general populations. Included studies elicited preferences on attributes regarding the design or delivery of carrier screening programs. We extracted preferences for each attribute, mapped qualitative findings to these preferences, assessed risk of bias and performed meta-analysis on the willingness-to-pay for screening using Bayesian multilevel modelling. All findings are reported in 2024 USD. Results Thirty one studies, including 16 quantitative, 11 qualitative, and 4 mixed-methods studies were included. Participants expressed preferences for which conditions to include in ECS, joint vs individual screening, the value of information provided before screening, in-person over online counselling, type of healthcare provider, and preconception testing. Willingness-to-pay was right-skewed with 9% of participants not willing to pay any amount, a median of $107 and an interquartile range between $41 and $226. Most studies demonstrated a high risk of bias. Conclusions We report preferences of the general population regarding expanded carrier screening programmes, including suggested amounts for copayment if subsidised by the health system.

Cancer Variant Interpretation Group UK was established in 2017 in response to the publication of the 2015 ACMG/AMP v3 guidance for the interpretation of sequence variants. Its initial purpose was to ensure consistency in the UK clinical-laboratory community implementation of ACMG/AMP v3 guidance for cancer susceptibility genes (CSGs). Still convening for monthly national meetings, the remit of CanVIG-UK now encompasses additional activities delivered under the following objectives: O_LICreation of a national multidisciplinary professional network and regular forum. C_LIO_LIDelivery of training and education. C_LIO_LIEstablishment of a consensus approach to the fundamentals of variant interpretation in cancer susceptibility genes. C_LIO_LIDevelopment and ratification of gene-specific frameworks for variant interpretation for cancer susceptibility genes. C_LIO_LIDevelopment and maintenance of an online platform to facilitate information sharing and variant interpretation within the UK clinical-laboratory community. C_LIO_LIFacilitation of UK contribution to international variant interpretation endeavours. C_LI A survey of CanVIG-UK members evaluating the impact of these activities conducted in November 2025 had 163 responses, including 113 clinical scientists/trainees and 27 Clinical Genetics consultants/trainees. The utility of the CanVIG-UK consensus recommendations for variant interpretation in cancer susceptibility genes was highly rated, with 89/145=61.4% of survey respondents reporting using the guidance at least weekly ([≥]4 times/month) and 124/128=96.9% rating it as extremely/very useful. The usage frequency and utility of the gene-specific guidance reported by survey respondents were similar to those reported for the main consensus specification. Both qualitative and quantitative survey responses clearly demonstrate the value of the CanVIG-UK activities to the clinical-diagnostic community. Key messagesO_LIWhat is already known on this topic: Cancer Variant Interpretation Group UK (CanVIG-UK) is a national subspeciality multidisciplinary network first established in 2017. It brings together members of the UK clinical-laboratory community to improve accuracy and consistency in the interpretation of variants in cancer susceptibility genes (CSG) C_LIO_LIWhat this study adds: this article presents the results of a survey of CanVIG-UK members, demonstrating the impact of CanVIG-UK activities on their services, as well as a review of progress in the six updated objectives of CanVIG-UK C_LIO_LIHow this study might affect research, practice or policy: this article presents current priorities and practices and potential future directions for variant interpretation in CSGs across the UK and Republic of Ireland C_LI

