Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Genome Medicine, Journal Year: 2023, Volume and Issue: 15(1)

Published: Nov. 9, 2023

Abstract Background Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, diagnostic yields many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This part because although entire genomes sequenced, analysis confined to silico gene panels or coding regions genome. Methods We undertook WGS on cohort 122 unrelated disease and their relatives (300 genomes) who had been pre-screened by arrays. Patients were recruited from broad spectrum clinical specialties. applied bioinformatics pipeline that would allow comprehensive all variant types. combined established tools phenotypic genomic our novel algorithms (SVRare, ALTSPLICE GREEN-DB) detect annotate structural, splice site non-coding variants. Results Our yield was 43/122 cases (35%), 47/122 (39%) considered solved when considering candidate genes supporting functional data into account. Structural, deep intronic variants contributed 20/47 (43%) cases. Five novel, time discovery, identified, whilst further three putative evidence causality. identified uncertain significance fourteen genes. The associated RMND1 expanded include polymicrogyria. Two secondary findings FBN1 KCNQ1 confirmed have previously unidentified Marfan long QT syndromes, respectively, referred interventions. Clinical diagnoses changed six treatment adjustments made eight individuals, which five life-saving. Conclusions Genome as first-line genetic test routine settings can make substantial contribution rapidly identifying causal aetiology patients, shortening odyssey. demonstrated significant essential maximise value sequencing.

Language: Английский

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A de novo ARIH2 gene mutation was detected in a patient with autism spectrum disorders and intellectual disability

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 9, 2024

Abstract E3 ubiquitin protein ligase encoded by ARIH2 gene catalyses the ubiquitination of target proteins and plays a crucial role in posttranslational modifications across various cellular processes. As prior documented, mutations genes involved process are often associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). In current study, de novo heterozygous mutation was identified splicing intronic region adjacent to last exon using whole exome sequencing (WES). We hypothesize that this mutation, found an ASD/ID patient, disrupts Ariadne domain which is autoinhibition enzyme. Predictive analyses elucidated implications novel confirmed its autosomal dominant inheritance model. Nevertheless, we cannot exclude possibility other genetic factors, undetectable WES, such as non-coding regions polygenic risk inter-allelic complementation, may contribute patient's phenotype. This work aims suggest potential relationship between detected both ASD ID, even though functional studies combined new approaches will be necessary validate hypothesis.

Language: Английский

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An Overview of Advances in Rare Cancer Diagnosis and Treatment

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1201 - 1201

Published: Jan. 18, 2024

Cancer stands as the leading global cause of mortality, with rare cancer comprising 230 distinct subtypes characterized by infrequent incidence. Despite inherent challenges in addressing diagnosis and treatment cancers due to their low occurrence rates, several biomedical breakthroughs have led significant advancement both areas. This review provides a comprehensive overview state-of-the-art diagnostic techniques that encompass new-generation sequencing multi-omics, coupled integration artificial intelligence machine learning, revolutionized diagnosis. In addition, this highlights latest innovations therapeutic options, immunotherapy, targeted therapy, transplantation, drug combination undergone clinical trials significantly contribute tumor remission overall survival patients. review, we summarize recent insights understanding pathophysiology, diagnosis, modalities, well faced development data interpretation development.

Language: Английский

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Ex vivo T-lymphopoiesis assays assisting corrective treatment choice for genetically undefined T-lymphocytopaenia

Clinical Immunology, Journal Year: 2025, Volume and Issue: unknown, P. 110453 - 110453

Published: Feb. 1, 2025

Language: Английский

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Parental Engagement in Identifying Information Needs After Newborn Screening for Families of Infants with Suspected Athymia

Journal of Clinical Immunology, Journal Year: 2024, Volume and Issue: 44(3)

Published: March 8, 2024

Abstract Congenital athymia is a rare T-lymphocytopaenic condition, which requires early corrective treatment with thymus transplantation (TT). Athymic patients are increasingly identified through newborn screening (NBS) for severe combined immunodeficiency (SCID). Lack of relatable information resources contributes to challenging patient and family journeys during the diagnostic period following abnormal NBS results. Patient Public Involvement Engagement (PPIE) activities, including parental involvement in paediatrics, valuable initiatives improve clinical communication strategies. Parents infants suspected were therefore invited discuss they received aim identify needs targeted strategies address these adequately. reported that was not considered them as possible differential diagnosis until weeks after initial Whilst appropriate about TT available upon referral specialist immunology services, improved access easy-to-understand from reliable sources, nurse specialists peer support systems, remained desirable. A roadmap concept, written or digital information, addressing real time potentially complex journey, proposed transferrable other inborn errors immunity (IEI) diseases. This PPIE activity provides insight into parents who SCID NBS, highlights role promoting patient- family-centred IEI care.

