European Journal of Human Genetics最新文献

Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are a group of proteins encoded by nuclear DNA that play a crucial role in mitochondrial protein synthesis. Mitochondrial diseases caused by mt-aaRS variants are phenotypically heterogenous but often present with significant neurological features such as childhood-onset encephalopathy and seizures. As such, these conditions are a diagnostic challenge. We present an approach that systematically quantifies phenotypic similarity of individuals with an mt-aaRS variant to published cases, to aid variant interpretation, in RD-Connect-a large Europe-wide rare disease cohort. Across 98 individuals with a mt-aaRS gene of interest, we prioritised 38 individuals with 63 variants following bioinformatic and manual analyses. We additionally reviewed Exomiser prioritisation using a pre-defined gene list for neurological disorders within the RD-Connect Genome-Phenome Analysis Platform (GPAP). We were able to generate likely diagnoses in 11 individuals and VUS findings in 13 individuals, following careful phenotype similarity analysis using a phenotype-genotype dataset generated from 234 published individuals. Four of these 24 individuals did not have an Exomiser-ranked gene variant in the GPAP. Therefore, this approach, using individual-level curated phenotype-genotype data to support variant interpretation, can highlight potentially significant variants that may not be captured by current pipelines. This workflow can be replicated in other heterogeneous rare diseases to support clinical practice.

Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. While most cases result from the cumulative risk of common genetic variants, a smaller proportion shows a monogenic etiology. We used germline exome sequencing data to assess the gene-based burden of loss-of-function pathogenic variants (LoF-PVs) in 471 early-onset GC cases as well as 666 GC cases from the UK Biobank (UKB), aiming to identify monogenic GC forms. In both datasets, LoF-PVs in CDH1 and ATM were enriched among GC cases. Beyond GC, ATM LoF-PVs were also enriched in UKB participants with pancreatic, oesophageal, breast, prostate, and lung cancer, though the effect size was notably high in GC. As an established disease gene for pancreatic, breast, ovarian, and prostate cancer, ATM should also be considered for genetic testing when monogenic GC is suspected. This is especially important for families in which other tumours associated with ATM PVs occur alongside GC.

Hereditary diffuse gastric cancer (HDGC) and Lynch syndromes are dominant hereditary diseases caused by pathogenic germline variants in specified genes, and characterised by a broad spectrum of malignancies. Whereas HDGC is associated with CDH1 and CTNNA1 variants and defined by an increased risk of diffuse gastric cancer and lobular breast cancer, Lynch syndrome results from alterations in mismatch repair genes, whose main manifestations include colorectal, endometrial, ovarian, breast, prostate, stomach, and urological tumours. Remarkably, a huge difference remains in the knowledge surrounding the molecular mechanisms that drive these disorders, and in current approaches for patient management. In fact, the HDGC narrative is still in its early stages when compared with Lynch syndrome, which accumulates more than a century of research. Herein, we propose an analogy between HDGC and Lynch syndromes, highlighting intricacies across genetic origin, variant effects, cellular landscapes, and associated clinical outcomes. Further, we postulate that the history of Lynch syndrome may be useful to advance HDGC aetiology, namely strategies for identification of new candidate genes, rules for variant interpretation, sources of phenotypic heterogeneity, and improved surveillance protocols. This collected data will impact clinical perspectives, as well as future research programs addressing HDGC unmet challenges.

Inherited cardiac conditions (ICCs), like inherited cardiomyopathies (ICMs) and long QT syndrome (LQTS), are serious genetic conditions that carry a risk of sudden death. Predictive genetic testing (PT) is routinely available, however, the impact of this testing during the adolescent period is understudied. To understand the lived experience of young people who have undergone PT for ICCs, semi-structured, in-depth interviews were conducted with young people who underwent PT for an ICC between the ages of 10-17 years between January 2009 and July 2020. Their parents were also invited to participate. Participant experiences and views relating to the PT process were explored. Inductive thematic analysis was used to elicit a deep understanding of the experiences and needs of this cohort. Nineteen predictively tested young people were interviewed (8 tested for ICM, 11 for LQTS; of these, 11 were gene-positive) as well as 15 parents. Three intersecting themes were identified: 'it's a family affair' (impact of/on family relationships and experience of the condition); 'post-test day-to-day implications' (impact of integrating gene-status on self-perception); and 'needing developmentally-appropriate intervention and support' (recognising the evolving needs of the young person as an individual and within their family unit). Young people, regardless of their gene status, require individualised support and follow-up. Family structure and experience influences perception and understanding of the PT process, highlighting the need to appropriately involve, support and educate all family members.

