-
Biomedical Journal Aug 2021Dysfunction of the FAS-FASLG pathway causes a lymphoproliferative disorder with autoimmunity called Autoimmune lymphoproliferative syndrome (ALPS) mainly caused by FAS... (Review)
Review
Dysfunction of the FAS-FASLG pathway causes a lymphoproliferative disorder with autoimmunity called Autoimmune lymphoproliferative syndrome (ALPS) mainly caused by FAS mutations. The goal of this review is to describe the genetic bases of the autoimmune lymphoproliferative syndrome and to underline their genetic complexity with the contribution of both germline and somatic events accounting for the variable clinical penetrance of the FAS mutations. Starting from the cohort of patients studied in the French cohort (>165 cases), we also reviewed the literature cases in order to depict a full description of the mutations affecting the FAS-FASLG pathway involved in the outcome of this rare non-malignant and non-infectious pediatric lymphoproliferative disease. We also discussed the variable clinical penetrance associated with mutations affecting the extracellular domain of the protein. Such non-penetrant germline mutations are frequently associated with an additional somatic event impacting the second allele of FAS. Moreover, the uncomplete clinical penetrance associated with mutations affecting the intracellular domain of FAS, in patient lacking additional FAS somatic event, suggested a potential digenic inheritance with a FAS mutation accompanied by a genetic modifier possibly impacting another player of the lymphocytes homeostasis (affecting the survival, activation or apoptosis of the peripheral leukocytes).
Topics: Apoptosis; Autoimmune Lymphoproliferative Syndrome; Child; Cohort Studies; Humans; Mutation; fas Receptor
PubMed: 34171534
DOI: 10.1016/j.bj.2021.06.005 -
Developmental Dynamics : An Official... Aug 2019Evolutionary conservation and experimental tractability have made animal model systems invaluable tools in our quest to understand human embryogenesis, both normal and... (Review)
Review
Evolutionary conservation and experimental tractability have made animal model systems invaluable tools in our quest to understand human embryogenesis, both normal and abnormal. Standard genetic approaches, particularly useful in understanding monogenic diseases, are no longer sufficient as research attention shifts toward multifactorial outcomes. Here, we examine this progression through the lens of holoprosencephaly (HPE), a common human malformation involving incomplete forebrain division, and a classic example of an etiologically complex outcome. We relate the basic underpinning of HPE pathogenesis to critical cell-cell interactions and signaling molecules discovered through embryological and genetic approaches in multiple model organisms, and discuss the role of the mouse model in functional examination of HPE-linked genes. We then outline the most critical remaining gaps to understanding human HPE, including the conundrum of incomplete penetrance/expressivity and the role of gene-environment interactions. To tackle these challenges, we outline a strategy that leverages new and emerging technologies in multiple model systems to solve the puzzle of HPE.
Topics: Animals; Gene-Environment Interaction; Holoprosencephaly; Humans; Mice; Models, Animal; Penetrance; Prosencephalon; Signal Transduction
PubMed: 30993762
DOI: 10.1002/dvdy.41 -
European Journal of Cancer Prevention :... Jul 2023The common use of genetic testing has reinvigorated discussions surrounding enhanced cancer surveillance, chemoprevention, and preventive surgery strategies due to... (Review)
Review
The common use of genetic testing has reinvigorated discussions surrounding enhanced cancer surveillance, chemoprevention, and preventive surgery strategies due to increasing recognition of pathogenic germline genetic variants. Prophylactic surgery for hereditary cancer syndromes can significantly reduce the risk of developing cancer. Hereditary diffuse gastric cancer (HDGC), characterized by high penetrance and an autosomal dominant inheritance pattern, is causally linked to germline mutations in the CDH1 tumor suppressor gene. Risk-reducing total gastrectomy is currently recommended in patients with pathogenic and likely pathogenic CDH1 variants; however, the physical and psychosocial sequelae of complete stomach removal are substantial and need to be investigated further. In this review, we address the risks and benefits of prophylactic total gastrectomy for HDGC in the context of prophylactic surgery for other highly penetrant cancer syndromes.
Topics: Humans; Stomach Neoplasms; Genetic Testing; Gastrectomy; Germ-Line Mutation; Adenocarcinoma; Cadherins; Genetic Predisposition to Disease
PubMed: 36977191
DOI: 10.1097/CEJ.0000000000000798 -
Journal of Medical Genetics Feb 2024Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most...
BACKGROUND
Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are , , and . Penetrance of disease-causing variants in these genes is known to be incomplete, but has not been well studied at population level.
OBJECTIVE
We sought to determine the population-level penetrance of pathogenic and likely pathogenic variants in genes commonly causing amyotrophic lateral sclerosis.
