CADD v1.7: using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(D1), P. D1143 - D1154

Published: Jan. 5, 2024

Machine Learning-based scoring and classification of genetic variants aids the assessment clinical findings is employed to prioritize in diverse studies analyses. Combined Annotation-Dependent Depletion (CADD) one first methods for genome-wide prioritization across different molecular functions has been continuously developed improved since its original publication. Here, we present our most recent release, CADD v1.7. We explored integrated new annotation features, among them state-of-the-art protein language model scores (Meta ESM-1v), regulatory variant effect predictions (from sequence-based convolutional neural networks) sequence conservation (Zoonomia). evaluated version on data sets derived from ClinVar, ExAC/gnomAD 1000 Genomes variants. For coding effects, tested 31 Deep Mutational Scanning (DMS) ProteinGym and, prediction, used saturation mutagenesis reporter assay promoter enhancer sequences. The inclusion features further overall performance CADD. As with previous releases, all sets, v1.7 scores, scripts on-site an easy-to-use webserver are readily provided via https://cadd.bihealth.org/ or https://cadd.gs.washington.edu/ community.

Language: Английский

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PIEZO Ion Channels in Cardiovascular Functions and Diseases

Circulation Research, Journal Year: 2024, Volume and Issue: 134(5), P. 572 - 591

Published: Feb. 29, 2024

The cardiovascular system provides blood supply throughout the body and as such is perpetually applying mechanical forces to cells tissues. Thus, this primed with mechanosensory structures that respond adapt changes in stimuli. Since their discovery 2010, PIEZO ion channels have dominated field of mechanobiology. These been proposed long-sought-after mechanosensitive excitatory involved touch proprioception mammals. However, more pieces evidence point importance activities disease development. channel-related cardiac functions include transducing hemodynamic endothelial vascular cells, red cell homeostasis, platelet aggregation, arterial pressure regulation, among others. contribute pathological conditions including hypertrophy pulmonary hypertension congenital syndromes generalized lymphatic dysplasia xerocytosis. In review, we highlight recent advances understanding role diseases. Achievements quickly expanding should open a new road for efficient control PIEZO-related diseases functions.

Language: Английский

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Genetic modifiers of rare variants in monogenic developmental disorder loci

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(5), P. 861 - 868

Published: April 18, 2024

Abstract Rare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DDs) and have also been shown milder subclinical phenotypes population cohorts. Here, we show that carrying multiple (2−5) rare across 599 dominant DD has an additive adverse effect on numerous cognitive socioeconomic traits UK Biobank, which can be partially counterbalanced by higher educational attainment polygenic score (EA-PGS). Phenotypic deviators from expected EA-PGS could partly explained the enrichment or depletion variants. Among carriers variants, those with DD-related clinical diagnosis had substantially lower more severe phenotype than without diagnosis. Our results suggest overall burden both common modify expressivity phenotype, may then influence whether individual reaches threshold for disease.

Language: Английский

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Antagonizing cis- regulatory elements of a conserved flowering gene mediate developmental robustness

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(8)

Published: Feb. 18, 2025

Developmental transitions require precise temporal and spatial control of gene expression. In plants, such regulation is critical for flower formation, which involves the progressive maturation stem cell populations within shoot meristems to floral meristems, followed by rapid sequential differentiation into organs. Across plant taxa, these are orchestrated F-box transcriptional cofactor UNUSUAL FLORAL ORGANS ( UFO ). The conserved pleiotropic functions offer a useful framework investigating how evolutionary processes have shaped intricate cis- key developmental genes. By pinpointing promoter sequence in an accessible chromatin region tomato ortholog , we engineered vivo series regulatory alleles that caused both loss- gain-of-function defects. These mutant phenotypes were linked disruptions predicted transcription factor binding sites known activators repressors. Allelic combinations revealed dosage-dependent interactions between opposing alleles, influencing penetrance expressivity phenotypes. phenotypic differences support robustness development requires expression dosage. Bridging our analysis Arabidopsis found although homologous sequences dispersed promoter, they maintain similar over development. However, from disrupting differ due differing patterns . Our study underscores complex dynamic genes demonstrates short stretches recruit activating repressing machinery robustness.

Language: Английский

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Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: a case series

