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Science (New York, N.Y.) Jun 2023We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes...
We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes implicated by genome-wide association studies confer ~10-fold larger effects than common variants in the same genes. Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared with common-variant polygenic risk scores, greatly improving the clinical utility of genetic-based risk prediction.
Topics: Humans; Genetic Predisposition to Disease; Genome-Wide Association Study; Multifactorial Inheritance; Mutation; Phenotype; Risk Factors; Penetrance
PubMed: 37262146
DOI: 10.1126/science.abo1131 -
Blood Aug 2023Systematic studies of germ line genetic predisposition to myeloid neoplasms in adult patients are still limited. In this work, we performed germ line and somatic...
Systematic studies of germ line genetic predisposition to myeloid neoplasms in adult patients are still limited. In this work, we performed germ line and somatic targeted sequencing in a cohort of adult patients with hypoplastic bone marrow (BM) to study germ line predisposition variants and their clinical correlates. The study population included 402 consecutive adult patients investigated for unexplained cytopenia and reduced age-adjusted BM cellularity. Germ line mutation analysis was performed using a panel of 60 genes, and variants were interpreted per the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines; somatic mutation analysis was performed using a panel of 54 genes. Of the 402 patients, 27 (6.7%) carried germ line variants that caused a predisposition syndrome/disorder. The most frequent disorders were DDX41-associated predisposition, Fanconi anemia, GATA2-deficiency syndrome, severe congenital neutropenia, RASopathy, and Diamond-Blackfan anemia. Eighteen of 27 patients (67%) with causative germ line genotype were diagnosed with myeloid neoplasm, and the remaining with cytopenia of undetermined significance. Patients with a predisposition syndrome/disorder were younger than the remaining patients and had a higher risk of severe or multiple cytopenias and advanced myeloid malignancy. In patients with myeloid neoplasm, causative germ line mutations were associated with increased risk of progression into acute myeloid leukemia. Family or personal history of cancer did not show significant association with a predisposition syndrome/disorder. The findings of this study unveil the spectrum, clinical expressivity, and prevalence of germ line predisposition mutations in an unselected cohort of adult patients with cytopenia and hypoplastic BM.
Topics: Humans; Leukemia, Myeloid; Genetic Predisposition to Disease; Clonal Hematopoiesis; Male; Female; Middle Aged; Anemia, Aplastic; Penetrance; Germ Cells; DNA Mutational Analysis
PubMed: 37216690
DOI: 10.1182/blood.2022019304 -
Advances in Experimental Medicine and... 2018The mode of inheritance is autosomal dominant (AD), with about 80% penetrance, but about half of cases have spontaneous mutations with no family history. (Review)
Review
The mode of inheritance is autosomal dominant (AD), with about 80% penetrance, but about half of cases have spontaneous mutations with no family history.
Topics: Humans; Mutation; Neurofibromatosis 1; Penetrance
PubMed: 30578517
DOI: 10.1007/978-3-319-95046-4_44 -
JAMA Jan 2022Population-based assessment of disease risk associated with gene variants informs clinical decisions and risk stratification approaches.
IMPORTANCE
Population-based assessment of disease risk associated with gene variants informs clinical decisions and risk stratification approaches.
OBJECTIVE
To evaluate the population-based disease risk of clinical variants in known disease predisposition genes.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study included 72 434 individuals with 37 780 clinical variants who were enrolled in the BioMe Biobank from 2007 onwards with follow-up until December 2020 and the UK Biobank from 2006 to 2010 with follow-up until June 2020. Participants had linked exome and electronic health record data, were older than 20 years, and were of diverse ancestral backgrounds.
EXPOSURES
Variants previously reported as pathogenic or predicted to cause a loss of protein function by bioinformatic algorithms (pathogenic/loss-of-function variants).
MAIN OUTCOMES AND MEASURES
The primary outcome was the disease risk associated with clinical variants. The risk difference (RD) between the prevalence of disease in individuals with a variant allele (penetrance) vs in individuals with a normal allele was measured.
