-
Genes Jul 2023Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women worldwide. Since the discovery of the highly penetrant susceptibility genes...
Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women worldwide. Since the discovery of the highly penetrant susceptibility genes and , many other predisposition genes that confer a moderate risk of BC have been identified. Advances in multigene panel testing have allowed the simultaneous sequencing of with these genes in a cost-effective way. Germline DNA from 521 cases with BC fulfilling diagnostic criteria for hereditary BC were screened with multigene NGS testing. Pathogenic (PVs) and likely pathogenic (LPVs) variants in moderate penetrance genes were identified in 15 out of 521 patients (2.9%), including 2 missense, 7 non-sense, 1 indel, and 3 splice variants, as well as two different exon deletions, as follows: ( = 4), ( = 5), ( = 2), ( = 1), and ( = 3). Moreover, the segregation analysis of PVs and LPVs into first-degree relatives allowed the detection of variant carriers diagnosed with in situ melanoma and clear cell renal cell carcinoma (ccRCC), respectively. Extended testing beyond identified PVs and LPVs in a further 2.9% of BC patients. In conclusion, panel testing yields more accurate genetic information for appropriate counselling, risk management, and preventive options than assessing alone.
Topics: Humans; Female; Breast Neoplasms; BRCA1 Protein; Penetrance; BRCA2 Protein; Kidney Neoplasms
PubMed: 37628581
DOI: 10.3390/genes14081530 -
Obesity (Silver Spring, Md.) Jul 2022Obesity has emerged as a prominent risk factor for multiple serious disease states, including a variety of cancers, and is increasingly recognized as a primary...
OBJECTIVE
Obesity has emerged as a prominent risk factor for multiple serious disease states, including a variety of cancers, and is increasingly recognized as a primary contributor to preventable cancer risk. However, few studies of leukemia have been conducted in animal models of obesity. This study sought to characterize the impact of obesity, diet, and sex in a murine model of acute promyelocytic leukemia (APL).
METHODS
Male and female C57BL/6J.mCG mice, genetically predisposed to sporadic APL development, and C57BL/6J (wild type) mice were placed on either a high-fat diet (HFD) or a low-fat diet (LFD) for up to 500 days.
RESULTS
Relative to LFD-fed mice, HFD-fed animals displayed increased disease penetrance and shortened disease latency as indicated by accelerated disease onset. In addition, a diet-responsive sex difference in APL penetrance and incidence was identified, with LFD-fed male animals displaying increased penetrance and shortened latency relative to female counterparts. In contrast, both HFD-fed male and female mice displayed 100% disease penetrance and insignificant differences in disease latency, indicating that the sexual dimorphism was reduced through HFD feeding.
CONCLUSIONS
Obesity and obesogenic diet promote the development of APL in vivo, reducing sexual dimorphisms in disease latency and penetrance.
Topics: Animals; Diet, High-Fat; Female; Leukemia, Promyelocytic, Acute; Male; Mice; Mice, Inbred C57BL; Obesity; Penetrance; Sex Characteristics
PubMed: 35610936
DOI: 10.1002/oby.23435 -
Bulletin Du Cancer 2021Genetic predisposition has been always noted in the context of familial hematological malignancies. Epidemiological studies have provided evidence consisting of an... (Review)
Review
Genetic predisposition has been always noted in the context of familial hematological malignancies. Epidemiological studies have provided evidence consisting of an increased risk to develop blood cancer in relatives diagnosed with the same pathology and characterized by early age at diagnosis and higher severity compared to sporadic forms. With the emergence of new genomic testing approaches, the prevalence of familial aggregations of hematological malignancies seems to be under estimated. The heterogeneity of clinical features explains the wide number of genes' mutations reported to date and the variable penetrance of variants. Nevertheless, the genetic basis of familial hematological malignancies is still not well understood. Identifying the genetic background in familial aggregations provides a valuable tool for prognostic evaluation, personalized treatment and better genetic counseling in high-risk families. Herein, we provide an overview of genes reported in the last few years in association to hematological malignancies including familial form of Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, acute Myeloid Leukemia and acute Lymphoblastic Leukemia.