BackgroundNewborn screening (NBS) has progressively expanded through technological innovations, from tandem mass spectrometry enabling expanded NBS (eNBS) to the prospect of genomic NBS (gNBS). While these developments promise earlier diagnosis and richer information, they also raise concerns regarding actionability, uncertainty, equity and psychosocial impact. As technological feasibility alone does not ensure public confidence, parental perspectives are central to evaluating future expansions. Using acceptability concept as an anticipatory lens, this study assessed parental views on NBS expansion in France, examining its determinants, distinguishing test modalities, and exploring whether genomics raises specific concerns. MethodsA nationwide cross-sectional survey (September 2022-February 2023) included 1,640 parents recruited postpartum in maternity wards and through an online quota panel. Acceptability of eNBS and gNBS, intermediate evaluative components, and sociodemographic characteristics were assessed. Analyses combined descriptive statistics, multivariable regression, and thematic analysis of free-text comments. ResultsSupport was very high for eNBS (93%) and remained high for gNBS (89%), with genetics mainly shifting responses from complete to partial acceptability. Affective attitude and perceived effectiveness were the strongest predictors of both outcomes, while ethical concerns distinguished assured from conditional support. Most parents prioritised minimising uncertain results, whereas a smaller subgroup accepted greater ambiguity. Foreign-born and single parents reported lower levels of complete acceptability, while health-sector workers and parents with rare-disease experience were more supportive. No independent association with the age of the youngest child was observed. ConclusionParental acceptability of eNBS and gNBS is high but nuanced, shaped primarily by anticipated health benefits, emotional orientation and tolerance for uncertainty, with trust and social distance modulating support. As genomic expansion progresses, implementation will require proportionate, culturally adapted information and clear governance, and should be informed by real-world evidence from pilots such as PERIGENOMED. Trial registrationClinicalTrials.gov, NCT06111456. Last verified: October 2023.

STUDY QUESTIONAre pathogenic variants in Homeodomain-interacting protein kinase (HIPK4) associated with sperm head abnormalities causing male infertility? SUMMARY ANSWERHIPK4 is a novel candidate gene associated with sperm head defects and human male infertility. WHAT IS KNOWN ALREADYNumerous genes causing male infertility due to Multiple Morphological Abnormalities of the sperm flagella (MMAF) have been described but the genetic basis of sperm head defects is less well understood. STUDY DESIGN, SIZE, DURATIONFour infertile brothers displaying varying degrees of quantitatively and/or qualitatively impaired spermatogenesis, their parents, and their fertile brother were included in the study. Further, the Male Reproductive Genomics (MERGE) cohort comprising exome/genome sequencing data of >3,300 men was queried. PARTICIPANTS/MATERIALS, SETTING, METHODSWe performed exome sequencing in all five brothers and their parents. To characterise the sperm phenotype, standard semen analysis, immunofluorescence staining, and transmission-electron microscopy (TEM) were carried out. Further, we evaluated the impact of the HIPK4 variant in cell culture experiments using HEK293T cells. MAIN RESULTS AND THE ROLE OF CHANCEAnalysing the exome data, we could not identify a common genetic cause in all four affected brothers. However, one of the affected brothers was compound heterozygous for two loss-of-function variants in DNAH17 (c.1076_1077dup p.(Lys360*) and c.7752+2T>A p.?) associated with markedly reduced sperm motility and MMAF. The variants pathogenicity was further validated by TEM of flagellar cross-sections revealing an outer dynein arm defect and axonemal disruption. On the contrary, his three infertile brothers were homozygous for the start-loss variant c.1A>G in HIPK4. This gene is expressed during spermiogenesis and is reportedly involved in sperm head shaping in mice. Heterologous expression of (partial) HIPK4 variant cDNA elucidated the alternative use of an in frame start codon located 35 amino acids downstream, resulting in an N-terminally truncated protein p.(Met1_Glu35del). The truncated HIPK4 protein lacks parts of its kinase domain and shows reduced protein stability. In line with published mouse models, all three brothers displayed 100% abnormal sperm head morphology with variable defects. Importantly, one brother affected by HIPK4 variants fathered a child after successful intracytoplasmic sperm injection demonstrating that it is a treatment option for HIPK4-related teratozoospermia. No further men from the MERGE cohort were affected by biallelic HIPK4 variants. Taken together, HIPK4 is an autosomal-recessive candidate gene associated with sperm head defects and male infertility. LARGE SCALE DATAThe reported variants in DNAH17 and HIPK4 were submitted to ClinVar. LIMITATIONS, REASONS FOR CAUTIONIndependent replication is required to assess the phenotypic spectrum and the reproductive outcome associated with biallelic HIPK4 variants and to formally establish the gene-disease relationship for male infertility. WIDER IMPLICATIONS OF THE FINDINGSThis study raises awareness of the significant genetic heterogeneity of male infertility. The described family highlights that distinct genetic causes may underlie a seemingly similar phenotype. Exome sequencing of families is helpful to efficiently disentangle individual causes among affected family members. STUDY FUNDING/COMPETING INTEREST(S)N.N., J.R., H.O., S.L., C.F., and F.T. were supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) within the Clinical Research Unit Male Germ Cells (CRU326, project number 329621271). R.T.W., N.N., J.R., H.O., and F.T. were supported by the Federal Ministry of Research, Technology and Space (BMFTR) as part of the project ReproTrack.MS (grant 01GR2303). S.A.K. was supported by the DFG Clinician Scientist programme CareerS Munster (project number 493624047). A.S.G. was supported by the Medical Faculty Munster via an Innovative Medical Research (IMF) grant (GA-122104).

