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Results for “Gene-disease validity”

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7 recordsLinked to original sources
PubMed2025

ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time.

PURPOSE: The Clinical Genome Resource (ClinGen) Hearing Loss Gene Curation Expert Panel was assembled in 2016 and has since curated 174 gene-disease relationships (GDRs) using ClinGen's semiquantitative framework. ClinGen mandates the timely recuration of all GDRs classified as Disputed, Limited, Moderate, and Strong every 2 to 3 years. METHODS: Thirty-five GDRs met the criteria for recuration within 2 years of original curation. Previous evidence was reevaluated using the latest curation guidelines, and a comprehensive literature review was performed to obtain new evidence. Recurations were approved by the Gene Curation Expert Panel and published on the ClinGen website (www.clinicalgenome.org). RESULTS: Eight of 35 GDRs (22%) changed their classification. Two Moderate and 5 Strong GDRs were upgraded to Definitive because of new case evidence. One Strong was subsumed under another Definitive GDR after evaluation of the lumping/splitting of disease entities. Twenty-seven of 35 patients remained unchanged, with little to no new evidence reported. CONCLUSION: Genes classified as Moderate and Strong were likely to build evidence and change their classification over time, whereas Limited were unlikely to gain evidence. These findings highlight the critical role of recuration in ensuring that genetic tests and research studies incorporate the most recent evidence into their efforts.

Humans↗
PubMed2026

Identification of biallelic loss-of-function PREP variants in three individuals with syndromic intellectual disability.

BACKGROUND: Neurodevelopmental disorders are one of the most prevalent reasons for genetic testing in childhood. Despite the identification of over 1950 associated genes, many proposed candidate genes lack convincing gene-disease validity. The gene PREP encodes the broadly expressed prolyl endopeptidase whose exact function remains largely unknown. A homozygous PREP variant has been reported once as a candidate gene in two siblings with intellectual disability but no functional studies were conducted. METHODS: Exome and trio genome sequencing were performed in two unrelated families as part of larger cohorts. Segregation analysis, RNA sequencing and immunoblots were performed to further examine the pathogenicity of detected PREP variants. RESULTS: We report three individuals from two unrelated families who presented with intellectual disability, behavioural abnormalities, strabismus, generalised muscular hypotonia, dysmorphic facial features and epilepsy. Exome and genome sequencing identified two different homozygous rare PREP variants: c.1570_1573dup, p.(Asn525Thrfs*5) and c.1839-2A>G, p.?. RNA sequencing confirmed the detected intronic variant to result in two aberrant mRNA isoforms. In patient-derived cells immunoblots showed absence of PREP protein. CONCLUSION: Our data suggest PREP deficiency as the underlying cause of a syndromic neurodevelopmental disorder.

Female↗
PubMed2026

Emerging genes implicated in human congenital heart disease: a 2023-2025 scoping review.

BACKGROUND: Congenital heart disease (CHD) is the most common major congenital anomaly and a leading cause of infant morbidity and mortality. The rapid expansion of genomic technologies has accelerated the discovery of rare genetic variants implicated in CHD pathogenesis. However, most individuals with CHD still lack an identifiable molecular etiology. The purpose of this scoping review is to systematically characterize genes reported in the recent literature as candidate CHD-associated genes and contextualize these findings within the stages of cardiac morphogenesis. METHODS: PubMed was searched using predefined terms related to CHD and genetic variants, supplemented by a prospectively maintained internal database. We included human studies published between January 2023 and December 2025 that identified pathogenic, likely pathogenic, or uncertain monogenic variants in at least one patient with CHD. Animal-only studies, chromosomal abnormalities, copy number variants, multigenic associations, transcriptomic/proteomic analyses, reviews, and maternal-only genetic studies were excluded. Gene-disease validity classifications were assigned using the Clinical Genome Resource (ClinGen) CHD Gene Curation Expert Panel framework. RESULTS: Of 2,834 screened articles, 391 studies met inclusion criteria, identifying 912 unique genes reported as candidate CHD-associated genes. Frequently reported genes included PTPN11, NOTCH1, GATA4, JAG1, MYH6, GATA6, and LZTR1. Identified genes spanned all major stages of cardiogenesis, including developmental priming, cardiac progenitor specification, left-right axis formation, neural crest migration, outflow tract development, septation, and postnatal structural remodeling. Studies increasingly implicated ciliary dysfunction, transcriptional regulation, ribosomal biology, and multigenic inheritance in CHD pathogenesis. Emerging methodologies included stem cell-derived cardiac models, machine learning-based gene prioritization, and epigenetic analyses. CONCLUSIONS: Recent literature substantially expands the catalog of candidate genes that may be associated with CHD and highlights the biologic complexity underlying cardiac morphogenesis. Integration of genomic, developmental, and functional approaches will be essential to improve mechanistic understanding, refine genetic counseling, and support future precision medicine strategies for CHD.

Cardiac development↗
PubMed2025

Impact of laboratory-driven proactive reanalysis: Reclassification to positive in 5% of initially negative or uncertain exome sequencing cases.