The Lancet Neurology, Journal Year: 2025, Volume and Issue: 24(3), P. 218 - 229

Published: Feb. 19, 2025

Through the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation type I interferon (IFN) signalling, we identified a cohort individuals heterozygous mutations in PTPN1, encoding protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe clinical phenotype and molecular cellular pathology this new disease. In case series, collected neuroradiological data through collaboration paediatric neurology genetics colleagues across Europe (Czechia, France, Germany, Italy, Slovenia, UK) Israel. Variants PTPN1 were by exome directed Sanger sequencing. The expression IFN-stimulated genes was determined quantitative (q) PCR or NanoString technology. Experiments assess RNA protein investigate 1 IFN signalling undertaken patient fibroblasts, hTERT-immortalised BJ-5ta RPE-1 cells using CRISPR-Cas9 editing standard cell biology techniques. Between Dec 20, 2013, Jan 11, 2023, 12 from 11 families who PTPN1. found ten novel very rare variants (frequency on gnomAD version 4.1.0 <1·25 × 10:sup>-6). Six predicted as STOP mutations, two involved canonical splice-site nucleotides, missense substitutions. three patients, variant occurred de novo, whereas nine affected individuals, inherited asymptomatic parent. characterised subacute onset (age range 1-8 years) loss motor language skills absence seizures after initially normal development, leading spastic dystonia bulbar involvement. Neuroimaging variably demonstrated cerebral atrophy (sometimes unilateral initially) high T2 white matter signal. Neopterin CSF elevated all tested, probands whole blood. Although stabilisation improvement seen both treated untreated six eight high-dose corticosteroids judged clinically result neurological status. Of four parents blood (three patients) minimally (one patient). Analysis fibroblasts showed that tested led reduced levels mRNA PTP1B protein, in-vitro assays function associated impaired negative regulation signalling. haploinsufficiency causes IFN-driven autoinflammatory encephalopathy. Notably, some stabilisation, even recovery, treatment, others, appeared be responsive immune suppression. Prospective studies are needed safety efficacy specific suppression approaches population. UK Medical Research Council, European Agence Nationale la Recherche.

Language: Английский

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The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings

The American Journal of Human Genetics, Journal Year: 2023, Volume and Issue: 110(9), P. 1482 - 1495

Published: Aug. 30, 2023

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is paramount importance with growing availability genetic testing. We estimated through large-scale analyses individuals referred for diagnostic sequencing hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated (DCM; 2,564 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank gnomAD). generated updated prevalence estimates HCM (1:543) DCM (1:220). In aggregate, by late adulthood rare, (23% HCM, 35% DCM) likely (7% 10% was substantial dominant (CM). Penetrance significantly higher variant subgroups annotated loss function or ultra-rare males compared to females in HCM-associated genes. variant-specific 316 recurrent most be SFs (found 51% HCM- 17% DCM-affected individuals). 49 were observed at least ten times (14% individuals) Median 14.6% (±14.4% SD). explore age, sex, ancestry simulate impact including future cohorts. This dataset reports individual scale will inform management undergoing screening SFs. While had low costs harms are unclear, some highly penetrant may benefit

Language: Английский

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Challenges of using whole genome sequencing in population newborn screening

BMJ, Journal Year: 2024, Volume and Issue: unknown, P. e077060 - e077060

Published: March 5, 2024

Rachel Horton and colleagues argue that making sense of genomic variation in newborn babies is difficult, so the UK Generation Study will analyse only a tiny proportion genome. Why then it collecting entire genomes?

Language: Английский

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Hereditary Breast Cancer: Comprehensive Risk Assessment and Prevention Strategies

Genes, Journal Year: 2025, Volume and Issue: 16(1), P. 82 - 82

Published: Jan. 13, 2025

Women carrying pathogenic/likely pathogenic (P/LP) variants in moderate- or high-penetrance genes have an increased risk of developing breast cancer. However, most P/LP associated with cancer show incomplete penetrance. Age, gender, family history, polygenic risk, lifestyle, reproductive, hormonal, and environmental factors can affect the expressivity penetrance disease. there are gaps translating how individual genomic variation affects phenotypic presentation. The expansion criteria for genetic testing increasing utilization comprehensive panels may enhance identification individuals linked to hereditary Individualized assessment could facilitate implementation personalized risk-reduction strategies these individuals. Preventive interventions encompass lifestyle modifications, chemoprevention, enhanced surveillance through imaging, risk-reducing surgeries. This review addresses current literature’s inconsistencies limitations, particularly regarding intensity preventive women genes. In addition, it synthesizes latest evidence on primary secondary prevention at high

Language: Английский

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Genetic insights into non-obstructive azoospermia: Implications for diagnosis and TESE outcomes

Journal of Assisted Reproduction and Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 11, 2025

Language: Английский

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The common HAQ STING allele prevents clinical penetrance of COPA syndrome

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(4)

Published: Feb. 27, 2025

COPA syndrome, an autosomal-dominant inborn error of immunity, is nonpenetrant in ∼20% individuals, with no known mediators protection. Recent studies implicate STING the pathogenesis syndrome. We show that common HAQ allele mediates complete clinical sequenced 35 individuals mutations, 26 affected patients and 9 unaffected carriers, finding co-segregation nonpenetrance. Exome sequencing identified only mutations comprising as variants shared by carriers absent patients. Experimentally, we found acts dominantly to dampen COPA-dependent signaling. Expressing patient cells rescued molecular phenotype Our study first report a well-tolerated mediating protection from severe genetic disorder. findings redefine diagnostic criteria for expose functional differences among alleles broad scientific implications, reveal potential universal gene therapy approach

Language: Английский

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