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Nature Oct 2020De novo mutations in protein-coding genes are a well-established cause of developmental disorders. However, genes known to be associated with developmental disorders...
De novo mutations in protein-coding genes are a well-established cause of developmental disorders. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent-offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.
Topics: Cohort Studies; DNA Copy Number Variations; DNA Mutational Analysis; Data Analysis; Databases, Genetic; Datasets as Topic; Delivery of Health Care; Developmental Disabilities; Europe; Female; Genetic Diseases, Inborn; Germ-Line Mutation; Haploinsufficiency; Humans; Male; Mutation, Missense; Penetrance; Perinatal Death; Sample Size
PubMed: 33057194
DOI: 10.1038/s41586-020-2832-5 -
Genes Jun 2021The genetic landscape of Parkinson's disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants... (Review)
Review
The genetic landscape of Parkinson's disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design.
Topics: Genetic Predisposition to Disease; Humans; Mutation; Parkinson Disease; Penetrance; Polymorphism, Single Nucleotide
PubMed: 34208795
DOI: 10.3390/genes12071006 -
Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges.Genes Jun 2020Identification of the cystic fibrosis transmembrane conductance regulator gene and its numerous variants opened the way to fantastic breakthroughs in diagnosis,... (Review)
Review
Identification of the cystic fibrosis transmembrane conductance regulator gene and its numerous variants opened the way to fantastic breakthroughs in diagnosis, research and treatment of cystic fibrosis (CF). The current and future challenges of molecular diagnosis of CF and CFTR-related disorders and of genetic counseling are here reviewed. Technological advances have enabled to make a diagnosis of CF with a sensitivity of 99% by using next generation sequencing in a single step. The detection of heretofore unidentified variants and ethnic-specific variants remains challenging, especially for newborn screening (NBS), CF carrier testing and genotype-guided therapy. Among the criteria for assessing the impact of variants, population genetics data are insufficiently taken into account and the penetrance of CF associated with variants remains poorly known. The huge diversity of diagnostic and genetic counseling indications for studies makes assessment of variant disease-liability critical. This is especially discussed in the perspective of wide genome analyses for NBS and CF carrier screening in the general population, as future challenges.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Counseling; Genotype; Humans; Infant, Newborn; Neonatal Screening; Pathology, Molecular; Penetrance
PubMed: 32512765
DOI: 10.3390/genes11060619 -
American Journal of Human Genetics Nov 2022The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the...
The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%-97%). We highlight that pathogenic variants in HNF1A, HNF4A, and GCK are not ultra-rare in the population. For HNF1A and HNF4A, we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list.
Topics: Humans; Penetrance; Diabetes Mellitus, Type 2; Cohort Studies; Prevalence; Mutation; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 4
PubMed: 36257325
DOI: 10.1016/j.ajhg.2022.09.014 -
Genetics in Medicine : Official Journal... Mar 2024Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease...
PURPOSE
Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community.
METHODS
The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group.
RESULTS
We formally recognize risk alleles and low-penetrance variants as distinct variant classes from those causing highly penetrant disease that require special considerations regarding their clinical classification and reporting. First, we provide a preferred terminology for these variants. Second, we focus on risk alleles and detail considerations for reviewing relevant studies and present a framework for the classification these variants. Finally, we discuss considerations for clinical reporting of risk alleles.
CONCLUSION
These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.
Topics: Humans; Alleles; Genetic Variation; Penetrance; Gene Frequency
PubMed: 38054408
DOI: 10.1016/j.gim.2023.101036 -
Breast (Edinburgh, Scotland) Oct 2022Breast cancer risk associated with germline likely pathogenic/pathogenic variants (PV) varies by gene, often by penetrance (high >50% or moderate 20-50%), and specific... (Review)
Review
Breast cancer risk associated with germline likely pathogenic/pathogenic variants (PV) varies by gene, often by penetrance (high >50% or moderate 20-50%), and specific locus. Germline PVs in BRCA1 and BRCA2 play important roles in the development of breast and ovarian cancer in particular, as well as in other cancers such as pancreatic and prostate cancers and melanoma. Recent studies suggest that other cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C and RAD51D confer differential risks of breast and other specific cancers. In the era of multigene panel testing, advances in next-generation sequencing technologies have notably reduced costs in the United States (US) and enabled sequencing of BRCA1/2 concomitantly with additional genes. The use of multigene-panel testing is beginning to expand in Europe as well. Further research into the clinical implications of variants in moderate penetrance genes, particularly in unaffected carriers, is needed for appropriate counselling and risk management with data-driven plans for surveillance and/or risk reduction. For individuals at high risk without any pathogenic or likely pathogenic variant in cancer susceptibility genes or some carriers of pathogenic variants in moderate-risk genes such as ATM and CHEK2, polygenic risk scores offer promise to help stratify breast cancer risk and guide appropriate risk management options. Cancer patients whose tumours are driven by the loss of function of both copies of a predisposition gene may benefit from therapies targeting the biological alterations induced by the dysfunctional gene e.g. poly ADP ribose polymerase (PARP) inhibitors and other novel pathway agents in cancers with DNA repair deficiencies. A better understanding of mechanisms by which germline variants drive various malignancies may lead to improvements in both therapeutic and preventive management options.
