European Journal of Human Genetics

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....

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 comparin...

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 ...

Congenital anomalies of the kidney and urinary tract (CAKUT) are the primary cause of pediatric kidney failure, yet the genetic etiologies remain elusive for most affected individuals. Reanalysis of trio exome sequencing data from 80 Chinese CAKUT patients identified 32 rare, predicted deleterious variants. Replication in unrelated families from a national multicenter database prioritized four novel candidate genes--DOCK11, MIB1, TENM2, and TNS1. These candidates are involved in both well-charac...

BackgroundBreast cancer susceptibility gene testing (BCSG-testing) is expanding in relation to both eligibility for testing and number of genes included on testing panels. However, uncertainty remains regarding the most effective testing strategies for identifying clinically actionable germline pathogenic variants (gPVs) while balancing increased burden on breast and genetics clinical services. Patients and MethodsThe North Thames Mainstreaming of Breast Cancer Genetic Testing (NT-MBGT) program...

STUDY QUESTION[Do structural genomic variants, that can be identified by using optical genome mapping, contribute to male infertility?] SUMMARY ANSWER[By using optical genome mapping we can identify several types of structural variants, both known and new, that may contribute to male infertility.] WHAT IS KNOWN ALREADY[Traditional approaches such as karyotyping, CFTR and chromosome Y microdeletion testing are successful in explaining clinical findings in [~]30% of MI patients, leaving the rest...

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 (2001-202...

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 Afri...

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 ute...

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 n...

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 ...

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...

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...

BACKGROUNDGenetic variant curation, an important step in the implementation of Genomic Medicine, requires literature-guided comparison of variant prevalence in affected individuals versus healthy controls. This evidence is categorized as the PS4 evidence code by the AMP/ACMG variant interpretation guidelines and its manual extraction is a major bottleneck in clinical variant curation. This study aimed to evaluate whether reasoning-capable large language models (LLMs) can support guideline-constr...

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 ([≤]18y) who received IEI genomic testing in Queensland, Australia, from 2017-2025. Descriptive analyses captured demographic and clinic...

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 det...

BackgroundHFE p.C282Y (c.845G>A; rs1800562) is a common missense mutation in persons of European ancestry, but we found no comprehensive tabulation of p.C282Y allele frequencies in Iberia. MethodsWe performed computerized and manual searches to identify evaluable reports of p.C282Y alleles in population/control cohorts [≥]50 subjects in Iberia. We tabulated numbers of subjects, nominal geographic sites of cohort recruitment, cohort characteristics, corresponding latitudes and longitudes, and...

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 evaluat...

Retinoblastoma (Rb) is a rare childhood eye cancer. Almost half of cases are heritable, associated with germline RB1 pathogenic variants that pre-dispose to Rb and extraocular cancers. This study aimed to investigate the prevalence and penetrance of RB1-heritable Rb in two adult population cohorts. We screened participants with whole genome sequencing in the UK Biobank (UKB) (n=490,413) and All of Us (AoU) (n=317,964) cohorts for predicted loss-of-function (pLoF) and/or ClinVar pathogenic/likely...

Systematic analysis of copy number variants (CNVs) in large datasets is challenging and there are limited studies of homozygous copy number losses in rare disease exome datasets. Here we leveraged the genomic uniqueness and relative under-representation of the Indian population in the current public genomic databases and identified 42,386 possible homozygous losses (median count 20 per individual, range 0 - 55; median size 2.95 kb, range 99 bp - 4.76 Mb) in a heterogeneous cohort of 2,021 indivi...