npj Genomic Medicine

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...

BackgroundMitochondrial diseases are the most common inherited metabolic disorders, characterized by pronounced clinical and genetic heterogeneity that complicates molecular diagnosis. Although DNA-based sequencing approaches have become standard in genetic testing, up to half of patients remain without a definitive diagnosis. RNA sequencing (RNA-seq) provides a complementary layer of evidence by revealing functional consequences of genetic variation, thereby improving diagnostic yield. Methods...

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental disorders (NDDs), a relationship likely driven by multiple interacting factors, including shared genetic influences, the underlying cardiac malformation, and risks associated with medical and surgical care. To investigate the genetic component of this association, we analyzed genome-wide association study (GWAS) summary statistics for CHD from the UK Biobank and FinnGen, focusing on two phenotypes presen...

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...

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...

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 ...

TUBB2B encodes a {beta}-tubulin isotype essential for neuronal proliferation, migration, and organization during brain development. Pathogenic heterozygous variants in TUBB2B have been associated with a range of neurodevelopmental disorders, with phenotypes including polymicrogyria and corpus callosum abnormalities. However, the phenotypic spectrum remains heterogeneous, likely influenced by variant-specific effects on microtubule formation and stability, an area that warrants further investigat...

Menieres disease (MD) is a chronic inner ear disorder characterized by recurrent vertigo, fluctuating sensorineural hearing loss, and tinnitus. Despite these distinctive symptoms, its etiology remains poorly understood. We performed a genome-wide meta-analysis of 8,969 cases and 1,962,542 controls across five large biobanks, identifying five independent genome-wide significant loci and estimating an observed-scale SNP heritability of 7% (SE 0.8%), consistent with a modest but significant genetic...

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...

Leber congenital amaurosis (LCA) and Early-onset severe retinal dystrophy (EOSRD) manifest within the first months and the first years of life, respectively. They are the leading cause of severe vision impairment in childhood. Using next generation sequencing, we identified eight families of patients with LCA/EOSRD carrying biallelic combination of six germline variants in DDX41, encoding a DEAD-box ATPase RNA helicase involved in RNA splicing, innate immunity and hematopoiesis. In fibroblasts f...

Functional brain networks are altered in Autism Spectrum Disorder (ASD), with differences in thalamocortical connectivity detectable as early as infancy. ASD shows distinct sex differences, not only in diagnostic rates, but also in brain and behavioral manifestations of the condition. Although common variants account for much of the genetic liability for ASD, little is known about the impact of ASD-associated genetic variation on functional brain connectivity and behavioral outcomes in early lif...

Next-generation sequencing has unraveled the genetic cause for many individuals with a rare disease, but a significant number of individuals remain undiagnosed using standard of care tests. It is anticipated that structural variants (SVs) have not been fully assessed in this context. Here, we performed optical genome mapping (OGM) for 57 trios and prioritized SVs using a two-step approach. First, we systematically identified all de novo SVs, and subsequently we studied all rare inherited SVs. Po...

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...

BackgroundDespite their profound impact on patients lives, most rare and intractable diseases still lack established treatments. Genomic variants that disrupt normal splicing by creating novel splice sites (splice-site creating variants, SSCVs) substantially contribute to the pathogenesis of those conditions. Deep intronic SSCVs are particularly amenable to antisense oligonucleotide (ASO)-mediated splice modulation, yet many of them remain undetected by conventional genomic analyses. Existing ap...

Antisense oligonucleotides (ASO) are versatile disease modifying therapies for genetic diseases. An accelerated FD) pathway enables ASO treatment trial initiation in single patients within a year. However, this rapid N-of-1 pathway lacks extensibility to broad use necessary for sustainability. Individualized ASOs bind pre-mRNAs encompassing an entire locus. Thus, ASOs targeting common heterozygous polymorphisms (SNPs) are potentially haplospecific in many patients with dominant disorders. We dev...

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 ...

BackgroundMolecular diagnosis of rare disease plateaus at [~]50%, partly due to technical limitations of short-read sequencing and the persistent challenge of interpreting variants of uncertain significance (VUS). Splice-altering variation represents a major source of unresolved cases, yet functional assessment remains difficult in routine practice. MethodsWe developed a fully modular, sample-to-answer workflow for targeted long-read RNA sequencing (lrRNA-seq) using Oxford Nanopore Technologies...

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...

Poly(rC)-binding protein 1 (PCBP1), a splicing factor and key member of the hnRNP E family, was initially characterized for its tumor suppressive properties. More recently, its role in regulating gene expression in the brain and nervous system has attracted growing interest. Through an international multicenter collaboration, we identified 13 de novo pathogenic variants in PCBP1 across 13 unrelated families. All affected individuals exhibited intellectual disability (ID), with autism spectrum di...

Several lines of evidence suggest that normal-range facial features and nonsyndromic orofacial clefts (OFCs) exhibit a shared genetic basis. Approaches designed to leverage this relationship hold the possibility of revealing new OFC risk loci by boosting discovery power. To test this idea, we applied a pleiotropy-informed GWAS method (cFDR-GWAS) with summary statistics from large, independent European GWASs of normal facial shape (n=4,680; n=3,566) and nonsyndromic cleft lip with or without clef...