RESULTS
Among 72 434 study participants, 43 395 were from the UK Biobank (mean [SD] age, 57 [8.0] years; 24 065 [55%] women; 2948 [7%] non-European) and 29 039 were from the BioMe Biobank (mean [SD] age, 56 [16] years; 17 355 [60%] women; 19 663 [68%] non-European). Of 5360 pathogenic/loss-of-function variants, 4795 (89%) were associated with an RD less than or equal to 0.05. Mean penetrance was 6.9% (95% CI, 6.0%-7.8%) for pathogenic variants and 0.85% (95% CI, 0.76%-0.95%) for benign variants reported in ClinVar (difference, 6.0 [95% CI, 5.6-6.4] percentage points), with a median of 0% for both groups due to large numbers of nonpenetrant variants. Penetrance of pathogenic/loss-of-function variants for late-onset diseases was modified by age: mean penetrance was 10.3% (95% CI, 9.0%-11.6%) in individuals 70 years or older and 8.5% (95% CI, 7.9%-9.1%) in individuals 20 years or older (difference, 1.8 [95% CI, 0.40-3.3] percentage points). Penetrance of pathogenic/loss-of-function variants was heterogeneous even in known disease predisposition genes, including BRCA1 (mean [range], 38% [0%-100%]), BRCA2 (mean [range], 38% [0%-100%]), and PALB2 (mean [range], 26% [0%-100%]).
CONCLUSIONS AND RELEVANCE
In 2 large biobank cohorts, the estimated penetrance of pathogenic/loss-of-function variants was variable but generally low. Further research of population-based penetrance is needed to refine variant interpretation and clinical evaluation of individuals with these variant alleles.
Topics: Aged; Biological Specimen Banks; Cohort Studies; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Loss of Function Mutation; Male; Mutation; Penetrance; United Kingdom
PubMed: 35076666
DOI: 10.1001/jama.2021.23686 -
Clinical and Experimental Dermatology Apr 2021Vascular malformations (VMs) are caused by localized defects of vascular development. Most VMs are due to sporadic, postzygotic mutations, while some are the result of... (Review)
Review
Vascular malformations (VMs) are caused by localized defects of vascular development. Most VMs are due to sporadic, postzygotic mutations, while some are the result of autosomal dominant germline mutations. Genotype-phenotype correlation is influenced by many factors. Individual genes can induce different phenotypes (pleiotropy), and similar phenotypes can be due to different genes/mutations (redundancy). The phenotypic spectrum of somatic mutations is wide, and depends on variant allele frequency, timing during embryogenesis, cell type(s) involved and type of mutation. The phenotype of germline mutations is determined by penetrance and expressivity, and is influenced by epigenetic factors (DNA methylation, histone modification) or 'second-hit' somatic mutations. Except for disorders with pathognomonic phenotypes such as Proteus syndrome or a characteristic constellation of symptoms such as CLOVES [congenital lipomatous (fatty) overgrowth, vascular malformations, epidermal naevi and scoliosis/skeletal/spinal anomalies] or PIK3CA-related overgrowth spectrum syndrome, differential diagnosis of VM is therefore difficult. It will be greatly facilitated with increasing analytic sensitivity of sequencing techniques such as next-generation sequencing. High-sensitivity molecular techniques are a prerequisite for targeted pharmacotherapy, i.e. selective therapeutic inhibition of activating mutations underlying VM, which has shown promising results in preliminary studies.
Topics: Epigenesis, Genetic; Genes, Dominant; Genotype; Germ-Line Mutation; Humans; Mutation; Penetrance; Phenotype; Vascular Malformations
PubMed: 33368487
DOI: 10.1111/ced.14513 -
Genes Oct 2020Inherited retinal diseases (IRDs) are a diverse and variable group of rare human disorders [...].
Inherited retinal diseases (IRDs) are a diverse and variable group of rare human disorders [...].
Topics: Gene Expression; Genetic Association Studies; Genetic Variation; Genetics, Population; Genotype; Humans; Penetrance; Phenotype; Retinal Diseases
PubMed: 33137882
DOI: 10.3390/genes11111274 -
Genetics in Medicine : Official Journal... Dec 2023Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse...
PURPOSE
Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYK variants.
METHODS
We phenotypically characterized Dstyk knockout mice of 3 separate inbred backgrounds and re-analyzed the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to as "SSV" below). DSTYK loss of function (LOF) and SSVs were annotated in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis vs controls. A phenome-wide association study analysis was also performed using United Kingdom Biobank (UKBB) data.
RESULTS
Results demonstrate ∼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk mice. Phenotypic penetrance increased to ∼40% in C3H/HeJ mutants, with mild-to-moderate severity. Re-analysis of the original family segregating the rare SSV showed low penetrance (43.8%) and no alternative genetic causes for CAKUT. LOF DSTYK variants burden showed significant excess for CAKUT and epilepsy vs controls and an exploratory phenome-wide association study supported association with neurological disorders.
