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Genetics in Medicine : Official Journal... Jul 2013In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for...
In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including an open forum at the 2012 Annual Meeting and review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. The ACMG recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the "normal" of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples. We recognize that there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.
Topics: Exome; Genetics, Medical; Genome, Human; Humans; Incidental Findings; Patient Preference; Penetrance
PubMed: 23788249
DOI: 10.1038/gim.2013.73 -
Annals of Surgical Oncology Sep 2022Risk-reducing mastectomy is considered a safe and effective surgical procedure in high-risk individuals with BRCA1/2 germline mutations. Multigene panels identify women... (Review)
Review
Risk-reducing mastectomy is considered a safe and effective surgical procedure in high-risk individuals with BRCA1/2 germline mutations. Multigene panels identify women with alterations in breast cancer susceptibility genes other than BRCA1/2. International guidelines classify these genes as high-, moderate-, and low-penetrance based on their associated relative risk for breast cancer. Classification of specific genes is not always concordant among guidelines, and the indications for risk-reducing mastectomy are not defined. In this opinion paper, we review some considerations to clarify these controversial points.
Topics: Breast Neoplasms; Female; Genes, BRCA1; Genes, BRCA2; Genetic Predisposition to Disease; Humans; Mastectomy; Mutation; Penetrance
PubMed: 35604619
DOI: 10.1245/s10434-022-11913-6 -
Frontiers of Medicine Dec 2021Proline-rich transmembrane protein 2 (PRRT2) is the leading cause of paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), and infantile...
Proline-rich transmembrane protein 2 (PRRT2) is the leading cause of paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), and infantile convulsions with choreoathetosis (ICCA). Reduced penetrance of PRRT2 has been observed in previous studies, whereas the exact penetrance has not been evaluated well. The objective of this study was to estimate the penetrance of PRRT2 and determine its influencing factors. We screened 222 PKD index patients and their available relatives, identified 39 families with pathogenic or likely pathogenic (P/LP) PRRT2 variants via Sanger sequencing, and obtained 184 PKD/BFIE/ICCA families with P/LP PRRT2 variants from the literature. Penetrance was estimated as the proportion of affected variant carriers. PRRT2 penetrance estimate was 77.6% (95% confidence interval (CI) 74.5%-80.7%) in relatives and 74.5% (95% CI 70.2%-78.8%) in obligate carriers. In addition, we first observed that penetrance was higher in truncated than in non-truncated variants (75.8% versus 50.0%, P = 0.01), higher in Asian than in Caucasian carriers (81.5% versus 68.5%, P = 0.004), and exhibited no difference in gender or parental transmission. Our results are meaningful for genetic counseling, implying that approximately three-quarters of PRRT2 variant carriers will develop PRRT2-related disorders, with patients from Asia or carrying truncated variants at a higher risk.
Topics: Dystonia; Epilepsy, Benign Neonatal; Humans; Membrane Proteins; Mutation; Nerve Tissue Proteins; Pedigree; Penetrance; Seizures
PubMed: 34825340
DOI: 10.1007/s11684-021-0863-4 -
Anesthesiology Nov 2019
Topics: Genetic Predisposition to Disease; Humans; Malignant Hyperthermia; Mutation; Penetrance; Ryanodine Receptor Calcium Release Channel
PubMed: 31335544
DOI: 10.1097/ALN.0000000000002884 -
Annual Review of Genomics and Human... 2009Genetic testing holds great promise as a screening tool to identify persons at risk for a disease at the presymptomatic stage. However, the complexities of gene-disease... (Review)
Review
Genetic testing holds great promise as a screening tool to identify persons at risk for a disease at the presymptomatic stage. However, the complexities of gene-disease associations, even in single-gene diseases, pose important challenges. These challenges include defining the role of screening for mutations that have low penetrance, which cause disease in only a minority of patients with the genotype. On the basis of the high rate of false positives, medical expert panels to date have largely discouraged genetic testing for low-penetrance mutations for use in population-based screening, although official recommendations currently exist for only a few genes. We examine the relatively limited experience of population-based screening for low-penetrance mutations in clinical settings to date, including screening for glucose-6-phosphate dehydrogenase deficiency and a low-penetrance mutation for cystic fibrosis in newborns, type 1 Gaucher disease carrier screening, and screening for adults for hemochromatosis. The trend toward recommending restricting use of these tests by medical experts is contrasted with the growing availability of genetic tests, including those for low-penetrance mutations, through direct-to-consumer outlets.
Topics: Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; History, 20th Century; Humans; Mutation; Open Reading Frames; Penetrance
PubMed: 19715441
DOI: 10.1146/annurev.genom.9.081307.164255 -
Current Neurology and Neuroscience... Nov 2013The dystonias comprise a group of syndromes characterized by prolonged involuntary muscle contractions resulting in repetitive movements and abnormal postures. Primary... (Review)
Review
The dystonias comprise a group of syndromes characterized by prolonged involuntary muscle contractions resulting in repetitive movements and abnormal postures. Primary dystonia has been associated with over 14 different genotypes, most of which follow an autosomal dominant inheritance pattern with reduced penetrance. Independent of etiology, the disease is characterized by extensive variability in disease phenotype and clinical severity. Recent neuroimaging studies investigating this phenomenon in manifesting and non-manifesting genetic carriers of dystonia have discovered microstructural integrity differences in the cerebello-thalamo-cortical tract in both groups related to disease penetrance. Further study suggests these differences to be specific to subrolandic white matter regions somatotopically related to clinical phenotype. Clinical severity was correlated to the degree of microstructural change. These findings suggest a mechanism for the penetrance and clinical variability observed in dystonia and may represent a novel therapeutic target for patients with refractory limb symptoms.