Topics: Age Factors; Family; Genetic Predisposition to Disease; Hematologic Neoplasms; Hodgkin Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Mutation; Penetrance; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis
PubMed: 34052033
DOI: 10.1016/j.bulcan.2021.03.013 -
Neurogastroenterology and Motility Nov 2019The objective of this mini-review is to provide insights on the advances in the understanding of the genetic variants associated with different manifestations of... (Review)
Review
The objective of this mini-review is to provide insights on the advances in the understanding of the genetic variants associated with different manifestations of Hirschsprung disease, which may present with a range of denervation from a short segment of colon to total colonic and small bowel or extensive aganglionosis. A recent article in this journal documented potential gene variants involved in long-segment Hirschsprung disease in 23 patients. Gene variants were identified using a 31-gene panel of genes related to Hirschsprung disease or enteric neural crest cell development, as previously reported in the literature. The study identified potentially harmful variants in eight genes across 13 patients, with a detection rate of 56.5% (13/23 patients). Five patients had pathologic variants in RET, NRG1, and L1CAM, and the remainder were considered variants of unknown significance. The authors attempted prenatal diagnosis of Hirschsprung disease utilizing an amniocentesis sample obtained for advanced maternal age in a family with a known deleterious RET mutation, manifested in the father (long-segment Hirschsprung disease) and older daughter (total colonic aganglionosis). The fetus had the same RET variant but, after several years of follow-up, has not developed any symptoms of Hirschsprung disease, supporting the conclusion that this RET mutation is an autosomal dominant gene with incomplete penetrance. This experience suggests that genetic counseling is appropriate to carefully assess the justification of prenatal testing, especially, when the phenotype of long-segment Hirschsprung disease is so variable and the disease is potentially curable with surgery.
Topics: Female; Genetic Predisposition to Disease; Genetic Variation; Hirschsprung Disease; Humans; Penetrance; Pregnancy; Prenatal Diagnosis
PubMed: 31609069
DOI: 10.1111/nmo.13732 -
Current Opinion in Neurology Aug 2019Recent advances in genetic technologies allowed researchers to identify large numbers of candidate risk genes associated with autism spectrum disorder (ASD). Both... (Review)
Review
PURPOSE OF REVIEW
Recent advances in genetic technologies allowed researchers to identify large numbers of candidate risk genes associated with autism spectrum disorder (ASD). Both strongly penetrant rare variants and the accumulation of common variants with much weaker penetrance contribute to the cause of ASD. To identify the highly confident candidate genes, software and resources have been applied, and functional evaluation of the variants has provided further insights for ASD pathophysiology. These studies ultimately identify the molecular and circuit alteration underlying the behavioral abnormalities in ASD. In this review, we introduce the recent genetic and genomic findings and functional approaches for ASD variants providing a deeper understanding of the etiology of ASD.
RECENT FINDINGS
Integrated meta-analysis that recruited a larger number of ASD cases has helped to prioritize ASD candidate genes or genetic loci into highly confidence candidate genes for further investigation. Not only coding but also noncoding variants have been recently implicated to confer the risk of ASD. Functional approaches of genes or variants revealed the disruption of specific molecular pathways. Further studies combining ASD genetics and genomics with recent techniques in engineered mouse models show molecular and circuit mechanisms underlying the behavioral deficits in ASD.
SUMMARY
Advances in ASD genetics and the following functional studies provide significant insights into ASD pathophysiology at molecular and circuit levels.
Topics: Animals; Autism Spectrum Disorder; DNA Copy Number Variations; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Mice
PubMed: 31135459
DOI: 10.1097/WCO.0000000000000718 -
Breast Cancer Research and Treatment Jan 2022Several male breast cancer (MBC) susceptibility genes have been identified, but the MBC risk for individuals with a pathogenic variant in each of these genes (i.e.,... (Review)
Review
PURPOSE
Several male breast cancer (MBC) susceptibility genes have been identified, but the MBC risk for individuals with a pathogenic variant in each of these genes (i.e., penetrance) remains unclear. We conducted a systematic review of studies reporting the penetrance of MBC susceptibility genes to better summarize current estimates of penetrance.
METHODS
A search query was developed to identify MBC-related papers indexed in PubMed/MEDLINE. A validated natural language processing method was applied to identify papers reporting penetrance estimates. These penetrance studies' bibliographies were reviewed to ensure comprehensiveness. We accessed the potential ascertainment bias for each enrolled study.
RESULTS
Fifteen penetrance studies were identified from 12,182 abstracts, covering five purported MBC susceptibility genes: ATM, BRCA1, BRCA2, CHEK2, and PALB2. Cohort (n = 6, 40%) and case-control (n = 5, 33%) studies were the two most common study designs, followed by family-based (n = 3, 20%), and a kin-cohort study (n = 1, 7%). Seven of the 15 studies (47%) adjusted for ascertainment adequately and therefore the MBC risks reported by these seven studies can be considered applicable to the general population. Based on these seven studies, we found pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 show an increased risk for MBC. The association between BRCA1 and MBC was not statistically significant.
CONCLUSION
This work supports the conclusion that pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 increase the risk of MBC, whereas pathogenic variants in BRCA1 may not be associated with increased MBC risk.
