European Journal of Human Genetics最新文献

The broad genetic heterogeneity of neurodevelopmental disorders (NDDs) makes their molecular diagnosis particularly challenging. In this context, Whole-Exome Sequencing (WES), specifically in a trio-based design, is a powerful strategy due to its ability to detect de novo variants, which are a major contributor to NDDs. However, its clinical implementation is often limited by its associated cost. In this study, we applied a sequential diagnostic workflow to a cohort of 221 individuals with syndromic NDDs and prior negative results from targeted sequencing. The workflow integrates initial solo-WES, followed by a second-tier trio-WES using pooled parental DNA (trio pooled-WES). Overall, this workflow achieved a diagnostic yield of 20.98% and led to the identification of 13 novel candidate genes. The pooling strategy was optimized and validated, demonstrating that trio pooled-WES retains the main advantages of conventional trio-WES while substantially reducing sequencing costs. These results support its implementation as a clinically applicable approach for the genetic diagnosis of NDDs.

Rupture of an intracranial aneurysm (IA) can result in aneurysmal subarachnoid hemorrhage (ASAH), a severe and often fatal form of stroke. The configuration of the intracranial arteries - collectively known as the circle of Willis (CoW) - influences the risk of IA development and rupture. Although CoW variation is known to be heritable, its genetic underpinnings and contribution to IA remain poorly understood. Here, we aimed to investigate the genetic architecture of CoW variation and its potential link with IA. Using a semi-automated detection tool, we characterized the diameters, bifurcation angles, and presence of arterial segments of the CoW in 1078 participants from a population-based cohort and 682 IA patients. Composite traits capturing variation in all CoW characteristics were generated through principal component analysis. We conducted a genome-wide association study (GWAS) on these composite traits and identified four loci with suggestively significant associations. Lead single-nucleotide polymorphisms (SNPs) were located in or near the genes DPYSL2, CSMD3, TRPC6, and PKD1L2. Notably, PKD1L2 is closely related to PKD1, a gene implicated in autosomal dominant polycystic kidney disease, a connective tissue disorder that increases IA susceptibility. We observed statistically significant SNP-based heritability for the second principal component of CoW variation (heritability estimate = 0.95, standard error = 0.25). All lead SNPs demonstrated nominal association (p < 0.05) with multiple CoW characteristics and other vascular traits. Our findings highlight a substantial genetic contribution to CoW morphology and offer new insights into the molecular mechanisms underlying CoW variation and its role in IA pathogenesis.

There is a growing international need to support somatic genomic testing, standardised variant curation and improved patient access to molecular profiling for somatic conditions, including cancer. We conducted a survey of scope, curation, reporting and sharing practices of diagnostic laboratories performing somatic testing in Australia and New Zealand. Laboratories with accreditation (n = 41) were invited in 2023 to complete a semi-structured, 25-question interview. Responses were received for 27 laboratories (66% response rate) offering solid tumour, haematological malignancy and non-cancer services. Only 36% of laboratories offered tests capturing the full breadth of variants, from single-nucleotide variants to gene fusions. Knowledge sharing was rare, with only one laboratory submitting variant classifications to a public knowledge base. Most laboratories (96%) conducted somatic testing in oncology. Of cancer laboratories, 35% offered testing considered capable of comprehensive genomic profiling (CGP). Almost half of cancer laboratories had already adopted the 2022 ClinGen/CGC/VICC oncogenicity guidelines, and 84% were using AMP/ASCO/CAP 2017 clinical significance guidelines. Only 47% of mixed discipline cancer laboratories reported biomarkers such as tumour mutational burden, with wide variation in reporting of matched therapy options. Our study has generated a unique overview of somatic laboratory practices in the region, and areas for global standardisation in somatic molecular testing and reporting. We also provide a model for practice and guideline uptake assessment, for application by other country-wide networks. This is particularly relevant in anticipation of CGP mainstreaming, with the increasing complexity of sequencing interpretation for laboratories and clinicians.

Oculocutaneous albinism (OCA) are genetically and clinically heterogeneous recessive disorders with at least 23 associated genes. Isolated OCA is characterized by hypopigmentation in the skin, hair, and eyes combined with ocular abnormalities. Hermansky Pudlak syndrome (HPS) and Chediak-Higaski syndrome are syndromic forms of OCA, distinguished by immunological and hematological symptoms in addition to hypopigmentation and ocular anomalies. Targeted clinical care is crucial for the patients and molecular genetic diagnosis is important for classification of patients. Current diagnostic yield is approximately 70%, and a high proportion of patients are heterozygous for pathogenic variants in OCA genes, suggesting the presence of disease-causing non-coding variants. We describe here next generation sequencing (NGS) analysis, including copy number variant (CNV) analysis, of 28 consanguineous families, comprising a total of 136 individuals presenting with OCA. We provide a molecular genetic diagnosis in all 28 families. Noteworthy, five families (18%) had pathogenic variants in a gene associated with HPS, showing the importance of an in-depth molecular genetic investigation, which should be offered to persons with albinism. Furthermore, we report the first deep intron variant in TYR causing OCA and show by minigene analysis that the variant causes inclusion of a pseudoexon.