The 2025 French Genomic Medicine Initiative (PFMG2025) aims to make clinical genome sequencing (GS) widely accessible across France through the deployment of dedicated care pathways for rare diseases (RDs), cancer genetic predisposition (CGP), and cancers. This framework includes the establishment of two national GS laboratories, the definition of seventy priority pre-indications and the integration of new digital tools for e-prescription. To support these transformations, the French Ministry of Health created an innovative and internationally unprecedented role: Genomic Pathway Manager (GPM). These professionals are positioned at the interface between clinical practice, operational organisation of care pathways, and interdisciplinary coordination. They assist clinicians in prescribing GS analyses, coordinating sampling processes, and managing multidisciplinary meetings. This study provides the first nationwide assessment of the GPM role, assessing their professional profiles, activities, and job satisfaction. A quantitative questionnaire was distributed in May 2023 to all GPMs recruited, with a 90% response rate (36/40). Results show considerable heterogeneity in GPM profiles and responsibilities across different institutions. Most GPMs actively contribute to data entry in prescription systems (90%), participate in multidisciplinary meetings (85%), and train clinicians (80%). GPMs with genetic counsellor (GC) training are significantly involved in patient information sessions, enhancing the overall efficiency of the prescription process. Although GPMs expressed high job satisfaction, challenges remain, including geographical disparities, role standardization, and the need for continuous training. GPMs have proven to be key players in streamlining genomic medicine pathways. This study offers unique insights into an emerging role that may inspire similar developments in other countries.

Implementation of genomics in newborn screening is rapidly becoming a reality through accelerated clinical research and investment in genomic sequencing programs. The perspectives of parents who have experienced genetic screening and technologies can inform effective clinical translation and co-design of a model of care for future programs. Semi-structured interviews were undertaken with 23 parents of children diagnosed with genetic conditions. Data were evaluated using inductive content analysis methods. Parents valued expeditious, contemporary and accurate information from specialists to manage uncertainties and aid decision-making upon receiving a genomic diagnosis, alongside coordination and collaboration with local services to provide child and family centred care. Integration of psychosocial support into genomic NBS programs was highlighted as an important strategy to mitigate potential psychological risks of receiving a newborn genomic screening result. Integrating genomic NBS in current health ecosystems requires a model that provides care and support across the healthcare journey for the child and family. Information provision and consent at screening facilitates familial understanding of the implications of genomic screening. Equitable access to post screening care and expertise is essential to optimise health and psychosocial outcomes for the child and family and maintain parental acceptability.

Limb-girdle muscular dystrophy type R3 (LGMDR3) is caused by pathogenic SGCA variants and typically presents as progressive muscle weakness with limited cardiac manifestations. We investigated five consanguineous families with substantial left ventricular dysfunction, arrhythmias, and life-threatening ventricular tachyarrhythmias. Cardiac assessments, including echocardiography, Holter monitoring, and cardiac magnetic resonance imaging, revealed a spectrum of findings from mild asymptomatic dysfunction to severe dilated cardiomyopathy and malignant arrhythmia requiring implantable cardioverter-defibrillators. Initial evaluation with exome sequencing showed no conclusive results until a genotype-phenotype correlation reanalysis pinpointed a single homozygous synonymous SGCA variant shared by all affected individuals. Despite being distant from canonical splice sites, this variant disrupted normal mRNA splicing, leading to aberrant transcripts and a presumably nonfunctional or structurally altered α-sarcoglycan protein. This study broadens the recognized clinical spectrum of LGMDR3 by revealing significant cardiac involvement and exemplifies how a splice-disrupting synonymous variant, initially classified as likely benign, can underlie a severe cardiac phenotype and merit reclassification. Our findings highlight the importance of integrating genotype-phenotype correlation with functional studies to improve diagnostic accuracy, particularly in underrepresented populations.