-
Genetics in Medicine : Official Journal... Jun 2013Although an increasing number of copy-number variations are being identified as susceptibility loci for a variety of pediatric diseases, the penetrance of these...
PURPOSE
Although an increasing number of copy-number variations are being identified as susceptibility loci for a variety of pediatric diseases, the penetrance of these copy-number variations remains mostly unknown. This poses challenges for counseling, both for recurrence risks and prenatal diagnosis. We sought to provide empiric estimates for penetrance for some of these recurrent, disease-susceptibility loci.
METHODS
We conducted a Bayesian analysis, based on the copy-number variation frequencies in control populations (n = 22,246) and in our database of >48,000 postnatal microarray-based comparative genomic hybridization samples. The background risk for congenital anomalies/developmental delay/intellectual disability was assumed to be ~5%. Copy-number variations studied were 1q21.1 proximal duplications, 1q21.1 distal deletions and duplications, 15q11.2 deletions, 16p13.11 deletions, 16p12.1 deletions, 16p11.2 proximal and distal deletions and duplications, 17q12 deletions and duplications, and 22q11.21 duplications.
RESULTS
Estimates for the risk of an abnormal phenotype ranged from 10.4% for 15q11.2 deletions to 62.4% for distal 16p11.2 deletions.
CONCLUSION
This model can be used to provide more precise estimates for the chance of an abnormal phenotype for many copy-number variations encountered in the prenatal setting. By providing the penetrance, additional, critical information can be given to prospective parents in the genetic counseling session.
Topics: Algorithms; Bayes Theorem; Case-Control Studies; DNA Copy Number Variations; Genetic Loci; Genetic Predisposition to Disease; Genotype; Humans; Models, Genetic; Penetrance
PubMed: 23258348
DOI: 10.1038/gim.2012.164 -
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 -
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 -
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 -
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 -
Trends in Cancer Nov 2018Inherited diseases are not always expressed in the same way in every individual that carries the same variant in a disease-causing gene. This phenomenon is known as... (Review)
Review
Inherited diseases are not always expressed in the same way in every individual that carries the same variant in a disease-causing gene. This phenomenon is known as reduced or incomplete penetrance. Variable and incomplete penetrance may explain why inherited diseases are occasionally transmitted through unaffected parents, but also why clinically healthy individuals can carry potentially pathogenic variants without expressing features of the disease. Here, we will provide an overview of factors that play a fundamental role in the concept of penetrance and expressivity of cancer predisposing genes in children with malignancies. These findings are important to understand the complexity of inherited diseases and cancer development and to improve genetic counselling for the affected families.
Topics: Genetic Predisposition to Disease; Genetic Variation; Humans; Neoplasms; Penetrance; Risk Factors; Syndrome
PubMed: 30352675
DOI: 10.1016/j.trecan.2018.09.002 -
Annals of Surgical Oncology Mar 2023Gastric adenocarcinoma (GAC) is the fifth most common cancer in the world, and the presence of germline pathogenic variants has been linked with approximately 5% of... (Review)
Review
BACKGROUND
Gastric adenocarcinoma (GAC) is the fifth most common cancer in the world, and the presence of germline pathogenic variants has been linked with approximately 5% of gastric cancer diagnoses. Multiple GAC susceptibility genes have been identified, but information regarding the risk associated with pathogenic variants in these genes remains obscure. We conducted a systematic review of existing studies reporting the penetrance of GAC susceptibility genes.
METHODS
A structured search query was devised to identify GAC-related papers indexed in MEDLINE/PubMed. A semi-automated natural language processing algorithm was applied to identify penetrance papers for inclusion. Original studies reporting the penetrance of GAC were included and the full-text articles were independently reviewed. Summary statistics, effect estimates, and precision parameters from these studies were compiled into a table using a predetermined format to ensure consistency.
