American Journal of Medical Genetics Part A

ObjectiveOrofacial clefts may involve the complete vertical thickness of the lip (complete) or partial thickness (incomplete). This study evaluates side preference for completeness in nonsyndromic asymmetric bilateral and unilateral cleft lip with or without cleft palate (NSCL/P). DesignWe studied 4 multiethnic cohorts from North and South America, Asia, and Africa, including 3,561 individuals with NSCL/P. Associations between cleft completeness, sex, ethnicity, and race were assessed using Chi-square or Fishers exact test (=0.05). ParticipantsPatients with NSCL/P with complete information on cleft type and completeness were included. Our main goal was to analyze side preference of complete clefting in different demographic groups, sex and race. ResultsAmongst asymmetric bilateral cases, left side completeness was significantly more frequent than the right side (73.7% vs. 26.3%; p<0.001). No associations observed for sex or race with ethnicity showing a trend toward significance (50.0% vs. 25.5%; p=0.088). Amongst symmetric bilateral and unilateral cases, Hispanics exhibited completeness more frequently than non-Hispanics (96.4% vs 89.5%; p<0.001; 84.1% vs. 79.7%; p<0.001). For unilateral cases, completeness showed no side preference. Caucasians were less likely to exhibit complete clefts compared to Asians, Blacks, or other racial groups (68.7% vs 84.9% or 81.2% or 81.7%; p<0.001). Females more frequently presented with completeness than males (81.2% vs 76.6%; p=0.003). ConclusionsIn NSCL/P with bilateral asymmetry, the left side is more often complete than the right side. Although unilateral left-sided clefts are more common overall, completeness shows no side preference. Race and ethnicity demonstrate significant associations with cleft severity patterns.

ObjectivesTo screen the entire genome for genes associated with risk for lateral epicondylopathy and improve understanding of underlying biological mechanisms and inform future research aimed at risk stratification and personalized prevention and treatment strategies. MethodsA genome-wide association study was conducted using UK Biobank data. Lateral epicondylopathy cases were identified based on electronic health records from individuals of European ancestry. Logistic regression tested associations between single-nucleotide polymorphisms and disease status, adjusting for sex, age, height, weight and ancestry principal components. Previously-identified candidate genes from the literature were also tested for association with lateral epicondylopathy. ResultsAmong 20,390 cases of lateral epicondylopathy, two loci reached genome-wide significance: one comprising 144 linked SNPs and one single SNP. The first locus, led by rs13127477 (p=7.7x10-12; OR 0.93, 95% CI 0.91 to 0.95), is located near three SIBLING genes (IBSP, MEPE and SPP1) involved in extracellular matrix remodelling at fibrocartilaginous entheses. The risk allele was associated with increased SIBLING gene expression, suggesting that excessive entheseal matrix remodelling contributes to disease susceptibility. The second locus was defined by rs138254824 (p=3.69x10-8; OR 3.42, 95% CI 2.23 to 5.25) near NEDD9 and TMEM170B. Previously reported collagen gene associations were not replicated. ConclusionIn the first genome-wide screen for lateral epicondylopathy, two loci were identified. These loci provide insight regarding the pathophysiology of lateral epicondylopathy and a roadmap for preventing and treating this injury with personalized medicine. Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSLateral epicondylopathy is a common and disabling overuse tendon condition, yet its genetic basis has remained poorly characterised, with prior studies limited to small candidate gene analyses. What this study addsThis study provides the first genome-wide association analysis of lateral epicondylopathy, identifying two risk loci on chromosomes 4 and 6 and implicating SIBLING genes (IBSP, MEPE, and SPP1) involved in entheseal extracellular matrix remodelling. How this study might affect research, practice or policyThese findings offer new biological insight into disease susceptibility and challenge previously reported collagen gene associations.