Genotype-phenotype databases are essential for variant interpretation and disease gene discovery. Genetic variation differs among human populations, mainly in allele frequencies and haplotype patterns shaped by ancestry and demographic history. Population-specific genotypes can influence traits and disease risk; this makes population specific characterization important. Most existing resources focus on the characterization of a population's genetic background, but do not represent the resulting phenotypes. We have developed PAVS (Phenotype-Associated Variants in Saudi Arabia), a curated, publicly accessible database that integrates 5,132 Saudi clinical cases from four Saudi cohorts and 522 cases from analysis of a mixed-population cohort, together with 1,856 cases from the Deciphering Developmental Disorders study (DDD) and 9,588 literature phenopackets. Each case record describes patient-level phenotypes, encoded with the Human Phenotype Ontology (HPO), and links them to genomic variants, gene identifiers, zygosity, pathogenicity classifications, and disease diagnoses mapped to standardized disease terminologies. The data is represented in Phenopackets format and as a knowledge graph in RDF. Additionally, a web interface provides phenotype-based similarity search, gene and variant browsers, and an HPO hierarchy explorer. We evaluate the utility of the phenotype annotations for gene prioritization using semantic similarity. While there are clear differences to global literature-curated databases, phenotypes in PAVS can successfully rank the correct gene at high rank (ROCAUC: 0.89). PAVS addresses a gap in population-specific genotype-phenotype resources and provides a benchmark for phenotype-driven variant prioritization in under-represented populations.

The German Twin Family Panel TwinLife is a nationwide longitudinal study of twins and their family members. Primarily focusing on the development of social inequalities over the life course, TwinLife has been collecting data since October 2014 starting with 4,096 twin families (Ntotal = 16,951 individuals). As Germanys largest twin study to date, TwinLife has been surveying four birth cohorts of monozygotic and dizygotic same-sex twin pairs (initially [~]5, 11, 17, and 23 years old) and their families for 11 years. Survey data have been collected through five biennial face-to-face interviews with four computer-assisted telephone interviews in the years between. In addition, saliva samples were collected before the COVID-19 pandemic (2018-2020), during the pandemic (2021), and after (2022-2024). In this Cohort Profile, we describe the curation and initial analyses of molecular genetic and epigenetic data from the two TwinLife satellite projects TwinSNPs and TECS. Together, these projects currently comprise 12,108 processed DNA samples from 6,450 participants, extracted from the first two saliva collections before and during the COVID-19 pandemic. We compared the subsamples with the overall TwinLife sample and provide an overview of derived polygenic scores (PGS), epigenetic clocks and other methylation profile scores (MPS). We found that PGS predicted sample attrition in TwinLife, with small but significant associations between higher PGS for educational attainment and continued participation. Epigenetic clocks derived from saliva were highly correlated with chronological age (r = .71 to r = .94) and were generally more stable over time than other MPS. PGS for epigenetic clocks were associated with the respective clock only during but not before the start of the pandemic. We discuss opportunities of combining prospectively assessed molecular (epi)genetic data in within-family designs such as TwinLife and its implications and avenues for future research.

