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Current Opinion in Immunology Dec 2015Common autoimmune diseases are relatively heterogeneous with both genetic and environmental factors influencing disease susceptibility and progression. As the... (Review)
Review
Common autoimmune diseases are relatively heterogeneous with both genetic and environmental factors influencing disease susceptibility and progression. As the populations in developed countries age, these chronic diseases will become an increasing burden in human suffering and health care costs. By contrast, rare immune diseases that are severe and develop early in childhood are frequently monogenic and fully penetrant, often with a Mendelian inheritance pattern. Although these may be incompatible with survival or cured by hematopoietic stem cell transplantation, we will argue that they constitute a rich source of genetic insights into immunological diseases. Here, we discuss five examples of well-studied Mendelian disease-causing genes and their known or predicted roles in conferring susceptibility to common, polygenic diseases of autoimmunity. Mendelian disease mutations, as experiments of nature, reveal human loci that are indispensable for immune regulation and, therefore, most promising as therapeutic targets.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Disease Susceptibility; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Immunomodulation; Mendelian Randomization Analysis; Mutation; Penetrance; Polymorphism, Genetic
PubMed: 26433354
DOI: 10.1016/j.coi.2015.09.001 -
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 -
The American Journal of Psychiatry Jan 2023Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic...
OBJECTIVE
Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic copy number variants (CNVs). Because rare variants are primarily investigated in clinical cohorts, population-based estimates of their prevalence and penetrance are lacking. The authors determined the prevalence, penetrance, and NPD risk of pathogenic single-gene variants in a large health care system population.
METHODS
The authors analyzed linked genomic and electronic health record (EHR) data in a subset of 90,595 participants from Geisinger's MyCode Community Health Initiative, known as the DiscovEHR cohort. Loss-of-function pathogenic variants in 94 high-confidence NPD genes were identified through exome sequencing, and NPD penetrance was calculated using preselected EHR diagnosis codes. NPD risk was estimated using a case-control comparison of DiscovEHR participants with and without NPD diagnoses. Results from single-gene variant analyses were also compared with those from 31 previously reported pathogenic NPD CNVs.
RESULTS
Pathogenic variants were identified in 0.34% of the DiscovEHR cohort and demonstrated a 34.3% penetrance for NPDs. Similar to CNVs, sequence variants collectively conferred a substantial risk for several NPD diagnoses, including autism, schizophrenia, and bipolar disorder. Significant NPD risk remained after participants with intellectual disability were excluded from the analysis, confirming the association with major psychiatric disorders in individuals without severe cognitive deficits.
CONCLUSIONS
Collectively, rare single-gene variants and CNVs were found in >1% of individuals in a large health care system population and play an important contributory role in mental health disorders. Diagnostic genetic testing for pathogenic variants among symptomatic individuals with NPDs could improve clinical outcomes through early intervention and anticipatory therapeutic support.
Topics: Humans; Penetrance; Prevalence; Schizophrenia; Genetic Testing; Delivery of Health Care; DNA Copy Number Variations
PubMed: 36475376
DOI: 10.1176/appi.ajp.22010062 -
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 -
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 -
Annals of Neurology Jul 2021The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.
OBJECTIVE
The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.
METHODS
We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.
RESULTS
A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.
INTERPRETATION
This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.
Topics: Aged; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Middle Aged; Mutation; Parkinson Disease; Penetrance
PubMed: 33938021
DOI: 10.1002/ana.26094 -
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 -
JAMA Ophthalmology Oct 2018The apparent genetic penetrance of macular telangiectasia type 2 (MacTel) is important for gene discovery studies and for clinical risk assessment of affected...
IMPORTANCE
The apparent genetic penetrance of macular telangiectasia type 2 (MacTel) is important for gene discovery studies and for clinical risk assessment of affected individuals' family members.
OBJECTIVE
To determine the genetic penetrance of MacTel.
DESIGN, SETTING, AND PARTICIPANTS
Descriptive cross-sectional study of patients with MacTel at a tertiary referral eye center. From 2008 to 2016, consecutive patients with MacTel were independently identified, and all of their available siblings and parents were recruited. Seventeen probands with MacTel were included in the study who satisfied the requirement of having at least 1 parent or sibling willing and able to participate. Data from these 17 families were included for the analysis of apparent genetic penetrance.
MAIN OUTCOMES AND MEASURES
Determination of MacTel genetic penetrance in probands' parents and siblings.
RESULTS
Of 80 study participants, 50 (62.5%) were women. The mean (SD) age of study participants with MacTel was 61.2 (14.0) years (range, 23-81 years) and without MacTel was 60.7 (16.4) years (range, 24-92 years). There were 17 MacTel probands, and there was a high rate of enrollment of living siblings and parents: 52 of 71 living siblings (73%) and 11 of 12 parents (92%). Of 52 enrolled siblings, 9 (17%) were affected. Of 11 enrolled parents, 3 (27%) had MacTel. Apparent genetic penetrance was calculated to be 0.35 (95% CI, 0.14-0.6) by sibling analysis and 0.55 (95% CI, 0.02-1.00) by parent analysis. Combining the sibling and parent analyses, the apparent penetrance was calculated to be 0.38 (95% CI, 0.19-0.57).
CONCLUSIONS AND RELEVANCE
The genetic penetrance of MacTel in rigorously phenotyped multiple large families is described. Families such as these could be critical for successful identification of MacTel genes.
Topics: Adult; Aged; Aged, 80 and over; Cross-Sectional Studies; Female; Fluorescein Angiography; Genetic Markers; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Optical Imaging; Parents; Pedigree; Penetrance; Phenotype; Retinal Telangiectasis; Risk Assessment; Siblings; Tomography, Optical Coherence; Visual Acuity; Young Adult
PubMed: 30098143
DOI: 10.1001/jamaophthalmol.2018.3283 -
Cancer Epidemiology, Biomarkers &... Apr 2018
Topics: Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Humans; Mutation; Neoplasms; Penetrance
PubMed: 29615418
DOI: 10.1158/1055-9965.EPI-16-0914 -
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