Journal of Medical 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 (2001-202...

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...

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...

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...

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...

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...

Leber hereditary optic neuropathy (LHON) is primarily caused by pathogenic mitochondrial DNA (mtDNA) variants, most commonly the m.11778G>A variant in the MT-ND4 gene. The presence of this variant alone is insufficient to trigger disease symptoms, of which vision loss is the hallmark. Given the incomplete penetrance and inter-population variability in modifying factors, this study aimed to investigate two previously proposed genetic risk factors for LHON in the Polish population. Using quantitat...

Study questionDo variants in HSP90AA1 cause human male infertility? Summary answerVariants in HSP90AA1 appear as a possible autosomal dominant cause of human male infertility. What is known alreadyMale infertility is a highly heterogeneous condition, with so far over 300 genes described in this context. HSP90AA1 appears as a promising candidate gene for human male infertility, because the gene is highly conserved between species and knock-out of Hsp90aa1 in mice results in male-specific infert...

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...

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...

BackgroundThe genetic architecture of Breast Cancer (BC) in Arab populations remains largely understudied, limiting the precision of current prevention and screening programs. The Emirati Genome Program (EGP), one of the worlds first nation-wide sequencing initiatives, offers an unprecedented opportunity to delineate inherited BC risk across an entire population. MethodsWe analyzed 436,780 EGP individuals, including 229,309 women, integrating whole-genome sequencing (WGS) with electronic health...

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 ...

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...

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...

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 ...

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...

ObjectiveTo evaluate the analytical and clinical performance of fetal fraction (FF) enriched genome-wide noninvasive prenatal testing (GW-NIPT) for detection of clinically relevant copy number variants (CNVs) down to 1 Mb. MethodsWe retrospectively analyzed 10,501 singleton pregnancies tested with FF enrichment-based GW-NIPT between August 2023 and July 2025. CNV analysis was performed using BinDel and WisecondorX. ResultsFF enrichment increased median FF to 24% (2.4-fold increase). Clinically...