Topics: Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms, Male; Checkpoint Kinase 2; Cohort Studies; Fanconi Anemia Complementation Group N Protein; Genes, BRCA2; Genetic Predisposition to Disease; Humans; Male; Penetrance
PubMed: 34642874
DOI: 10.1007/s10549-021-06413-2 -
Genetics in Medicine : Official Journal... Mar 2023The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias....
PURPOSE
The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon.
METHODS
We generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure.
RESULTS
Bayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among "hot spot" regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain.
CONCLUSIONS
Bayesian penetrance estimates provide a continuous framework for variant interpretation.
Topics: Humans; KCNQ1 Potassium Channel; Mutation; Penetrance; Bayes Theorem; Channelopathies; Arrhythmias, Cardiac
PubMed: 36496179
DOI: 10.1016/j.gim.2022.12.002 -
Nature Reviews. Genetics Mar 2024Inborn errors of immunity (IEIs) are generally considered to be rare monogenic disorders of the immune system that cause immunodeficiency, autoinflammation,... (Review)
Review
Inborn errors of immunity (IEIs) are generally considered to be rare monogenic disorders of the immune system that cause immunodeficiency, autoinflammation, autoimmunity, allergy and/or cancer. Here, we discuss evidence that IEIs need not be rare disorders or exclusively affect the immune system. Namely, an increasing number of patients with IEIs present with severe dysregulations of the central nervous, digestive, renal or pulmonary systems. Current challenges in the diagnosis of IEIs that result from the segregated practice of specialized medicine could thus be mitigated, in part, by immunogenetic approaches. Starting with a brief historical overview of IEIs, we then discuss the technological advances that are facilitating the immunogenetic study of IEIs, progress in understanding disease penetrance in IEIs, the expanding universe of IEIs affecting distal organ systems and the future of genetic, biochemical and medical discoveries in this field.
Topics: Humans; Penetrance; Rare Diseases
PubMed: 37863939
DOI: 10.1038/s41576-023-00656-z -
American Journal of Human Genetics Jan 2023The risk of Leber hereditary optic neuropathy (LHON) has largely been extrapolated from disease cohorts, which underestimate the population prevalence of pathogenic...
The risk of Leber hereditary optic neuropathy (LHON) has largely been extrapolated from disease cohorts, which underestimate the population prevalence of pathogenic primary LHON variants as a result of incomplete disease penetrance. Understanding the true population prevalence of primary LHON variants, alongside the rate of clinical disease, provides a better understanding of disease risk and variant penetrance. We identified pathogenic primary LHON variants in whole-genome sequencing data of a well-characterized population-based control cohort and found that the prevalence is far greater than previously estimated, as it occurs in approximately 1 in 800 individuals. Accordingly, we were able to more accurately estimate population risk and disease penetrance in LHON variant carriers, validating our findings by using other large control datasets. These findings will inform accurate counseling in relation to the risk of vision loss in LHON variant carriers and disease manifestation in their family. This Matters Arising paper is in response to Lopez Sanchez et al. (2021), published in The American Journal of Human Genetics. See also the response by Mackey et al. (2022), published in this issue.
Topics: Humans; Optic Atrophy, Hereditary, Leber; Penetrance; Mutation; DNA, Mitochondrial; Risk Factors
PubMed: 36565700
DOI: 10.1016/j.ajhg.2022.11.013 -
Best Practice & Research. Clinical... Mar 2024Myeloid neoplasms with germline predisposition have been recognized increasingly over the past decade with numerous newly described disorders. Penetrance, age of onset,... (Review)
Review
Myeloid neoplasms with germline predisposition have been recognized increasingly over the past decade with numerous newly described disorders. Penetrance, age of onset, phenotypic heterogeneity, and somatic driver events differ widely among these conditions and sometimes even within family members with the same variant, making risk assessment and counseling of these individuals inherently difficult. In this review, we will shed light on high malignant penetrance (e.g., CEBPA, GATA2, SAMD9/SAMD9L, and TP53) versus variable malignant penetrance syndromes (e.g., ANKRD26, DDX41, ETV6, RUNX1, and various bone marrow failure syndromes) and their clinical features, such as variant type and location, course of disease, and prognostic markers. We further discuss the recommended management of these syndromes based on penetrance with an emphasis on somatic aberrations consistent with disease progression/transformation and suggested timing of allogeneic hematopoietic stem cell transplant. This review will thereby provide important data that can help to individualize and improve the management for these patients.
Topics: Humans; Myelodysplastic Syndromes; Genetic Predisposition to Disease; Penetrance; Myeloproliferative Disorders; Neoplasms; Germ Cells; Germ-Line Mutation; Intracellular Signaling Peptides and Proteins
PubMed: 38490765
DOI: 10.1016/j.beha.2024.101537