Background: Mainstreaming genetic testing has emerged as a strategy to improve access and reduce wait times for patients who may benefit from genetic testing. Ensuring patients fully grasp the implications of testing when formal genetic counselling is not provided, remains a focus for ongoing research. Methods: Patients diagnosed with hypertrophic or dilated cardiomyopathy were offered genetic testing between September 2024 and September 2025 through either the mainstreaming model conducted in cardiology clinics or a referral to Medical Genetics where patients attended an online webinar or a one-on-one genetic counselling appointment. Uptake of testing, time to testing, informed choice and patient satisfaction were evaluated. Results: Among patients offered genetic testing, uptake was higher in the mainstreaming pathway (82%) compared with a referral to Medical Genetics (69%). The difference in access was predominately due to patients not following through with their Genetics referral. Mainstreaming reduced wait times where patients referred to Genetics waited a median of 94-185 additional days to be offered genetic testing. Despite improved access, only 62% of mainstreamed patients were considered informed, compared to 91% of patients that attended a patient webinar through Medical Genetics (p < 0.01). Satisfaction with decision-making was high across both pathways. Conclusion: Integrating genetic testing into cardiology practices increased access and reduced wait times; however, patients demonstrated significantly lower rates of informed decision making compared to those who attended a patient webinar offered through Medical Genetics. These findings highlight the importance of structured education to support informed decision making within mainstreaming pathways.

Introduction: Accurate estimation of disease prevalence is crucial for public health and therapeutic development, but traditional methods are often inaccurate. Genetic prevalence, which estimates the proportion of a population with a causal genotype, using allele frequencies from population data, offers an important alternative. Methods: We partnered with 18 Rare As One patient organizations to estimate genetic prevalence for 22 autosomal recessive conditions using population data from two releases of the Genome Aggregation Database (gnomAD). To standardize and democratize these analyses, we developed the Genetic Prevalence Estimator (GeniE), a publicly available tool, for accessible calculations. Results: Conservative carrier frequencies in gnomAD v4.1 ranged from 1/164 to 1/11,888. The median change in genetic prevalence frequency between v2.1 to v4.1 was 0.806. Partnership with patient advocacy groups provided critical real-world context that refined the interpretation of these estimates. Discussion: These findings highlight that genetic prevalence is not a static figure but a dynamic, evolving measure with important caveats that need to be considered. Our study underscores the necessity of re-evaluations as databases expand. By integrating patient-partnered insights with the GeniE platform, we empower the genomics community to maintain transparent, up-to-date, and actionable data for rare disease advocacy and drug development.

UK Biobank has released whole genome sequence data for 500,000 participants, including allele counts for hundreds of millions of variants and these were considered in the context of the pentanucleotide background on which they occurred. Frequencies of singleton variants were obtained and compared with frequencies of more common variants. Results were highly correlated across chromosomes, reflecting systematic effects. C>T singleton variants were less frequent in the CG context but the opposite was true for more common variants, suggesting that they are relatively well tolerated and not subject to strong negative selection. The frequencies of singleton variant types were strongly influenced by their trinucleotide context and the total counts of variants in their trinucleotide context could be well approximated by combining five mutational signatures obtained from genomes of cancer cells. For some variant types, there were marked asymmetries in counts between plus and minus DNA strands. The patterns of these asymmetries for singleton variants differed between chromosomes, with five being negatively correlated with the rest. These asymmetries did not appear related to strand-specific gene content. It was noted that there were also strand asymmetries for some pentanucleotide sequences in the reference genome and that these were consistent across chromosomes. The sequence TTCGT is seen 673300 times on the plus strand but only 465807 times on the minus strand. These findings must reflect strand-specific mechanisms affecting mutation and selection which are not currently well understood and which could be investigated further. This research has been conducted using the UK Biobank Resource.