RESULTS
Forty-five studies were identified reporting the penetrance of GAC among patients harboring mutations in 13 different genes: APC, ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, PMS2, MUTYH-Monoallelic, NBN, and STK11.
CONCLUSION
Our systematic review highlights the importance of testing for germline pathogenic variants in patients before the development of GAC. Management of patients who harbor a pathogenic mutation is multifactorial, and clinicians should consider cancer risk for each applicable gene-cancer association throughout the screening and management process. The scarcity of studies we found investigating the risk of GAC among patients with pathogenic variants in GAC susceptibility genes highlights the need for more investigations that focus on producing robust risk estimates for gene-cancer associations.
Topics: Humans; Penetrance; Stomach Neoplasms; Genetic Predisposition to Disease; Mutation; Germ-Line Mutation; Adenocarcinoma
PubMed: 36528743
DOI: 10.1245/s10434-022-12829-x -
Human Genetics Jun 2020Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are... (Review)
Review
Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are classically considered as Mendelian disorders with complete penetrance, we now understand that absent or partial clinical disease is often noted in individuals harboring disease-causing genotypes. Despite the frequency of incomplete penetrance in PID, no conceptual framework exists to categorize and explain these occurrences. Here, by reviewing decades of reports on incomplete penetrance in PID we identify four recurrent themes of incomplete penetrance, namely genotype quality, (epi)genetic modification, environmental influence, and mosaicism. For each of these principles, we review what is known, underscore what remains unknown, and propose future experimental approaches to fill the gaps in our understanding. Although the content herein relates specifically to inborn errors of immunity, the concepts are generalizable across genetic diseases.
Topics: Epigenesis, Genetic; Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Variation; Humans; Mosaicism; Penetrance; Primary Immunodeficiency Diseases
PubMed: 32067110
DOI: 10.1007/s00439-020-02131-9 -
Endocrinology, Diabetes & Metabolism Nov 2022Numerous genes have been proposed as causal for maturity-onset diabetes of the young (MODY). Scoring systems to annotate mutation pathogenicity have been widely used;...
AIMS
Numerous genes have been proposed as causal for maturity-onset diabetes of the young (MODY). Scoring systems to annotate mutation pathogenicity have been widely used; however, statistical evidence for being a highly penetrant MODY gene has not been well-established.
METHODS
Participants were from the UK Biobank with whole-exome sequencing data, including 14,622 with and 185,509 without diagnosis of diabetes. Pathogenic/likely pathogenic (P/LP) mutations in 14 reported and 3 possible MODY genes were annotated using American College of Medical Genetics criteria. Evidence for being a high-penetrant MODY gene used two statistical criteria: frequency of aggregate P/LP mutations in each gene are (1) significantly more common in participants with a diagnosis of diabetes than without using the SKAT-O (p < .05) and (2) lower than the maximum credible frequency in the general population.
RESULTS
Among the 17 genes, 6 (GCK, HNF1A, HNF4A, NEUROD1, KCNJ11 and HNF1B) met both criteria, 7 (ABCC8, KLF11, RFX6, PCBD1, WFS1, INS and PDX1) met only one criterion, and the remaining 4 (CEL, BLK, APPL1 and PAX4) failed both criteria, and were classified as 'consistent', 'inconclusive' and 'inconsistent' for being highly penetrant diabetes genes, respectively. Diabetes participants with mutations in the 'consistent' genes had clinical presentations that were most consistent with MODY. In contrast, the 'inconclusive' and 'inconsistent' genes did not differ clinically from non-carriers in diabetes-related characteristics.
CONCLUSIONS
Data from a large population-based study provided novel statistical evidence to identify 6 MODY genes as consistent with being highly penetrant. These results have potential implications for interpreting genetic testing results and clinical diagnosis of MODY.
Topics: Humans; Penetrance; Diabetes Mellitus, Type 2; Mutation; Cohort Studies
PubMed: 36208030
DOI: 10.1002/edm2.372 -
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