-
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 -
Ophthalmic Genetics Apr 2022To investigate the penetrance of gene mutation in primary open-angle glaucoma (POAG) through systematic review and meta-analysis. To explore the factors affecting the... (Meta-Analysis)
Meta-Analysis
PURPOSE
To investigate the penetrance of gene mutation in primary open-angle glaucoma (POAG) through systematic review and meta-analysis. To explore the factors affecting the penetrance of and provide evidence-based medical evidence for clinical work.
METHODS
We searched all studies that reported the penetrance of mutation in PubMed, Embase, Web of Science, and Chinese databases including Wanfang, CNKI (China National Knowledge Infrastructure), and CBM (China Bio-Med). Random effects meta-analysis was conducted to estimate the penetrance of mutation in POAG.
RESULTS
Fifty-two studies were included in this analysis after screening. Meta-analysis of the penetrance of mutation showed that the penetrance of mutation in POAG was 60% (95% CI: 51.0% to 68.0%) and the penetrance of mutation in POAG and suspected POAG was 68% (95% CI: 60.0% to 75.0%). The penetrance of mutation increases with age. Among Caucasians, Asians, and Africans, the penetrance of mutation in POAG was 55%, 71%, 54%, respectively, and the penetrance of mutation in POAG and suspected POAG was 64%, 83%, and 57%, respectively. Besides, the penetrance of different mutation sites was significantly discrepant. The penetrance of mutation in POAG ranged from 10.3% to 100% depending on the mutation sites. Some mutation sites have a certain population specificity, which is only pathogenic in Caucasians or Asians.
CONCLUSIONS
The penetrance of mutation in POAG showed significant differences due to different mutation sites. The penetrance increased with the accrescent of age. Ethnic difference was an important factor affecting the penetrance of mutation. Knowing the rules and influencing factors of the penetrance of mutations is significant for the assessment of the risk of POAG in carriers with the mutation.
Topics: Cytoskeletal Proteins; DNA Mutational Analysis; Eye Proteins; Glaucoma, Open-Angle; Glycoproteins; Humans; Mutation; Penetrance
PubMed: 35014583
DOI: 10.1080/13816810.2021.2021427 -
Best Practice & Research. Clinical... Jun 2005Since its original description as a rare disease of iron overload resulting in liver disease, diabetes mellitus, and bronzing of the skin ('bronze diabetes'), hereditary... (Meta-Analysis)
Meta-Analysis Review
Since its original description as a rare disease of iron overload resulting in liver disease, diabetes mellitus, and bronzing of the skin ('bronze diabetes'), hereditary hemochromatosis has undergone several redefinitions leading to widely varying estimates of its prevalence. Over the last decade, the finding of a relatively high prevalence of the C282Y polymorphism of the HFE gene associated with hemochromatosis in Northern European populations suggested that the disease may be much more common than previously thought. However, several large population-based studies have now shown that the penetrance of the C282Y/C282Y genotype is very low, indicating that C282Y homozygosity is a necessary but not sufficient factor in causation of the disease. Studies are now focusing on other genetic and environmental factors, including alcohol, that may contribute to differential expression of C282Y homozygosity.
Topics: Age Factors; Genotype; Hemochromatosis; Heterozygote; Homozygote; Humans; Penetrance; Phenotype; Polymorphism, Genetic
PubMed: 15737885
DOI: 10.1016/j.beha.2004.08.023 -
Trends in Cancer Oct 2018Synthetic lethality has long been proposed as an approach for targeting genetic defects in tumours. Despite a decade of screening efforts, relatively few robust... (Review)
Review
Synthetic lethality has long been proposed as an approach for targeting genetic defects in tumours. Despite a decade of screening efforts, relatively few robust synthetic lethal targets have been identified. Improved genetic perturbation techniques, including CRISPR/Cas9 gene editing, have resulted in renewed enthusiasm for searching for synthetic lethal effects in cancer. An implicit assumption behind this enthusiasm is that the lack of reproducibly identified targets can be attributed to limitations of RNAi technologies. We argue here that a bigger hurdle is that most synthetic lethal interactions (SLIs) are not highly penetrant, in other words they are not robust to the extensive molecular heterogeneity seen in tumours. We outline strategies for identifying and prioritising SLIs that are most likely to be highly penetrant.