Microtia is a common congenital craniofacial malformation characterized by the partial or complete absence of the external ear structure. Despite its relatively high incidence, the pathogenesis of microtia remain poorly understood. In this study, we analyzed both single-cell and bulk RNA sequencing data from microtia cases and identified a population of COL1+HES1+ mesenchymal stem cell in perichondrium with significantly higher expression of the CRABP2 gene, a gene that encodes a nuclear transporter of retinoic acid. Gene expression analysis further confirmed that the RA signaling intensity and stemness are both higher in COL1+HES1+ perichondral stem cells from microtia patients, possibly due to elevated CRABP2 levels. Through histological verification we further confirmed the presence of this cell population with high CRABP2 expression in the perichondrium. Mechanistically, the elevated CRABP2 expression in perichondral stem cells seen in microtia patients may cause dysregulated RA signaling and disrupt the regulation of stem cell differentiation during auricular development. Histological analysis further revealed higher KLF2 expression as well as cartilage hypoplasia in microtia samples. Our study identified that the CRABP2-induced RA dysregulation in COL1+HES1+ perichondral stem cells may contribute to microtia. These findings offer new insights into the etiology of microtia and provide potential directions for prenatal prevention and tissue engineering treatments.

CTNNB1 syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in the CTNNB1 gene. Although its core clinical manifestations have been increasingly recognised, longitudinal data on cognitive, behavioural and motor trajectories remain limited, and the craniofacial phenotype has not previously been quantitatively characterised. This study provides longitudinal evidence on the cognitive, clinical and psychological profile of individuals with CTNNB1 syndrome, together with a detailed three-dimensional morphometric analysis of facial morphology. Cognitive, clinical, psychological and neuropsychological data were collected at two time points (T0 and T1), separated by a one-year interval, using a comprehensive and standardised assessment protocol. Longitudinal analyses indicated stability across most domains, with no evidence of systematic regression. A significant improvement in gross motor functioning was observed, particularly among younger participants. Linear mixed-effects models showed that age moderated developmental change, with younger individuals exhibiting greater gains over time in gross motor skills and adaptive behaviour compared to older participants. Three-dimensional facial morphometric analyses revealed a distinctive and statistically significant craniofacial pattern associated with CTNNB1 syndrome, independent of age and facial size. This phenotype was characterised by midfacial narrowing, reduced midface projection and mandibular retrusion. Importantly, facial shape variation was significantly associated with externalising behavioural problems and clinically relevant behavioural difficulties, suggesting a link between craniofacial morphology and behavioural severity. This study represents the first integrated longitudinal characterisation of CTNNB1 syndrome combining neurodevelopmental follow-up with quantitative craniofacial phenotyping. The findings indicate slow but progressive improvement in specific clinical domains during childhood and adolescence, alongside relative stability in global adaptive functioning, and highlight three-dimensional facial morphology as a sensitive structural biomarker for phenotypic stratification and clinical monitoring in CTNNB1 syndrome. Lay summaryThis study is the first to describe how children with CTNNB1 syndrome, a rare genetic condition that leads to global developmental delays, develop over time. We also performed advanced facial analysis to look for common facial features among patients.

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.

Burnout is common among genetic counselors (GCs). Clinician burnout has been found to adversely affect individual well-being, patient care, and likelihood of staying in a role. Both individual and systems solutions are needed to address clinician burnout. Mindfulness meditation (MM) is one individual-level solution that has shown promise for reducing burnout in other clinicians but has not been studied in GCs. We conducted a decentralized, parallel, three-arm randomized controlled trial comparing MM to a novel active control meditation (ACM) and a no-meditation control (NMC), with 1:1:1 randomization. Participants were clinical GCs in the US. MM and ACM participants were asked to do 10 minutes of daily app-based meditation for 8 weeks. ACM was designed to control for non-specific aspects of MM by mimicking MM length and structure without including mindfulness techniques. The primary outcome, burnout, was assessed using the Professional Fulfillment Index. Secondary outcomes included other indicators of professional well-being, such as stress and professional fulfillment. Outcomes were assessed via an intention-to-treat approach, with multiple imputation for missing outcome data. Outcome analyses controlled for baseline trait mindfulness. 397 participants (mean age 33 years; 97.7% female, 94.2% White) were randomized, and 76% completed post-intervention outcome measures. There was no difference in burnout reduction between MM and ACM groups (p = 0.44). However, multiple measures suggest that ACM did not perform well as an inert active meditation control, thus the primary hypothesis could not be effectively tested. In pre-planned secondary analyses, MM reduced burnout (Cohens d = -0.84, p < 0.001) compared to NMC, a passive control. Similar results were seen for stress. These findings suggest MM may be beneficial for GC professional well-being; however, further research on MM for GCs is needed with more diverse study samples and better active controls.