PIK3CA-related overgrowth spectrum (PROS) comprises a heterogeneous group of disorders caused by postzygotic activating variants in PIK3CA, leading to mosaic activation of the PI3K pathway. PROS natural history is highly variable across patients and depends on the timing and distribution of the somatic mutation. To better characterize this natural history, we analyzed a cohort of patients with PROS. This multicenter study was conducted at Hopital Femme Mere Enfant (Lyon, France) and Hopital Necker-Enfants Malades (Paris, France). We included pediatric and adult patients with PROS who had a documented PIK3CA variant and at least two MRI examinations performed at least 2 months apart. Patients undergoing interventional surgical or radiological procedures, or receiving targeted therapies were excluded. In all patients, target lesions were identified on baseline MRI scans, and assessed on follow-up scans according to the RECIST criteria. Among 67 PROS patients screened from 2008 to 2021, 30 met the inclusion criteria, including 43.3% female patients. The median age at first MRI was 19 years (interquartile range, 5 to 34) and the median interval between the two scans was 75.7 months (range, 2.1 to 160.3 months). Recurrent localizations included the face (n = 6; 20%), ear, nose and throat region (n = 3; 10%), upper limbs (n = 5; 16.7%), thorax (n = 3; 10%), abdomen (n = 4; 13.3%), pelvis (n = 5; 16.7%), and lower limbs (n = 10; 33.3%), with some patients presenting multisite involvement. During the observation period, 86.6% (n = 26) of patients exhibited an increase in target lesion volume, with a median progression of 37.8% (range, 2.6 to 233.0%) and a mean progression of 52% (standard error of the mean, 7.2%), reflecting a right-skewed distribution driven by a subset of rapidly enlarging lesions. In conclusion, this study provides the first radiological description of the natural history of PROS, demonstrating that tissue malformations most often enlarge over time, with sustained progression persisting into adulthood.

Objective The decline of the perinatal demise rate is slowing and demises are often unexplained. Significant research has been done regarding diagnostic yield and genetic causes of demise, but little is known about how Geneticist involvement impacts outcomes. The goal of the study was to evaluate post-mortem genetic testing practices and effects of the geneticists involvement. Methods Retrospective data from 111 perinatal demise cases was examined, including rates of prenatal genetic counseling, post-delivery genetics consult, genetic testing, and autopsy investigation. Results In this cohort 54% received genetic testing and 25% received a genetics consult. When compared to those without, cases with genetic specialist involvement were associated with significant increases in testing uptake (p=0.007), diagnostic yield (p<0.001), and patient education (p<0.001). Second trimester stillbirths and those with fewer ultrasound (US) abnormalities were less likely to receive genetic testing (both p values <0.001) and consults (p<0.001, p=0.020). Conclusion Though it was not possible to avoid ascertainment bias, this data demonstrates that geneticist involvement correlates with a higher rate of testing, greater diagnostic yield, and more thorough counseling. These findings underscore the importance of integrating genetics providers into perinatal postmortem healthcare teams.

This study examined awareness, attitudes, and perceived barriers regarding genetic counseling among individuals in Derna District, focusing on its role in preventing genetic disorders. A descriptive cross-sectional design was employed, involving 278 participants aged 17 to 45 years, selected through stratified random sampling. Data were collected using structured questionnaires and analyzed with descriptive statistics via SPSS version 26.0. The findings revealed that while 65.5% of participants reported a high level of knowledge about genetic counseling, significant gaps remain, with 34.5% indicating low knowledge. Most participants demonstrated positive attitudes: 90.6% believed genetic counseling is important for preventing genetic disorders, and 90.3% expressed willingness to undergo counseling if recommended by a physician. However, perceived barriers such as fear of results (39.9%) and lack of awareness (30.9%) were reported. The study highlights the need for targeted educational initiatives and policy measures to promote genetic counseling services and address identified barriers. The findings provide valuable guidance for public health programs aiming to enhance the utilization of genetic counseling in the region.

Abstract Background Spontaneous coronary artery dissection (SCAD) is a well-recognised cause of acute coronary syndrome particularly among women without conventional cardiovascular risk factors. Increasing evidence indicates a genetic contribution; however, the underlying genetic architecture of SCAD remains insufficiently understood. Objective The aim of this study was to assess the prevalence of rare variants in previously reported SCAD associated genes and to explore the potential presence of novel genetic alterations in well-characterised Swedish patients with SCAD. Methods The study comprised 201 patients enrolled in SweSCAD, a national project examining the clinical characteristics, aetiology, and outcomes of SCAD. All individuals had a confirmed diagnosis based on invasive coronary angiography. Comprehensive exome sequencing was performed to identify rare variants contributing to disease susceptibility. Results Genetic variants that have been associated with SCAD according to current clinical genetics practice for variant reporting were identified in approximately 4 % of patients. In addition, rare potentially relevant variants were detected in almost 60 % of patients in genes associated with vascular integrity and vascular remodelling. Conclusion This study supports SCAD as a genetically complex arteriopathy, driven by rare high?impact variants together with broader polygenic susceptibility. Variants in collagen, vascular extracellular matrix, and oestrogen?responsive pathways provide biologically plausible links to female?predominant disease. Although the diagnostic yield of clearly actionable variants is modest, these findings support broader genomic evaluation beyond overt syndromic presentations and highlight the need for larger integrative genomic and functional studies to refine risk stratification and management.