CONCLUSION
These data support causality for DSTYK LOF variants and highlights the need for large-scale sequencing studies (here >200,000 cases) to accurately assess causality for genes and variants to lowly penetrant traits with common population prevalence.
Topics: Animals; Mice; Humans; Penetrance; Mice, Inbred C3H; Mice, Inbred C57BL; Urinary Tract; Urogenital Abnormalities; Kidney; Risk Factors; Epilepsy; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37746849
DOI: 10.1016/j.gim.2023.100983 -
Nature Communications Dec 2023Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and...
Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and COL4A-associated nephropathy (COL4A-AN) represent the most common forms of monogenic kidney diseases. These disorders have incomplete penetrance and variable expressivity, and we hypothesize that polygenic factors explain some of this variability. By combining SNP array, exome/genome sequence, and electronic health record data from the UK Biobank and All-of-Us cohorts, we demonstrate that the genome-wide polygenic score (GPS) significantly predicts CKD among ADPKD monogenic variant carriers. Compared to the middle tertile of the GPS for noncarriers, ADPKD variant carriers in the top tertile have a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile have only a 3-fold increased risk of CKD. Similarly, the GPS significantly predicts CKD in COL4A-AN carriers. The carriers in the top tertile of the GPS have a 2.5-fold higher risk of CKD, while the risk for carriers in the bottom tertile is not different from the average population risk. These results suggest that accounting for polygenic risk improves risk stratification in monogenic kidney disease.
Topics: Humans; Penetrance; Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic; Multifactorial Inheritance; Risk Factors
PubMed: 38097619
DOI: 10.1038/s41467-023-43878-9 -
Reviews in Endocrine & Metabolic... Aug 2023Monogenic Forms of Diabetes (MFD) account for about 3% of all diabetes, and their accurate diagnosis often results in life-changing therapeutic reassignment for the... (Review)
Review
Monogenic Forms of Diabetes (MFD) account for about 3% of all diabetes, and their accurate diagnosis often results in life-changing therapeutic reassignment for the patients. Like other Mendelian diseases, reduced penetrance and variable expressivity are often seen in several different types of MFD, where symptoms develop only in a portion of the persons who carry the pathogenic variant or vary widely in symptom severity and age of onset. This complicates diagnosis and disease management in MFD. In addition to its clinical importance, knowledge of genetic modifiers that confer penetrance and expressivity variability opens possibilities to identify protective genetic variants which may help probe the mechanisms of more common forms of diabetes and shed light in new therapeutic strategies. In this review, we will mainly address penetrance and expressivity variation in different types of MFD, factors that confer such variations and opportunities that come with such knowledge. Related literature was searched in PubMed, Medline and Embase. Papers with publication year from 1974 to 2023 are included. Data are either sourced from literatures or from OMIM, Clinvar and 1000 genome browser.
Topics: Humans; Penetrance; Diabetes Mellitus; Mutation
PubMed: 37165203
DOI: 10.1007/s11154-023-09809-1 -
European Journal of Medical Genetics Jun 2024Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants...
PURPOSE
Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants (SNV/MNVs) is usually based on the paradigm of complete penetrance.
METHOD
From 2020 to 2022, we proposed a collaboration study with the French molecular diagnosis for intellectual disability network. The aim was to recruit families for whom the index case, diagnosed with a neurodevelopmental disorder, was carrying a pathogenic or likely pathogenic variant for an OMIM morbid gene and inherited from an asymptomatic parent. Grandparents were analyzed when available for segregation study.
RESULTS
We identified 12 patients affected by a monogenic neurodevelopmental disorder caused by likely pathogenic or pathogenic variant (SNV/MNV) inherited from an asymptomatic parent. These genes were usually associated with de novo variants. The patients carried different variants (1 splice-site variant, 4 nonsense and 7 frameshift) in 11 genes: CAMTA1, MBD5, KMT2C, KMT2E, ZMIZ1, MN1, NDUFB11, CUL3, MED13, ARID2 and RERE. Grandparents have been tested in 6 families, and each time the variant was confirmed de novo in the healthy carrier parent.
CONCLUSION
Incomplete penetrance for SNV and MNV in neurodevelopmental disorders might be more frequent than previously thought. This point is crucial to consider for interpretation of variants, family investigation, genetic counseling, and prenatal diagnosis. Molecular mechanisms underlying this incomplete penetrance still need to be identified.
Topics: Humans; Penetrance; Female; Male; Neurodevelopmental Disorders; Pedigree; Child; Child, Preschool; Adult; Adolescent; Mutation; Infant
PubMed: 38453051
DOI: 10.1016/j.ejmg.2024.104932