ObjectiveAutism shows a male-biased diagnostic sex ratio. Given the heritability of autism, genetic factors likely contribute to this ratio. This study systematically reviews sex differences in additive common genetic effects related to autism and autistic traits. MethodsOriginal research was collected from PubMed, Web of Science, APA PsycInfo and Scopus (2008 - July 2025) following PRISMA guidelines. Genome wide association studies (GWASs) on autism, and related downstream analyses, including polygenic scores (PGS), Single-Nucleotide Polymorphism (SNP) heritability, and genetic correlations were included when sex-stratified results were reported. Risk of bias was assessed, followed by a best-evidence synthesis. ResultsOf 6,053 records screened, 21 studies were eligible. In clinical populations, results on mean PGS differences were inconclusive. In subgroups without intellectual disability, strong evidence indicated higher mean PGS in females. In general population samples, weak evidence supported this pattern. PGS associations with autistic traits showed inconsistent results, although stronger associations were reported for sensory sensitivity in males with weak evidence. SNP heritability findings were inconclusive. Genetic correlations between the sexes were significantly different from 1 (rg = 0.80 (SE = 0.09), but evidence was considered weak. DiscussionFindings suggest an axis of heterogeneity around intellectual disability. Inconsistent findings largely resulted in inconclusive evidence. Results highlight a lack of sex-stratified reporting and were limited by sample makeup such as male- and European ancestry dominated cohorts. Future sex-balanced and stratified GWAS and downstream analyses with complete reporting of female and male data are needed to clarify potential genetic sex differences in autism.

Adenylosuccinate synthetase 1 (ADSS1) myopathy is an ultra-rare disease characterized by progressive muscle dysfunction. The objective of this investigation was to employ a non-invasive biomarker approach to phenotype (fine-)motor skills, speech production and cognition in adults with ADSS1 myopathy. Five individuals with ADSS1 myopathy and five age-sex-matched healthy controls (HCs) underwent a comprehensive multimodal evaluation. Assessments included, (i) evaluation of motor performance, (ii) speech production and cognitive test batteries, (iii) patient-reported outcomes, (iv) electrical impedance myography (EIM), (v) musculoskeletal magnetic resonance imaging (MRI) and (vi) plasma proteomics. ADSS1 participants vs. HCs demonstrated reduced performance on the 9-Hole Peg and grip strength tests as well as lower self-reported mobility. Speech production analysis revealed asthenia (p=0.02), lower intelligibility (p=0.008), and worse voice quality during the sustained vowel task (p=0.03) in the ADSS1 cohort. Cognitive functioning remained unaffected in patients with ADSS1. On EIM, ADSS1 participants vs. HCs, demonstrated a pattern of higher resistance and lower reactance and phase across upper- and lower-extremity measurements, indicative of poorer muscle health, with large effect sizes (Cliffs 8=0.5-0.9). MRI revealed intramuscular fat infiltration, particularly in posterior compartments of the upper leg (e.g., biceps femoris). Proteomics indicated reduced (p=0.04) Neurotrophin-3 (NTF3; implicated in neuronal development, survival and differentiation) levels in the ADSS1 cohort relative to HCs. Lower NTF3 levels associated with poorer performance on hand-motor tasks as well as higher resistance and lower reactance and phase on EIM. This study highlighted the value of multimodal phenotyping for quantifying disease expression and advancing monitoring strategies in ADSS1 myopathy. Take-home messageThis multimodal investigation demonstrates that integrating electrical impedance myography with quantitative motor, speech, musculoskeletal imaging, and proteomic assessments provides a sensitive and non-invasive research framework for capturing neuromuscular dysfunction and functional disease burden in patients with ADSS1 myopathy, thereby supporting the current biomarker strategy for refined phenotyping and longitudinal disease monitoring in this ultra-rare condition.

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.