Topics: Animals; Comprehension; Dystonia; Humans; Penetrance; Phenotype
PubMed: 24114145
DOI: 10.1007/s11910-013-0401-0 -
Current Opinion in Oncology Nov 2022We summarize recent evidence regarding commonly tested breast cancer susceptibility genes and review indications derived from recently published guidelines regarding... (Review)
Review
PURPOSE OF REVIEW
We summarize recent evidence regarding commonly tested breast cancer susceptibility genes and review indications derived from recently published guidelines regarding management of carriers affected by early breast cancer (BC).
RECENT FINDINGS
Management of affected women with a known genetic predisposition to BC was matter of debate at the most relevant international conferences, such as St. Gallen International Consensus Conference and San Antonio Breast Cancer Symposium held both in 2021. At the same time, a joint Experts Panel from American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Surgical Oncology (ASCO/ASTRO/SSO) convened to develop recommendations to support clinical decision-making in this specific setting and results about administration of new systemic therapies such as poly adenosine diphosphate-ribose polymerase (PARP) inhibitors became available.
SUMMARY
Population of patients affected by BC and carriers of mutations in susceptibility genes is progressively increasing, but new mutations identified do not always have a clear clinical impact.To date, we have data to support consideration of different local management choices for affected patients carrying specific mutations, but some issues especially relating to breast-conserving surgery or administration of radiotherapy in these patients, still need to be better addressed. Opinions about the best way to treat these patients are still heterogeneous and information deriving from different sources seems to be conflicting at times. Our purpose is to offer a synopsis of the different evidence available that may be helpful in clinical decision making.
Topics: Adenosine Diphosphate; Breast Neoplasms; Female; Germ-Line Mutation; Humans; Penetrance; Poly(ADP-ribose) Polymerase Inhibitors; Ribose
PubMed: 36170166
DOI: 10.1097/CCO.0000000000000872 -
Genetics Aug 2023Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity...
Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.
Topics: Penetrance; RNA Splicing; Exons; Genotype; RNA, Messenger; RNA Splice Sites; Alternative Splicing
PubMed: 37348055
DOI: 10.1093/genetics/iyad115 -
Human Mutation Nov 2020The penetrance of the p.[Met694Val];[Met694Val] genotype of pyrin in adult familial Mediterranean fever (FMF) patients is close to 100%. Disease penetrance of the...
The penetrance of the p.[Met694Val];[Met694Val] genotype of pyrin in adult familial Mediterranean fever (FMF) patients is close to 100%. Disease penetrance of the p.[Met694Val];[Glu148Gln] genotype (M694V/E148Q), and the heterozygous p.[Met694Val];[=] genotype is unknown. A difference in the penetrance of the latter two may indicate functionality for the p.Glu148Gln variant. We performed a penetrance estimation study using controls and patients of North African Jewish (NAJ) decent. FMF in this population is highly prevalent and mutation frequencies are well known. The ratio between the calculated frequencies of the three genotypes obtained from the control cohort and the actual frequency obtained from the patient cohort were used to determine the penetrance of p.[Met694Val];[Glu148Gln] and p.[Met694Val];[=]. We found a penetrance of 0.135 and 0.008 for p.[Met694Val];[Glu148Gln] and p.[Met694Val];[=], respectively. Thus, the penetrance of p.[Met694Val];[Glu148Gln] is more than 17 times higher than p.[Met694Val];[=], indicating an active role for p.Glu148Gln when combined with p.Met694Val.
Topics: Africa, Northern; Cohort Studies; Familial Mediterranean Fever; Genotype; Heterozygote; Humans; Jews; Penetrance; Pyrin
PubMed: 32741030
DOI: 10.1002/humu.24090 -
Genome Medicine Dec 2022Genetic penetrance is the probability of a phenotype when harbouring a particular pathogenic variant. Accurate penetrance estimates are important across biomedical...
BACKGROUND
Genetic penetrance is the probability of a phenotype when harbouring a particular pathogenic variant. Accurate penetrance estimates are important across biomedical fields including genetic counselling, disease research, and gene therapy. However, existing approaches for penetrance estimation require, for instance, large family pedigrees or availability of large databases of people affected and not affected by a disease.
METHODS
We present a method for penetrance estimation in autosomal dominant phenotypes. It examines the distribution of a variant among people affected (cases) and unaffected (controls) by a phenotype within population-scale data and can be operated using cases only by considering family disease history. It is validated through simulation studies and candidate variant-disease case studies.
RESULTS
Our method yields penetrance estimates which align with those obtained via existing approaches in the Parkinson's disease LRRK2 gene and pulmonary arterial hypertension BMPR2 gene case studies. In the amyotrophic lateral sclerosis case studies, examining penetrance for variants in the SOD1 and C9orf72 genes, we make novel penetrance estimates which correspond closely to understanding of the disease.
CONCLUSIONS
The present approach broadens the spectrum of traits for which reliable penetrance estimates can be obtained. It has substantial utility for facilitating the characterisation of disease risks associated with rare variants with an autosomal dominant inheritance pattern. The yielded estimates avoid any kinship-specific effects and can circumvent ascertainment biases common when sampling rare variants among control populations.
Topics: Humans; Penetrance; Pedigree; Amyotrophic Lateral Sclerosis; Phenotype; Family Characteristics
PubMed: 36522764
DOI: 10.1186/s13073-022-01142-7