Splice-disrupting variants are estimated to account for one-third of disease-causing variants, yet many remain underrepresented in clinical databases due to limitations in detecting splicing changes beyond canonical splice sites. Short-read RNA sequencing (RNA-seq) has proved to be a valuable complement in clinical practice to address this gap, however, the added value of long-read RNA-seq is unclear. We evaluated the potential of PacBio long-read RNA-seq to detect pathogenic splicing events in rare disorders, comparing its performance to short-read RNA-seq. Participants from the UK (n = 23) and the Netherlands (n = 2) with suspected splice-altering variants underwent long-read RNA-seq following the Kinnex full-length RNA protocol. HiFi reads from the Revio instrument were processed using the Read Segmentation and Iso-Seq workflow and then classified and filtered using Pigeon. Detection of disease genes was comparable with short reads, with fibroblast capturing more transcripts overall. Novel isoforms accounted for ~14% of detected transcripts in both tissues, increasing following cycloheximide treatment in fibroblasts and decreasing following globin depletion in blood. Transcript abundance estimates showed strong concordance between short- and long-read platforms (Pearson r = 0.86 and 0.61 in blood and fibroblasts, respectively). LRS captured 21 confirmed known events, and revealed additional transcript-level effects in eight cases. This included intron retention, multiple exon skipping, leaky splicing, variant phasing, and isoform switching. These results demonstrate that long-read RNA-seq enhances detection and interpretation of clinically relevant splicing events, supporting its integration into diagnostic workflows for rare diseases.

Indigenous communities are under-represented in genomics research, contributing to inequitable health-related knowledge, outcomes, and benefits. Under-representation reflects enduring consequences of colonial research practices that have engendered cultural, ethical, legal, and social (CELS) concerns among communities. Researchers must understand, navigate, and address these in their research practices. This study aimed to identify and synthesise CELS considerations to inform Indigenous genomics research practices. A systematic scoping review was conducted, including peer-reviewed papers on genomics that discussed cultural, ethical, legal, or social matters relevant to Indigenous Peoples globally; available in full-text and in English. Inductive content analysis using NVivo 12 Plus was undertaken to identify CELS considerations and develop content categories, with papers coded to multiple categories where relevant. As of May 2024, 186 papers were identified for inclusion: n = 70 (38%) included cultural, n = 91 (49%) ethical, n = 49 (26%) legal, and n = 125 (67%) social considerations. Cultural considerations included cultural harm, significance of blood, and the need to integrate Indigenous knowledges. Ethical considerations included consent, data access and sharing, privacy, and confidentiality. Legal considerations included laws protecting Indigenous interests, control of genomic samples and data, biovalue and DNA as a commodity, genetic discrimination, and the use of genomic data in constructing and defining racial identity. Social considerations included collective decision-making, genetic determinism, and stigmatisation, and the importance of contextualising findings within wider social determinants of health frameworks. Overall, researchers need to understand, navigate, and address CELS considerations of relevance to Indigenous Peoples to build trust, promote inclusion, and support equitable benefit-sharing in genomics research.

Hereditary cancer syndromes are among the most common inherited disorders and contribute to nearly 10% of solid tumours. While genetic testing is now central to diagnosis, surveillance, and cascade prevention, its impact is constrained by the persistent challenge of variants of uncertain significance (VUS), which comprise almost 40% of reported hereditary cancer syndrome-associated variants in ClinVar. These unresolved classifications undermine the interpretive power of testing, limiting its translational and preventive potential. In this review, we examine the foundations of variant interpretation, the role of expert-guided specifications, and emerging methods for VUS reclassification, including population-level data, RNA- and protein-based functional assays, computational predictors, and long-read sequencing. We further highlight how systematic re-evaluation structures and curation infrastructures translate new evidence into clinical practice. We conclude with an outlook on future directions to reduce the burden of VUS and increase the clinical utility of hereditary cancer syndrome testing.

In the era of rapidly accumulating genomic data, largely driven by the broad use of whole-genome sequencing (WGS) in clinical settings, interpreting lesser-known genes with varied phenotypes remains challenging. PubMatcher is a new tool that simplifies bibliographic research for multiple genes at once and grants quick and easy access to relevant gene information. It helps users efficiently identify potential genotype-phenotype associations using PubMed complemented by additional data. By significantly reducing analysis time, PubMatcher supports the interpretation of novel or under-documented genes. Freely available for academic and non-commercial use, PubMatcher is a user-friendly and efficient solution for researchers, clinical scientists and clinical geneticists working on pan-genomics analyses.