The prevalence of the two types of horizontal strabismus, esotropia and exotropia, varies considerably between studies. This variability has been attributed to factors such as geography/environment, research methodology, age of study subjects, and/or ethnicity. Comprehensive estimates of regional and global prevalences of esotropia and exotropia are lacking, making it difficult to recognize true patterns, trends, and etiologies. Our systematic review compiles prevalences and ratios of esotropia to exotropia from 315 population-based studies and 374 clinic-based studies. We analyze data to assess effects of ethnicity, geography, age, and identify generational changes of horizontal strabismus. Major ethnicities differ in patterns and ratios of esotropia and exotropia prevalence, not only Caucasians and East Asians, but also Latinos/Hispanics, South Asians, Africans, and Native Americans. Compared to population-based studies, clinic-based studies underestimate exotropia frequency. By weighing prevalences according to the population size of ethnicities, we estimate the worldwide prevalence of horizontal strabismus in the current generation at 1.81% (138.5 million), comprising 60.0 million people with esotropia (0.67%) and 87.5 million with exotropia (1.14%). In the previous generation, the worldwide prevalence of horizontal strabismus was 1.64% (86.5 million people), comprising 50.5 million with esotropia (0.96%) and 36.0 million with exotropia (0.68%). Generational trends in esotropia and exotropia prevalences differ between ethnicities, indicating that extrinsic factors can modify the underlying intrinsic (genetic) disposition.

Irreversible profound hearing loss in early childhood impairs severely the development of spoken language, behavior and cognition. Hearing loss caused by aminoglycoside antibiotics in neonates treated for sepsis in intensive care units is linked to variants in the MT-RNR1 gene. Identifying the population at risk in acute medical settings is substantially limited by genotyping restricted to m.1555A>G only with 20% failure rate of the currently approved point-of-care test. We report an innovative prenatal pharmacogenetic approach based on the parallel genome-wide analysis of mitochondrial and nuclear cell-free DNA which co-exist in routine non-invasive prenatal testing (NIPT) sequencing data. Following analysis of 5,529 NIPT cases, we reached to 99.3% cumulative call rate with100% sensitivity and specificity for the clinically actionable variants m.1095T>C, m.1494C>T and m.1555A>G. Since NIPT is a globally adopted first and second-tier prenatal test, our approach could revolutionize early intervention strategies for aminoglycoside-induced hearing loss and improve clinical decision-making.

PurposeGenetic diseases often present and are first diagnosed in the neonatal intensive care unit (NICU). Accurate identification of neonates with genetic diagnoses (GDs) in electronic health records (EHR) would enable a more complete understanding of their phenotypic spectrum, advancing care and personalized medicine. Prior research has used International Classification of Diseases (ICD) billing codes as proxies for GDs, though their accuracy for detecting confirmed GDs is uncertain. We evaluate the ICD codes for neonates with confirmed GDs and compare ICD billing code patterns between neonates with and without GD in two independent NICU cohorts. MethodsRetrospective analysis of patients admitted to the Boston Childrens Hospital (BCH) level IV NICU (1,344 neonates) and Nationwide Childrens Hospital (NCH)s neonatal network (33,315 neonates, mixed Level III/IV). For both cohorts, GDs captured by phecodes, aggregates of ICD codes, were compared with confirmed GDs. Two separate phenome-wide association studies (PheWAS) compared phecode patterns between neonates with GDs and those without, adjusting for sex, age at admission, gestational age, and NICU length of stay. ResultsGenetic phecodes were able to correctly identify 43.5% of neonates that received a GD in the BCH or NCH NICUs. Among 719 individuals with two or more genetic phecodes at BCH or NCH, 566 (78.72%) had a true GD. The BCH PheWAS analysis revealed a statistically significant positive association with atrioventricular septal defects and a negative association with bronchopulmonary dysplasia. The NCH pheWAS revealed 179 significantly associated phecodes, including many congenital anomalies. ConclusionThe use of ICD codes to identify NICU infants with GDs is neither sensitive nor accurate, though phecode analysis demonstrated stronger accuracy than sensitivity. Our data highlight clinical features of NICU infants more commonly seen in those that receive a GD (congenital heart defects) and those that are not (BPD). Our results can help to better predict and identify NICU neonates that receive a GD.