Topics: CRISPR-Cas Systems; Computational Biology; Gene Editing; Genetic Therapy; Humans; Molecular Targeted Therapy; Neoplasms; Oncogenes; Penetrance; RNA Interference; Synthetic Lethal Mutations
PubMed: 30292351
DOI: 10.1016/j.trecan.2018.08.003 -
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 -
JAMA Ophthalmology Jan 2019
Topics: Cytoskeletal Proteins; Eye Proteins; Glaucoma; Glycoproteins; Humans; Mutation; Penetrance; Registries
PubMed: 30267050
DOI: 10.1001/jamaophthalmol.2018.4470 -
Journal of Medical Genetics Jun 2021Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an X-linked motor neuron disorder caused by an expanded CAG repeat in the gene coding for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an X-linked motor neuron disorder caused by an expanded CAG repeat in the gene coding for the androgen receptor (AR). The range and significance of reduced penetrance alleles in SBMA has not been fully determined to date. We presently sought to determine the range of reduced penetrance alleles in SBMA.
METHODS
Through systematic literature review and meta-analysis, we collected and analysed data from 2576 patients with SBMA and compared the distributions of the CAG repeat number (CAG) in the AR gene between patients and 112 248 control alleles of the general population.
RESULTS
Our analysis revealed an unexpectedly high frequency of expanded SBMA-associated alleles, with (CAG) ≥35 present in 107/100,000 and (CAG) ≥38 present in 27/100,000 of the general population. Consequently, we suggest an updated model describing the distribution of expanded alleles in the general population. We argue against the established cut-off principle for the penetrance of SBMA and suggest that penetrance gradually increases from 35 to approximately 46 (CAG), above which it reaches a plateau approaching maximum value.
CONCLUSION
Asymptomatic men of the general population with no/unknown SBMA family history are free of risk when carrying (CAG) ≤34, are at intermediate but increasing risk for developing SBMA when carrying (CAG) ≈35-46 and have close to 100% risk of developing the disease when carrying (CAG) ≥47. The above observations should be helpful and clinically useful when providing genetic counselling to individuals and families bearing SBMA-associated alleles.
Topics: Age of Onset; Alleles; Bulbo-Spinal Atrophy, X-Linked; Female; Gene Frequency; Humans; Meiosis; Models, Genetic; Penetrance
PubMed: 32571900
DOI: 10.1136/jmedgenet-2020-106963 -
Journal of the American College of... Aug 2020
Topics: Cardiomyopathy, Hypertrophic; Genetic Testing; Humans; Mutation; Penetrance; Sarcomeres
PubMed: 32731934
DOI: 10.1016/j.jacc.2020.06.023 -
Trends in Neurosciences Sep 2020HIV attacks the body's immune cells, frequently compromises the integrity of the blood-brain barrier (BBB), and infects the CNS in the early stages of infection.... (Review)
Review
HIV attacks the body's immune cells, frequently compromises the integrity of the blood-brain barrier (BBB), and infects the CNS in the early stages of infection. Dysfunction of the BBB further potentiates viral replication within the CNS, which can lead to HIV-associated neuropathology. Antiretroviral therapy (ART) significantly improves HIV patient outcomes and reduces mortality rates. However, there has been limited progress in targeting latent viral reservoirs within the CNS, which may eventually lead to rebound viremia. While ART drugs are shown to be effective in attenuating HIV replication in the periphery, the protection of the brain by the BBB offers an isolated sanctuary to harbor HIV and maintains chronic and persistent replication within the CNS. In this review, we elucidate the pathology of the BBB, its ability to potentiate viral replication, as well as current therapies and insufficiencies in treating HIV-infected individuals.
Topics: Blood-Brain Barrier; Brain; HIV Infections; Humans; Penetrance; Pharmaceutical Preparations
PubMed: 32682564
DOI: 10.1016/j.tins.2020.06.007 -
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