METHODS
Published epidemiological data for amyotrophic lateral sclerosis and frontotemporal dementia were used to calculate expected frequencies of disease-causing variants per gene at population level. Variant data from gnomAD and ClinVar databases were used to ascertain observed numbers of disease-causing variants and to estimate population-level penetrance per gene. Data for were obtained from the published literature.
RESULTS
Maximum population penetrance for either amyotrophic lateral sclerosis or frontotemporal dementia was found to be 33% for (95% CI (20.9 to 53.2)), 54% for (95% CI (32.7 to 88.6)), 38% for (95% CI (21.1 to 69.8)) and 19% for (95% CI (13.0 to 28.4)).
CONCLUSION
Population-level penetrance of amyotrophic lateral sclerosis disease genes is reduced. This finding has implications for the genetic testing and counselling of affected individuals and their unaffected relatives.
Topics: Humans; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; C9orf72 Protein; Penetrance; Superoxide Dismutase-1
PubMed: 38123999
DOI: 10.1136/jmg-2023-109580 -
Tremor and Other Hyperkinetic Movements... Nov 2020Myoclonus-Dystonia (M-D) is a pleiotropic neuropsychiatric disorder of variable penetrance. Pathogenic variants in , a maternally imprinted gene, are the most frequent...
BACKGROUND
Myoclonus-Dystonia (M-D) is a pleiotropic neuropsychiatric disorder of variable penetrance. Pathogenic variants in , a maternally imprinted gene, are the most frequent known genetic cause of M-D. The population prevalence of -linked M-D is unknown, the pathogenicity of variants identified in patients with M-D may be indeterminant, and variants predicted to be deleterious by analysis may appear in patients undergoing whole-exome or whole-genome sequencing for seemingly unrelated disorders. The Genome Aggregation Database (gnomAD) v2 provides variant data on 125,748 exomes and 15,708 genomes from unrelated individuals sequenced as part of various disease-specific and population genetic studies.
METHODS
variants included in the gnomAD v2 dataset were analyzed with Combined Annotation Dependent Depletion (CADD), and database for nonsynonymous single nucleotide polymorphisms' functional predictions (dbNSFP). We determined the frequency of annotated variants, ranked by scores of deleteriousness, within the gnomAD v2 dataset. Deleteriousness scores were compared to a subset of published disease associated pathogenic variants.
RESULTS
Within gnomAD v2, there were 56, 408, and 1250 alleles harboring variants with CADD scores greater than 30, 25, and 20, respectively. We estimate that approximately 1/348 individuals in the United States population harbors an variant with a CADD score ≥ 25.
DISCUSSION
M-D may be underdiagnosed due to pleiotropy, mild phenotypes, variable penetrance, and impaired access to genetic testing. Due to the high population prevalence of deleterious variants, caution should be used when asserting pathogenicity without co-segregation analyses and expert neurological examination of phenotypes within pedigrees.
HIGHLIGHTS
analyses of a large population database of genetic variants revealed that over 0.2% of individuals in the United States harbor a highly deleterious variant. This finding suggests that M-D and minor phenotypic variants such as mild isolated myoclonus may be underdiagnosed.
Topics: Computer Simulation; Databases, Genetic; Dystonic Disorders; Genetic Testing; Health Services Accessibility; Humans; Mutation; Penetrance; Phenotype; Polymorphism, Single Nucleotide; Prevalence; Sarcoglycans; Exome Sequencing; Whole Genome Sequencing
PubMed: 33200041
DOI: 10.5334/tohm.567 -
Movement Disorders : Official Journal... Jun 2021The THAP1 gene encodes a transcription factor, and pathogenic variants cause a form of autosomal dominant, isolated dystonia (DYT-THAP1) with reduced penetrance. Factors...
BACKGROUND
The THAP1 gene encodes a transcription factor, and pathogenic variants cause a form of autosomal dominant, isolated dystonia (DYT-THAP1) with reduced penetrance. Factors underlying both reduced penetrance and the disease mechanism of DYT-THAP1 are largely unknown.
METHODS
We performed transcriptome analysis on 29 cortical neuronal precursors derived from human-induced pluripotent stem cell lines generated from manifesting and nonmanifesting THAP1 mutation carriers and control individuals.
RESULTS
Whole transcriptome analysis showed a penetrance-linked signature with expressional changes more pronounced in the group of manifesting (MMCs) than in nonmanifesting mutation carriers (NMCs) when compared to controls. A direct comparison of the transcriptomes in MMCs versus NMCs showed significant upregulation of the DRD4 gene in MMCs. A gene set enrichment analysis demonstrated alterations in various neurotransmitter release cycle pathways, extracellular matrix organization, and deoxyribonucleic acid methylation between MMCs and NMCs. When specifically considering transcription factors, the expression of YY1 and SIX2 differed in MMCs versus NMCs. Further, THAP1 was upregulated in the group of MMCs.