Infertility generates profound psychological and social distress for both women and men, yet mens communicative experiences remain comparatively underexamined. Male infertility (MI) is often shaped by stigma, norms of masculinity, and limited opportunities for emotional disclosure, constraining help-seeking in offline settings. This study investigates how men use anonymous online peer-support spaces to discuss MI by analyzing discussions from the r/maleinfertility subreddit on Reddit. Using natural language processing techniques, we examined 10,769 posts and 80,381 comments published between 2013 and 2025. Analyses assessed sentiment and emotional expression, topic structure, hyperlink networks, and discussions related to diagnostic testing, treatment decision-making, and donor sperm use. Topic modeling revealed a functional differentiation between posts and comments. Original posts primarily focused on clinical sense-making, including interpretation of semen analyses, hormonal testing, and assisted reproduction options. In contrast, comments emphasized emotional validation, experiential knowledge-sharing, and normalization of alternative family-building pathways. Emotional expression varied by discussion topic, with heightened fear and sadness in conversations involving genetic testing, surgical sperm retrieval, and donor sperm. Hyperlink analysis indicated frequent engagement with peer-reviewed medical information, reflecting active evidence-seeking alongside peer exchange. Taken together, findings suggest that anonymous online communities function as critical infrastructures of support for men experiencing infertility, enabling forms of disclosure and vulnerability often constrained in offline contexts. These spaces facilitate interpretation of medical information, collective coping, and decision-making regarding treatment and donor options. The study highlights the role of digital anonymity in mitigating stigma and expanding communicative possibilities for men navigating infertility alongside clinical care.

Introduction Lung cancer is rare before age 45, and its inherited genetic basis remains poorly defined. Methods We performed whole-genome sequencing in 171 predominantly young-onset lung cancer patients and integrated these data with whole-exome sequencing from six major lung cancer consortia, yielding 9,065 patients. After quality control, analyses focused on 6,545 individuals of European ancestry, the largest ancestral group. We compared the prevalence of rare pathogenic and likely pathogenic (P/LP) germline variants between 186 young-onset (age <45 years) and 6,359 older patients at gene and gene-set levels using Fisher's exact test, stratified by histology, sex, and smoking status. Polygenic risk scores (PRS) derived from common variants were also evaluated. Results Young-onset patients carried a higher burden of rare germline P/LP variants in DNA damage response (DDR) genes (including BRIP1, ERCC6, MSH5), and in cilia-related genes, notably GPR161. At the pathway level, DDR genes were significantly enriched (OR=1.66, p=0.007), with the strongest signal in the Fanconi Anemia pathway and among females (OR=1.96, p=0.01). Enrichment was also observed in inborn errors of immunity pathways, with strongest signals in antibody deficiency and the complement system genes. Young-onset patients additionally exhibited higher lung cancer PRS. Conclusion Young-onset lung cancer exhibits a distinct germline genetic architecture, characterized by enrichment of rare P/LP variants in DDR, cilia-related, and immune pathways, and an elevated lung cancer PRS. These findings support a greater role for inherited susceptibility in early-onset disease and have implications for risk stratification, earlier screening, and precision prevention.