Disease-causing genetic variants can be found in a subset of individuals with cerebral palsy (CP), with variants deemed causal of CP having been published for at least 515 genes. We develop a statistical approach that treats CP as a phenotypic feature for which some genetic disorders confer an increased risk. Based on comprehensive literature curation we show that the null hypothesis of no CP association can be rejected for only 89 of the 515 genes. We applied these findings to the analysis of a cohort of 460 children diagnosed with CP in the Shriner Childrens network. We identified pathogenic or likely pathogenic (P/LP) variants in 60 genes in 15.8% of the children. Only 16 of the 60 genes had significant evidence for CP association in our literature analysis. Our results suggest that a stratified approach to attributing causality to genetic variants in CP could support precision genomic medicine for affected individuals.

PurposeWhile genomic testing is integral to pediatric inborn errors of immunity (IEI) care, few studies have examined strategies to support its optimal delivery. This study aimed to characterize a pediatric IEI cohort and assess the impact of implementing a mainstream model-of-care (MoC). Materials/MethodsComprehensive chart audit was conducted for patients ([&le;]18y) who received IEI genomic testing in Queensland, Australia, from 2017-2025. Descriptive analyses captured demographic and clinical characteristics, genomic testing and results, and management outcomes. Inferential analyses assessed changes in genomic practices pre-MoC (<2021) and post-MoC ([&ge;]2021). Results322 patients met eligibility criteria (n=481 genomic test). Diagnostic yield (27.6%) varied by testing indication, with the highest rate among phagocytic defects (n=4/4;100%) and severe combined immunodeficiency (n=8/10;80%). Very-early-onset inflammatory bowel disease had the lowest diagnostic yield (n=3/68;4.4%), prompting changes to testing criteria. Molecular diagnosis resulted in management changes for 90.5% patients. Genomic testing was widely used pre-MoC (n=251 genomic tests). All outcomes significantly improved pre-and post-MoC (p<0.05): duplicate testing decreased (13.9% to 0%); variants of uncertain significance reduced (37.7% to 7.1%); informed consent documentation increased (70.5% to 88.4%); and diagnostic yield increased (16.2% to 27.4%). ConclusionTargeted interventions are needed to support delivery of genomic testing and strengthen service effectiveness.

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.

IntroductionVestibular schwannoma (VS) is a benign tumor of the vestibulocochlear nerve, often causing hearing loss, balance disturbances, and psychosocial challenges. While surgical resection is standard, the long-term biopsychosocial impact of surgery is poorly understood. Research questionWhat are the physical, psychological, and social challenges experienced by patients up to five years after VS surgery? Material and MethodsA qualitative study was conducted using semi-structured video call interviews with 12 patients recruited via a patient advocacy group. Interviews explored postoperative experiences across physical, psychological, and social domains. Transcripts were analyzed using thematic content analysis with a coding system developed deductively and refined inductively. Data saturation was reached after 12 interviews. ResultsParticipants reported diverse physical symptoms, including hearing loss, tinnitus, dizziness, pain, fatigue, and facial nerve palsy. Psychological challenges included anxiety, depression, cognitive difficulties, and reduced stress tolerance. Social changes encompassed strained relationships, withdrawal from work and leisure activities, and limited social participation. Physical, psychological, and social challenges interacted dynamically, with emotional distress amplifying social isolation and healthcare provider support influencing coping and adaptation. Discussion and ConclusionVS surgery has a multifaceted, long-term impact on patients lives. The interplay of physical, psycho-logical, and social challenges underscores the need for holistic, multidisciplinary care, early patient education, and integration of supportive interventions. Engagement from healthcare providers plays a key role in mitigating distress and facilitating adaptation. These findings highlight the importance of addressing biopsychosocial aspects to improve long-term recovery and health-related quality of life in VS patients.

Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder caused by pathogenic variants in GBE1, resulting in deficient glycogen branching enzyme (GBE) activity and formation of abnormal glycogen ("polyglucosan"). GSD IV manifests across a spectrum of clinical dimensions - including hepatic, neurologic, muscular, and cardiac involvement - which vary in severity. The early-onset forms, historically referred to as Andersen disease, present at different stages ranging from in utero to adolescence. The adult-onset form, referred to as adult polyglucosan body disease (APBD), typically presents in middle to late adulthood. To date, no epidemiological study of GSD IV has been performed. Understanding the global prevalence of GSD IV is critical to increase disease awareness, improve diagnostic rates, inform therapeutic development, and engage pharmaceutical companies. In collaboration with the Rare Genomes Project at the Broad Institute of MIT and Harvard and the APBD Research Foundation, this study curated variants in GBE1 and calculated prevalence across nine genetic ancestry groups. The estimated global carrier frequency of GSD IV is 1 in 243 individuals, and the global genetic prevalence is 1 in 235,784 individuals. Based on the 2024 world population, the estimated number of affected individuals with GSD IV is approximately 34,800. These estimates highlight a significant underdiagnosis of GSD IV and underscore the urgent need for increased awareness of this metabolic disorder. This model of collaboration between researchers, patient advocacy organizations, and genetic data sharing programs provides a framework for estimating the prevalence of other rare diseases in the global population. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/25342386v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1a1ad7dorg.highwire.dtl.DTLVardef@1851576org.highwire.dtl.DTLVardef@442c19org.highwire.dtl.DTLVardef@1ab2ddb_HPS_FORMAT_FIGEXP M_FIG Created in BioRender. Koch, R. (2025) https://BioRender.com/j0sg30n. C_FIG

PurposeFuchs endothelial corneal dystrophy (FECD) is a common corneal disease and a leading indication for endothelial keratoplasty (EK). Although CTG18.1 repeat expansion is a major genetic risk factor, the contribution of polygenic background to disease progression remains unclear. We evaluated whether combining CTG18.1 expansion status with a FECD-specific polygenic risk score (PRS) enables genomic prediction of progression to EK. MethodsWe retrospectively analysed 589 individuals with FECD from two European centers, with replication in an independent cohort of 185 individuals. Association of CTG18.1 expansion ([&ge;]50 repeats) and PRS with time to EK were evaluated using Cox models adjusted for sex and ancestry. ResultsExpansion-positive status was associated with earlier EK (HR 2.30; 95% CI 1.62- 3.26; P<.001). Addition of PRS improved prediction (C-index 0.614 vs 0.602; P=.014). Each 1-SD increase in PRS was associated with earlier EK (HR 1.16; 95% CI 1.03-1.30; P=.015), with replication in the validation cohort (HR 1.42; 95% CI 1.15-1.75; P=.001). ConclusionIntegration of monogenic and polygenic risk enables genomic prediction of FECD progression, supporting clinical genomic risk stratification to inform individualized monitoring and timing of intervention.

Copy number variants (CNV) contribute significantly to the pathogenic variation associated with developmental disorders. CNV detection is often not included in standard exome sequencing (ES) analysis. Complementary methods such as chromosomal microarray are typically offered in diagnostic laboratories to diagnose pathogenic CNV. In this study, we aimed to develop an optimal approach for incorporating CNV detection within our ES analysis process for the Deciphering Developmental Disorders in Africa (DDD-Africa) cohort. We analyzed ES data from 505 probands with a developmental disorder, applying a CNV detection approach that assessed data generated using the tools CANOES and XHMM. When available, parental ES data was used to assess inheritance patterns. We confirmed a diagnosis in 42/505 (8,3%) patients with 44 pathogenic CNV identified in the probands. There were 31 deletions and 13 duplications. Among the 27 probands with parental data, all identified CNV were de novo. The addition of CNV analysis to our ES analysis pipeline resulted in an 8.3% increase in diagnostic yield in the DDD-Africa cohort without additional laboratory cost. This approach offers a feasible approach which is likely to reduce analytical cost and is suitable for low- and middle-income countries where funding and resources for genomic medicine initiatives are limited.

Obstructive sleep apnea (OSA) is a common, heritable disorder with diverse clinical presentations and etiologies. We conducted a genome-wide association meta-analysis of 492,107 individuals, including 46,028 OSA cases, identifying 14 genome-wide significant loci, eight of which are novel. Analyses adjusting for body mass index (BMI) revealed three loci independent of obesity, implicating alternative biological pathways contributing to disease. Integrative functional analyses, including chromatin interaction mapping, fine-mapping, and eQTL colocalization, prioritized candidate effector genes. Notably, implicated genes in chondrocytes were associated with craniofacial morphology in both mouse and human multivariate genotype-phenotype mapping, supporting a role for craniofacial structure in OSA risk. These findings highlight key genetic pathways (obesity-related, neurological, and craniofacial) underlying the development of OSA, offering new insights into its complex etiology.