-
Genes Jun 2021The genetic landscape of Parkinson's disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants... (Review)
Review
The genetic landscape of Parkinson's disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design.
Topics: Genetic Predisposition to Disease; Humans; Mutation; Parkinson Disease; Penetrance; Polymorphism, Single Nucleotide
PubMed: 34208795
DOI: 10.3390/genes12071006 -
American Journal of Human Genetics Nov 2022The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the...
The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%-97%). We highlight that pathogenic variants in HNF1A, HNF4A, and GCK are not ultra-rare in the population. For HNF1A and HNF4A, we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list.
Topics: Humans; Penetrance; Diabetes Mellitus, Type 2; Cohort Studies; Prevalence; Mutation; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 4
PubMed: 36257325
DOI: 10.1016/j.ajhg.2022.09.014 -
Circulation Research Feb 2019Dissections or ruptures of aortic aneurysms remain a leading cause of death in the developed world, with the majority of deaths being preventable if individuals at risk... (Review)
Review
Dissections or ruptures of aortic aneurysms remain a leading cause of death in the developed world, with the majority of deaths being preventable if individuals at risk are identified and properly managed. Genetic variants predispose individuals to these aortic diseases. In the case of thoracic aortic aneurysm and dissections (thoracic aortic disease), genetic data can be used to identify some at-risk individuals and dictate management of the associated vascular disease. For abdominal aortic aneurysms, genetic associations have been identified, which provide insight on the molecular pathogenesis but cannot be used clinically yet to identify individuals at risk for abdominal aortic aneurysms. This compendium will discuss our current understanding of the genetic basis of thoracic aortic disease and abdominal aortic aneurysm disease. Although both diseases share several pathogenic similarities, including proteolytic elastic tissue degeneration and smooth muscle dysfunction, they also have several distinct differences, including population prevalence and modes of inheritance.
Topics: Animals; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Fibrillin-1; Humans; Multifactorial Inheritance; Penetrance
PubMed: 30763214
DOI: 10.1161/CIRCRESAHA.118.312436 -
Pflugers Archiv : European Journal of... May 2019The introduction of next-generation sequencing technology has revealed that mutations in the gene that encodes titin (TTN) are linked to multiple skeletal and cardiac... (Review)
Review
The introduction of next-generation sequencing technology has revealed that mutations in the gene that encodes titin (TTN) are linked to multiple skeletal and cardiac myopathies. The most prominent of these myopathies is dilated cardiomyopathy (DCM). Over 60 genes are linked to the etiology of DCM, but by far, the leading cause of DCM is mutations in TTN with truncating variants in TTN (TTNtvs) associated with familial DCM in ∼ 20% of the cases. Titin is a large (3-4 MDa) and abundant protein that forms the third myofilament type of striated muscle where it spans half the sarcomere, from the Z-disk to the M-line. The underlying mechanisms by which titin mutations induce disease are poorly understood and targeted therapies are not available. Here, we review what is known about TTN mutations in muscle disease, with a major focus on DCM. We highlight that exon skipping might provide a possible therapeutic avenue to address diseases that arise from TTNtvs.
Topics: Animals; Cardiomyopathies; Connectin; Humans; Mutation; Penetrance
PubMed: 30919088
DOI: 10.1007/s00424-019-02272-5 -
Genetics in Medicine : Official Journal... Mar 2024Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease...
PURPOSE
Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community.
METHODS
The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group.
RESULTS
We formally recognize risk alleles and low-penetrance variants as distinct variant classes from those causing highly penetrant disease that require special considerations regarding their clinical classification and reporting. First, we provide a preferred terminology for these variants. Second, we focus on risk alleles and detail considerations for reviewing relevant studies and present a framework for the classification these variants. Finally, we discuss considerations for clinical reporting of risk alleles.
CONCLUSION
These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.
Topics: Humans; Alleles; Genetic Variation; Penetrance; Gene Frequency
PubMed: 38054408
DOI: 10.1016/j.gim.2023.101036 -
American Journal of Human Genetics Sep 2023Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing....
Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.
Topics: Female; Male; Humans; Adult; Penetrance; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Cardiomyopathy, Dilated; Gene Frequency
PubMed: 37652022
DOI: 10.1016/j.ajhg.2023.08.003 -
American Journal of Human Genetics Feb 2019More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and...
More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as "clinically relevant" variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.
Topics: Alleles; Databases, Genetic; Developmental Disabilities; Diabetes Mellitus, Type 2; Disease; Female; Genetics, Population; Heterozygote; Humans; Male; Mutation; Penetrance; Reproducibility of Results; Sunburn; Uncertainty; United Kingdom; Xeroderma Pigmentosum
PubMed: 30665703
DOI: 10.1016/j.ajhg.2018.12.015 -
Genetics in Medicine : Official Journal... Oct 2017PurposeWhole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from...
PurposeWhole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants.MethodsWe present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets.ResultsUsing the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, without removing true pathogenic variants (false-positive rate<0.001).ConclusionWe outline a statistically robust framework for assessing whether a variant is "too common" to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.
Topics: Cardiomyopathies; Databases, Genetic; Exome; Gene Frequency; Genetic Variation; Humans; Penetrance; Sequence Analysis, DNA; Exome Sequencing; Whole Genome Sequencing
PubMed: 28518168
DOI: 10.1038/gim.2017.26 -
Endocrinology, Diabetes & Metabolism Nov 2022Numerous genes have been proposed as causal for maturity-onset diabetes of the young (MODY). Scoring systems to annotate mutation pathogenicity have been widely used;...
AIMS
Numerous genes have been proposed as causal for maturity-onset diabetes of the young (MODY). Scoring systems to annotate mutation pathogenicity have been widely used; however, statistical evidence for being a highly penetrant MODY gene has not been well-established.
METHODS
Participants were from the UK Biobank with whole-exome sequencing data, including 14,622 with and 185,509 without diagnosis of diabetes. Pathogenic/likely pathogenic (P/LP) mutations in 14 reported and 3 possible MODY genes were annotated using American College of Medical Genetics criteria. Evidence for being a high-penetrant MODY gene used two statistical criteria: frequency of aggregate P/LP mutations in each gene are (1) significantly more common in participants with a diagnosis of diabetes than without using the SKAT-O (p < .05) and (2) lower than the maximum credible frequency in the general population.
RESULTS
Among the 17 genes, 6 (GCK, HNF1A, HNF4A, NEUROD1, KCNJ11 and HNF1B) met both criteria, 7 (ABCC8, KLF11, RFX6, PCBD1, WFS1, INS and PDX1) met only one criterion, and the remaining 4 (CEL, BLK, APPL1 and PAX4) failed both criteria, and were classified as 'consistent', 'inconclusive' and 'inconsistent' for being highly penetrant diabetes genes, respectively. Diabetes participants with mutations in the 'consistent' genes had clinical presentations that were most consistent with MODY. In contrast, the 'inconclusive' and 'inconsistent' genes did not differ clinically from non-carriers in diabetes-related characteristics.
CONCLUSIONS
Data from a large population-based study provided novel statistical evidence to identify 6 MODY genes as consistent with being highly penetrant. These results have potential implications for interpreting genetic testing results and clinical diagnosis of MODY.
Topics: Humans; Penetrance; Diabetes Mellitus, Type 2; Mutation; Cohort Studies
PubMed: 36208030
DOI: 10.1002/edm2.372 -
Science (New York, N.Y.) Jun 2023We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes...
We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes implicated by genome-wide association studies confer ~10-fold larger effects than common variants in the same genes. Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared with common-variant polygenic risk scores, greatly improving the clinical utility of genetic-based risk prediction.
Topics: Humans; Genetic Predisposition to Disease; Genome-Wide Association Study; Multifactorial Inheritance; Mutation; Phenotype; Risk Factors; Penetrance
PubMed: 37262146
DOI: 10.1126/science.abo1131