BackgroundExome sequencing (ES) has become a key diagnostic tool for rare diseases (RDs). However, most evidence on ES performance comes from high-income countries and patients from European ancestry. In countries such as Chile, limited access to next generation sequencing amplifies health disparities and highlights the need to identify which patients are most likely to benefit from ES. MethodsThis study presents the second phase of the Chilean DECIPHERD project, in which we performed ES in a new group of patients with RDs presenting with multiple congenital anomalies (MCA), neurodevelopmental disorders (NDD), and/or suspected inborn errors of immunity. To identify clinical and demographic factors associated with an increased probability of obtaining an informative ES result, we conducted a logistic regression analysis, combining the results of the first and second phases of the project. We also objectively evaluated global ancestry measured using ADMIXTURE, as a potential factor. ResultsSixty-seven patients participated in this second phase of DECIPHERD with a median age of 6 years (range: 0-27); 55.2% were female, with an average ({+/-} s.d.) proportion of Native American ancestry of 0.615 {+/-} 0.18. Clinically, 52.2% presented with both MCA and NDD, and the rest had other phenotype combinations. An informative result, including pathogenic or likely pathogenic variants in genes consistent with the patients phenotype, was identified in 34.3% of the cohort; 61% of these variants had not been previously reported in databases such as ClinVar. By combining the two phases of the study, we reached a total of 167 patients, in whom the presence of NDD and/or MCA significantly increased the probability of achieving an informative ES outcome. In contrast, previous use of gene panel testing was associated with a decreased likelihood of receiving an informative result. Ancestry was not associated with diagnostic yield. ConclusionsThis study demonstrates the utility of ES in achieving a diagnosis in a clinically diverse cohort of Chilean patients with RDs, and characterized features associated with a higher diagnostic yield. These findings may contribute to evidence-based patient prioritization strategies in settings with limited access to NGS resources.

Lipoedema is a chronic adipose tissue disorder mainly affecting women with excess subcutaneous fat deposition on the lower limbs, associated with pain and tenderness. There is often a family history of lipoedema, suggesting a genetic origin, but the contribution of genetics is not well studied. We conducted a genome-wide association study (GWAS) for this disorder in a clinically ascertained cohort from Spain and performed a meta-analysis with the UK lipoedema cohort GWAS. We then used the results of this study as a replication of the inferred UK Biobank "lipoedema phenotype" study. Whilst our meta-analysis alone did not identify any genome-wide significant associations, our clinical cohorts provide support for three loci identified through the UKBB study: the chr2q24.3 GRB14-COBLL1 locus (rs6753142, PMETA=1.64x10-6), chr6p21.1 VEGFA locus (rs4711750, PMETA=8.99x10-7) and the chr5q11.2 ANKRD55-MAP3K1 locus (rs3936510, PMETA=1.67x10-5). We identify numerous rare SNPs with strong association signals in our meta-analysis (P<1x10-6) with support in both UK and Spanish datasets, three of which also show nominal support in the UKBB (P<0.05). These findings provide a starting point towards understanding the genetic basis of clinical lipoedema and demonstrate the utility of the interplay of large-scale biobanks genetic data and clinically ascertained cohorts to elucidate the genetic architecture of lipoedema.

Predicting the effects of genetic variants and assessing prediction performance are key computational tasks in genomic medicine. It has been shown that well-calibrated variant effect predictors can be reliably used as evidence towards establishing pathogenicity (or benignity) of missense variants, thereby rendering these variants suitable for use in (or exclusion from) the genetic diagnosis of rare Mendelian conditions. However, most predictors have been trained or calibrated on data that may not be sufficiently representative to lead to similar performance across all genetic ancestries. This raises questions about the responsible deployment of these tools to improve human health. To better understand the utility of computational predictors, we set out to assess their ancestry-specific performance in terms of accuracy and evidence strength according to the ACMG/AMP guidelines. First, we determined that the expected count of rare variants in an individuals genome and the allele frequency distribution of these variants are the key confounders when evaluating a predictors performance across different genetic ancestries. Second, we found that a predictors accuracy itself inversely correlates with the allele frequency of the rare variant. After stratifying according to allele frequency, we show that established methods for predicting the pathogenicity of missense variants have comparable performance levels across major ancestry groups. Our results therefore support the wide deployment of such models in the context of genetic diagnosis and related applications.