Topics: Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms; Checkpoint Kinase 2; DNA-Binding Proteins; Female; Genes, BRCA2; Genetic Predisposition to Disease; Genetic Testing; Germ-Line Mutation; Humans; Male; Penetrance; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases
PubMed: 35772246
DOI: 10.1016/j.breast.2022.06.003 -
Circulation Research May 2021Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium characterized by a hypertrophic left ventricle with a preserved or increased ejection fraction....
Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium characterized by a hypertrophic left ventricle with a preserved or increased ejection fraction. Cardiac hypertrophy is often asymmetrical, which is associated with left ventricular outflow tract obstruction. Myocyte hypertrophy, disarray, and myocardial fibrosis constitute the histological features of HCM. HCM is a relatively benign disease but an important cause of sudden cardiac death in the young and heart failure in the elderly. Pathogenic variants (PVs) in genes encoding protein constituents of the sarcomeres are the main causes of HCM. PVs exhibit a gradient of effect sizes, as reflected in their penetrance and variable phenotypic expression of HCM. and , encoding β-myosin heavy chain and myosin binding protein C, respectively, are the two most common causal genes and responsible for ≈40% of all HCM cases but a higher percentage of HCM in large families. PVs in genes encoding protein components of the thin filaments are responsible for ≈5% of the HCM cases. Whereas pathogenicity of the genetic variants in large families has been firmly established, ascertainment causality of the PVs in small families and sporadic cases is challenging. In the latter category, PVs are best considered as probabilistic determinants of HCM. Deciphering the genetic basis of HCM has enabled routine genetic testing and has partially elucidated the underpinning mechanism of HCM as increased number of the myosin molecules that are strongly bound to actin. The discoveries have led to the development of mavacamten that targets binding of the myosin molecule to actin filaments and imparts beneficial clinical effects. In the coming years, the yield of the genetic testing is expected to be improved and the so-called missing causal gene be identified. The advances are also expected to enable development of additional specific therapies and editing of the mutations in HCM.
Topics: Calcium; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Carrier Proteins; Death, Sudden, Cardiac; Genetic Testing; Homeostasis; Humans; Hypertrophy, Left Ventricular; Mutation; Myosin Heavy Chains; Myosin Light Chains; Penetrance; Phenotype; Sarcomeres; Stroke Volume; Ventricular Outflow Obstruction
PubMed: 33983830
DOI: 10.1161/CIRCRESAHA.121.318346 -
American Journal of Human Genetics Sep 2023Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing....
Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.
Topics: Female; Male; Humans; Adult; Penetrance; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Cardiomyopathy, Dilated; Gene Frequency
PubMed: 37652022
DOI: 10.1016/j.ajhg.2023.08.003 -
Gastroenterology Mar 2022Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of individual genes in pathways and networks safeguarding immune tolerance and gut...
BACKGROUND & AIMS
Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of individual genes in pathways and networks safeguarding immune tolerance and gut homeostasis.
METHODS
To build a taxonomy model, we assessed 165 disorders. Genes were prioritized based on penetrance of IBD and disease phenotypes were integrated with multi-omics datasets. Monogenic IBD genes were classified by (1) overlapping syndromic features, (2) response to hematopoietic stem cell transplantation, (3) bulk RNA-sequencing of 32 tissues, (4) single-cell RNA-sequencing of >50 cell subsets from the intestine of healthy individuals and patients with IBD (pediatric and adult), and (5) proteomes of 43 immune subsets. The model was validated by addition of newly identified monogenic IBD defects. As a proof-of-concept, we explore the intersection between immunometabolism and antimicrobial activity for a group of disorders (G6PC3/SLC37A4).
RESULTS
Our quantitative integrated taxonomy defines the cellular landscape of monogenic IBD gene expression across 102 genes with high and moderate penetrance (81 in the model set and 21 genes in the validation set). We illustrate distinct cellular networks, highlight expression profiles across understudied cell types (e.g., CD8 T cells, neutrophils, epithelial subsets, and endothelial cells) and define genotype-phenotype associations (perianal disease and defective antimicrobial activity). We illustrate processes and pathways shared across cellular compartments and phenotypic groups and highlight cellular immunometabolism with mammalian target of rapamycin activation as one of the converging pathways. There is an overlap of genes and enriched cell-specific expression between monogenic and polygenic IBD.
CONCLUSION
Our taxonomy integrates genetic, clinical and multi-omic data; providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses.
Topics: Age of Onset; Antiporters; Cells, Cultured; Classification; Gene Expression Profiling; Genetic Association Studies; Genotype; Glucose-6-Phosphatase; Glucose-6-Phosphate; Humans; Inflammatory Bowel Diseases; Macrophages; Metabolomics; Monosaccharide Transport Proteins; Penetrance; Phenotype; Signal Transduction
PubMed: 34780721
DOI: 10.1053/j.gastro.2021.11.014 -
Nature Oct 2020The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the...
The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
Topics: Aged; Bone Density; Collagen Type VI; Databases, Genetic; Demography; Exome; Female; Genes, BRCA1; Genes, BRCA2; Genotype; Humans; Ion Channels; Loss of Function Mutation; Male; Middle Aged; Neoplasms; Penetrance; Peptide Fragments; Phenotype; United Kingdom; Varicose Veins; Exome Sequencing; ras GTPase-Activating Proteins
PubMed: 33087929
DOI: 10.1038/s41586-020-2853-0