PURPOSE: Reanalysis of exome sequencing (ES) data increases diagnostic utility; however, there is no consensus on when and under what circumstances reanalysis should occur. Requesting and performing ES reanalysis burdens both clinical and laboratory workflows. Maximizing the potential for reclassification is essential. Here, we describe the impact of a laboratory-driven proactive reanalysis process that triggers reanalysis when new evidence is identified. METHODS: We reviewed reanalysis outcomes of an ES cohort. Reanalysis events were categorized based on initiating factors (laboratory-driven proactive, family studies, and clinician-initiated). Laboratory-driven proactive reclassifications are prompted by systematic review of new scientific data. Outcomes were evaluated by initiating factors, reclassification types, evidence used, and time since original report. RESULTS: Overall, 23% of cases underwent at least 1 reanalysis, with 35% of reanalyses resulting in reclassification. There was a 4% increase in diagnostic yield, including 5% of initially unsolved ES receiving diagnostic reports. Diagnostic reclassifications rates were significantly higher for laboratory-driven proactive reanalyses (54%; P < .0001) than family studies (18%) and clinician-initiated reanalyses (4%). New gene-disease relationships were the most efficacious evidence source. Laboratory-driven proactive reclassifications occurred steadily over time. CONCLUSION: Laboratory-driven proactive reanalysis effectively provides more diagnostic reclassifications compared with clinician-initiated reanalysis. Laboratories should curate and integrate emerging evidence into ES reanalysis.

Humans↗
PubMed2025

Toward an integrated resource for pharmacogenomics (PGx): Survey findings from the genomic medicine communities.

PURPOSE: Pharmacogenomics (PGx) is a critical component of precision health care that aims to improve drug efficacy and reduce adverse events. Terminologies and standards have not always aligned between PGx and broader genomic medicine communities, which is a barrier to PGx implementation. An updated assessment of community barriers, needs, and perspectives is critical to enable more standardized terminologies and interpretation frameworks. METHODS: The Clinical Genome Resource's PGx Interpretation Committee (PGxIC, formerly referred to as the PGx Working Group, PGxWG) conducted 2 surveys targeting the PGx and genomic medicine communities (n = 508) to evaluate perspectives on PGx clinical validity and actionability frameworks, as well as other barriers to PGx implementation. Surveys were tailored toward self-reported familiarity with PGx. Data primarily consisted of free text, which were analyzed using qualitative content analysis methods. RESULTS: Survey responses indicated conflation of terminology across disciplines, including confusion around differing definitions of terms in PGx and non-PGx contexts. Data also indicated broad support for leveraging existing PGx guidelines and framework structures alongside the standardization of approaches and centralization of resources. CONCLUSION: These novel survey results demonstrate broad consensus on the importance of integrating PGx into clinical practice, including support for development of gene-drug response clinical validity and actionability frameworks aligned with Clinical Genome Resource's frameworks for gene-disease relationships.

Humans↗
PubMed2025

Increased yield of genetic diagnoses in inherited heart diseases using expanded genome and RNA-splicing analyses.

PURPOSE: The Australian Genomics Cardiovascular Disorders Flagship investigated genome sequencing as a first-line genetic test in 600 individuals with cardiomyopathy, primary arrhythmia syndromes, or congenital heart disease. Analysis of disease-specific virtual gene panels achieved a genetic diagnosis in 38% of participants. We sought to increase genetic diagnosis yields by analyzing lesser-evidenced disease genes, the mitochondrial genome, and by functional analysis of predicted splice-altering variants. METHODS: Genome sequences of 520 participants with cardiomyopathy or primary arrhythmia syndromes were reanalyzed in 572 cardiac genes and the mitochondrial genome. Participants with congenital heart disease were excluded. Variants predicted in silico to disrupt splicing were assessed with blood RNA and minigenes. RESULTS: A new genetic diagnosis was achieved in 4% (19/520) of participants, including deep intronic and mitochondrial genome variants. Ten participants had diagnostic variants in lesser evidenced disease genes; 9 had splicing variant pathogenicity functionally validated. Eleven participants had a newly identified variant of uncertain significance with high suspicion of pathogenicity, warranting clinical review. Our data supported the gene-disease association of 1 new cardiomyopathy gene, TBX20. CONCLUSION: Identifying new gene-disease relationships, maintaining contemporary gene panels, and integrating functional studies to refine splicing variant classifications increase genetic diagnoses for cardiomyopathies and primary arrhythmia syndromes.

Humans↗
PubMed2026

Identification of mitochondrial energy metabolism-related candidate genes UQCR10 and NDUFA6 in pediatric tetralogy of fallot: an exploratory bioinformatics study.

BACKGROUND: Tetralogy of Fallot (TOF) is one of the most common cyanotic congenital heart diseases in infants and young children. Its molecular basis remains incompletely understood. This study aimed to identify mitochondrial energy metabolism-related candidate genes associated with pediatric TOF using public heart tissue transcriptomic datasets from the GEO database. METHODS: Datasets GSE146218 and GSE217772 were downloaded and merged, followed by batch-effect correction. Differential expression analysis was performed to identify differentially expressed genes (DEGs). Functional enrichment analysis, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network analysis were used to prioritize candidate genes. The Comparative Toxicogenomics Database (CTD) was used as an exploratory literature-based tool to summarize gene-disease associations. RESULTS: A total of 960 DEGs were identified. Functional enrichment analyses showed that these genes were mainly enriched in mitochondrial energy metabolism-related pathways, including oxidative phosphorylation and the mitochondrial respiratory chain. WGCNA and PPI network analyses further prioritized UQCR10 and NDUFA6 as candidate genes, and both genes showed increased expression in TOF heart tissue samples. CTD analysis suggested literature-based associations between these genes and cardiovascular or developmental disease-related terms. CONCLUSION: This exploratory bioinformatics study identified UQCR10 and NDUFA6 as mitochondrial energy metabolism-related candidate genes upregulated in pediatric TOF heart tissue. These findings suggest that mitochondrial respiratory chain-related transcriptional alterations may be involved in TOF-associated myocardial remodeling or stress responses. Further experimental and clinical validation is required to confirm their biological relevance.

Humans↗