CONCLUSIONS
To our knowledge, this is the first report systematically analyzing reduced penetrance in DYT-THAP1 in a human model using transcriptomes. Our findings indicate that transcriptional alterations during cortical development influence DYT-THAP1 pathogenesis and penetrance. We reinforce previously linked pathways including dopamine and eukaryotic translation initiation factor 2 alpha signaling in the pathogenesis of dystonia including DYT-THAP1 and suggest extracellular matrix organization and deoxyribonucleic acid methylation as mediators of disease protection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Apoptosis Regulatory Proteins; DNA-Binding Proteins; Humans; Induced Pluripotent Stem Cells; Mutation; Penetrance
PubMed: 33547842
DOI: 10.1002/mds.28506 -
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... Sep 2021Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the...
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.
OBJECTIVES
The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults.
METHODS
This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.
RESULTS
The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001).
CONCLUSIONS
In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.
Topics: Aged; Cardiomyopathy, Hypertrophic; Cohort Studies; Deep Learning; Female; Heart Ventricles; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Penetrance; Phenotype; Sarcomeres
PubMed: 34503678
DOI: 10.1016/j.jacc.2021.07.017 -
Clinical Genetics Apr 2022The aim of this study was to explore kidney failure (KF) in Bardet-Biedl syndrome (BBS), focusing on high-risk gene variants, demographics, and morbidity. We employed...
The aim of this study was to explore kidney failure (KF) in Bardet-Biedl syndrome (BBS), focusing on high-risk gene variants, demographics, and morbidity. We employed the Clinical Registry Investigating BBS (CRIBBS) to identify 44 (7.2%) individuals with KF out of 607 subjects. Molecularly confirmed BBS was identified in 37 KF subjects and 364 CRIBBS registrants. KF was concomitant with recessive causal variants in 12 genes, with BBS10 the most predominant causal gene (26.6%), while disease penetrance was highest in SDCCAG8 (100%). Two truncating variants were present in 67.6% of KF cases. KF incidence was increased in genes not belonging to the BBSome or chaperonin-like genes (p < 0.001), including TTC21B, a new candidate BBS gene. Median age of KF was 12.5 years, with the vast majority of KF occurring by 30 years (86.3%). Females were disproportionately affected (77.3%). Diverse uropathies were identified, but were not more common in the KF group (p = 0.672). Kidney failure was evident in 11 of 15 (73.3%) deaths outside infancy. We conclude that KF poses a significant risk for premature morbidity in BBS. Risk factors for KF include female sex, truncating variants, and genes other than BBSome/chaperonin-like genes highlighting the value of comprehensive genetic investigation.
Topics: Bardet-Biedl Syndrome; Chaperonins; Child; Female; Humans; Male; Mutation; Penetrance; Renal Insufficiency
PubMed: 35112343
DOI: 10.1111/cge.14119 -
European Heart Journal Apr 2020We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a...
AIMS
We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a longitudinal cohort study.
METHODS AND RESULTS
Structural progression was defined as the development of new Task Force imaging criteria from inclusion to follow-up and progression rates as annual changes in imaging parameters. We included 144 AC patients and family members (48% female, 47% probands, 40 ± 16 years old). At genetic diagnosis and inclusion, 58% of family members had penetrant AC disease. During 7.0 [inter-quartile range (IQR) 4.5-9.4] years of follow-up, 47% of family members without AC at inclusion developed AC criteria, resulting in a yearly new AC penetrance of 8%. Probands and family members had a similar progression rate of right ventricular outflow tract diameter (0.5 mm/year vs. 0.6 mm/year, P = 0.28) by mixed model analysis of 598 echocardiographic examinations. Right ventricular fractional area change progression rate was even higher in family members (-0.6%/year vs. -0.8%/year, P < 0.01). Among 86 patients without overt structural disease or arrhythmic history at inclusion, a first severe ventricular arrhythmic event occurred in 8 (9%), of which 7 (88%) had concomitant structural progression. Structural progression was associated with higher incidence of severe ventricular arrhythmic events adjusted for age, sex, and proband status (HR 21.24, 95% CI 2.47-182.81, P < 0.01).
CONCLUSION
More than half of family members had AC criteria at genetic diagnosis and yearly AC penetrance was 8%. Structural progression was similar in probands and family members and was associated with higher incidence of severe ventricular arrhythmic events.
Topics: Adult; Arrhythmogenic Right Ventricular Dysplasia; Disease Progression; Family; Female; Humans; Longitudinal Studies; Male; Middle Aged; Penetrance; Young Adult
PubMed: 31504415
DOI: 10.1093/eurheartj/ehz570