Language: Английский

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Lessons and pitfalls of whole genome sequencing

Practical Neurology, Journal Year: 2024, Volume and Issue: 24(4), P. 263 - 274

Published: March 28, 2024

Whole-genome sequencing (WGS) has recently become the first-line genetic investigation for many suspected neurological disorders. While its diagnostic capabilities are innumerable, as with any test, it limitations. Clinicians should be aware of where WGS is extremely reliable (detecting single-nucleotide variants), reliability much improved copy number variants and small repeat expansions) may miss/misinterpret a variant (large expansions, balanced structural or low heteroplasmy mitochondrial DNA variants). Bioinformatic technology virtual gene panels constantly evolving, important to know what genes types being tested; current National Health Service Genomic Medicine offers more than early iterations 100 000 Genomes Project analysis. Close communication between clinician laboratory, ideally through multidisciplinary team meeting, encouraged there uncertainty.

Language: Английский

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Discordance between a deep learning model and clinical-grade variant pathogenicity classification in a rare disease cohort

npj Genomic Medicine, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 28, 2025

Genetic testing is essential for diagnosing and managing clinical conditions, particularly rare Mendelian diseases. Although efforts to identify phenotype-associated variants have focused on protein-truncating variants, interpreting missense remains challenging. Deep learning algorithms excel in various biomedical tasks1,2, yet distinguishing pathogenic from benign elusive3–5. Our investigation of AlphaMissense (AM)5, a deep tool predicting the potential functional impact assessing gene essentiality, reveals limitations identifying over 45 diseases, including very early onset inflammatory bowel disease. For expert-curated identified our cohort, AM's precision was 32.9%, recall 57.6%. Notably, AM struggles evaluate pathogenicity intrinsically disordered regions (IDRs), resulting unreliable gene-level essentiality scores genes containing IDRs. This observation underscores ongoing challenges genetics, highlighting need continued refinement computational methods variant prediction.

Language: Английский

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Lessons from national biobank projects utilizing whole-genome sequencing for population-scale genomics

Genomics & Informatics, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 6, 2025

Large-scale national biobank projects utilizing whole-genome sequencing have emerged as transformative resources for understanding human genetic variation and its relationship to health disease. These initiatives, which include the UK Biobank, All of Us Research Program, Singapore's PRECISE, Biobank Japan, National Project Bio-Big Data Korea, are generating unprecedented volumes high-resolution genomic data integrated with comprehensive phenotypic, environmental, clinical information. This review examines methodologies, contributions, challenges major WGS-based genome worldwide. We first discuss landscape highlighting their distinct approaches collection, participant recruitment, phenotype characterization. then introduce recent technological advances that enable efficient processing analysis large-scale WGS data, including improvements in variant calling algorithms, innovative methods creating multi-sample VCFs, optimized storage formats, cloud-based computing solutions. The synthesizes key discoveries from these projects, particularly identifying expression quantitative trait loci rare variants associated complex diseases. Our introduces latest findings has advanced our population-specific diseases Korean East Asian populations. Finally, we future directions maximizing impact on precision medicine global equity. examination demonstrates how revolutionizing research healthcare delivery while importance continued investment diverse, resources.

Language: Английский

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Rare pathogenic structural variants show potential to enhance prostate cancer germline testing for African men

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 10, 2025

Abstract Prostate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack representation in genomic data means germline testing guidelines exclude for Africans. Established that structural variations (SVs) are major contributors to human disease prostate tumourigenesis, their role under-appreciated familial therapeutic testing. Utilising clinico-methodologically matched deep-sequenced whole-genome 113 versus 57 European PCa patients, we interrogate 42,966 high-quality SVs using a best-fit pathogenicity prediction workflow. We identify 15 potentially pathogenic representing 12.4% 7.0% which 72% 86% met standard-of-care recommendations, respectively. Notable African-specific loss-of-function gene candidates include DNA damage repair MLH1 BARD1 tumour suppressors FOXP1, WASF1 RB1 . Representing only fraction the vast diaspora, this study raises considerations respect contribution kilo-to-mega-base rare variants African-associated disparity.

Language: Английский

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Non-canonical splice variants in thoracic aortic dissection cases and Marfan syndrome with negative genetic testing

npj Genomic Medicine, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 21, 2025

Individuals with heritable thoracic aortic disease (HTAD) face a high risk of deadly dissections, but genetic testing identifies causative variants in only minority cases. We explored the contribution non-canonical splice (NCVAS) to (TAD) using SpliceAI and sequencing data from diverse cohorts, including 551 early-onset sporadic dissection cases 437 HTAD probands exome sequencing, 57 pedigrees whole genome select clinical panel testing. NCVAS were identified syndromic genes such as FBN1, SMAD3, COL3A1, intronic FBN1 two Marfan syndrome (MFS) families. Validation Penn Medicine BioBank UK Biobank showed enrichment HTAD-associated among dissections. These findings suggest are an underrecognized contributor TAD, particularly unsolved MFS cases, highlighting potential advanced prediction tools diagnostics.

Language: Английский

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