npj Genomic Medicine

Several medical societies including the American College of Medical Genetics and Genomics, the American Academy of Neurology, and the Association of Molecular Pathology recommend chromosomal microarray (CMA) as the first-tier test in the genetic work-up for individuals with neurodevelopmental disorders such as developmental delay and intellectual disability, autism spectrum disorder, as well as other disorders suspected to be of genetic etiology. Although CMA has significantly increased the diag...

A recently described, rare genetic condition known as Neurodevelopmental Disorder with Microcephaly, Arthrogryposis, and Structural Brain Anomalies (NEDMABA) has been identified in children with bi-allelic loss-of-function variants in SMPD4. The progression of this condition is not well understood with the limited case reports described so far exhibiting a severe and clinically diverse phenotype. A gap exists in the understanding of associations present in the heterogenous features of the clinic...

22q11.2 deletion syndrome (22q11DS) has an incidence of 1 in 4,000. Most cases occur de novo, but about 10-15% of cases are inherited. Features include congenital heart disease, cleft palate, developmental delay, and other characteristics that can vary even among family members. The presence of nuclear mitochondrial genes in the deleted region, and the requirement of mitochondrial function for proper embryonic development, suggests that intrafamilial variability in maternally transmitted 22q11DS...

BackgroundHeterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder; childhood apraxia of speech (CAS), yet few cases have been reported, limiting knowledge of the condition. MethodsHere we phenotyped 29 individuals from 18 families with pathogenic FOXP2-only variants (13 loss-of-function, 5 missense variants; 14 males; aged 2 years to 62 years). Health and development (cognitive, motor, social domains) was examined, including speech and language out...

Colour agnosia is a disorder that impairs colour knowledge (naming, recognition) despite intact colour perception. Previously, we have identified the first and only-known family with hereditary developmental colour agnosia. The aim of the current study was to explore genomic regions and candidate genes that potentially cause this trait in this family. For three family members with developmental colour agnosia and three unaffected family members CGH-array analysis and exome sequencing was perform...

This study investigates the genetic underpinnings of congenital tooth agenesis (CTA) using a multi-omics approach, integrating whole exome sequencing (WES)and RNA expression analysis. WES was used to analyze the genetic basis of CTA in six affected individuals one with syndromic and five with non-syndromic CTA alongside three healthy and two internal controls. We identified both known and novel variants in candidate genes (EDA, WNT10A, PAX9, TSPEAR) and assessed the functional impacts of novel v...

Rare diseases (RDs) are an extremely heterogeneous and underserved category of medical conditions. While the majority of RDs are strongly genetic, it remains largely unknown via which physiological mechanisms genetics cause RD. Therefore, we sought to systematically characterise the cell type-specific mechanisms underlying all RD phenotypes with a known genetic cause by leveraging the Human Phenotype Ontology and transcriptomic single-cell atlases of the entire human body from embryonic, foetal,...

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...

Germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders. Heterozygous missense variants at a hotspot encoding a canonical degron lead to SETBP1 accumulation and Schinzel-Giedion syndrome (SGS), a rare severe developmental disorder involving multisystem malformations. Heterozygous loss-of-function variants result in SETBP1 haploinsufficiency disorder which is phenotypically much milder than SGS. Following an initial description of four individuals...

Solve-RD is a pan-European rare disease (RD) research program that aims to identify disease-causing genetic variants in previously undiagnosed RD families. We utilised 10-fold coverage HiFi long-read sequencing (LRS) for detecting causative structural variants (SVs), single nucleotide variants (SNVs), insertion-deletions (InDels), and short tandem repeat (STR) expansions in extensively studied RD families without clear molecular diagnoses. Our cohort includes 293 individuals from 114 genetically...

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...

Cleavage and polyadenylation of pre-mRNAs are essential for transcription termination and the normal expression of eukaryotic genes. However, the extent to which mutations in cleavage and polyadenylation signals act as causal variants in rare Mendelian disorders remains unknown. Using deep learning models, we identified enrichment of alleles predicted to disrupt polyadenylation in a large cohort of undiagnosed probands with rare disease disorders from the Genomics England 100kGP dataset. These a...

BackgroundTerminal 6q deletions are rare, and the number of well-defined published cases is limited. Since parents of children with these aberrations often search the internet and unite via international social media platforms, these dedicated platforms may hold valuable knowledge about additional cases. The Chromosome 6 Project is a collaboration between researchers and clinicians at the University Medical Center Groningen and members of a Chromosome 6 support group on Facebook. The aim of the ...

While many Rare Inborn Errors of Metabolism are treatable conditions their optimal diagnosis and treatment is a challenge for nations with low resources. Moreover, the population prevalence of these conditions is largely unknown. The availability of large genomic datasets brings the opportunity to estimate population carrier frequency of autosomal recessive IEMs. This would help to generate diseases burden statistics for better allocation of resources. In the current work we estimated the gene s...

Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment and legal blindness that has significant genetic risk factors, including genetic variation within a locus on chromosome 10 encompassing several extensively studied protein-coding genes (ARMS2, HTRA1 and PLEKHA1). Here, through transcriptome-wide association and fine-mapping approaches that integrate newly available high coverage transcriptome datasets for the human eye, we provide robust statistical assoc...

BackgroundIncontinentia pigmenti (IP) is a rare, hereditary multisystemic disorder affecting 1.2 in 100,000 live births, predominantly females. Conventional genetic analyses through short-read sequencing are complicated in case of IP due to the presence of a highly homologous pseudogene. Traditionally, long-range PCR is employed in order to overcome this challenge, however, detection of skewed X-Inactivation can also aid in correctly assign a variant to IKBKG. MethodsWe employed a comprehensive...

Intellectual disability (ID) is a neurodevelopmental disorder affecting up to 1-3% of people worldwide. Genetic factors, including rare de novo or rare homozygous mutations, explain many cases of autosomal dominant or recessive forms of ID. ID is clinically and genetically heterogeneous, with hundreds of genes associated with it. In this study, we performed high-depth whole-genome sequencing of twenty individuals from five consanguineous families from Pakistan, with nine individuals affected by ...

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...

PurposeIn genome-wide association studies (GWAS), X chromosome (ChrX) variants are often not investigated. Sex-specific effects and ChrX-specific quality control (QC) are needed to examine these effects. Previous analyses identified 52 autosomal variants associated with age-related macular degeneration (AMD) via the International AMD Genomics Consortium (IAMDGC), but did not analyze ChrX. Therefore, our goal was to investigate ChrX variants for association with AMD. MethodsWe genotyped 29,629 n...

Age-related macular degeneration (AMD) is a multifactorial retinal disease with a large genetic risk contribution. Reticular pseudodrusen (RPD) is a sub-phenotype of AMD with a high risk of progression to late vision threatening AMD. In a genome-wide association study of 2,165 AMD+/RPD+ and 4,181 AMD+/RPD-compared to 7,660 control participants, both chromosomes 1 (CFH) and 10 (ARMS2/HTRA1) major AMD risk loci were reidentified. However association was only detected for the chromosome 10 locus wh...