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Human Molecular Genetics Feb 2024Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known...
Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (<1:9000). Aggregated or single variant analysis of pathogenic variants showed low penetrance in unselected settings for the relevant phenotypes, except m.3243A>G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5, respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk. Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.
Topics: Humans; Penetrance; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Mitochondrial Diseases; Heart Failure; Deafness; Mutation
PubMed: 37988592
DOI: 10.1093/hmg/ddad194 -
Comptes Rendus Biologies 2016Elucidating the underlying rules that govern the phenotypic diversity observed in natural populations is an old but still unaccomplished goal in biology. In 1865, Gregor... (Review)
Review
Elucidating the underlying rules that govern the phenotypic diversity observed in natural populations is an old but still unaccomplished goal in biology. In 1865, Gregor Mendel paved the way for the dissection of the underlying genetic basis of traits by setting out to understand the principles of heredity. To date, we still lack a global overview of the spectrum and continuum existing between Mendelian and complex traits within any natural population. In this respect, we recently performed a species-wide survey of Mendelian traits across a large population of isolates using the yeast Saccharomyces cerevisiae. By analyzing the distribution and the inheritance patterns of the trait, we have clearly shown that monogenic mutations can display a significant, variable, and continuous expressivity across different genetic backgrounds. Our study also demonstrated that combining the elegancy of both classical genetics and high-throughput genomics is more than valuable to dissect the genotype-phenotype relationship in natural populations.
Topics: Genetics; Genotype; Humans; Mutation; Penetrance; Phenotype; Saccharomyces cerevisiae
PubMed: 27344551
DOI: 10.1016/j.crvi.2016.04.006 -
American Journal of Human Genetics Jan 2023Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision....
Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484T>C and m.11778G>A, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484T>C carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson et al. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.
Topics: Humans; Penetrance; DNA, Mitochondrial; Optic Atrophy, Hereditary, Leber; Australia; Mutation; Pedigree
PubMed: 36565701
DOI: 10.1016/j.ajhg.2022.11.014 -
Molecular Genetics and Metabolism Jan 2014The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes.... (Review)
Review
The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. These processes range from a central role in anterior-posterior patterning of the developing embryo to roles in oncogenesis that are yet to be fully elucidated. In vertebrates there are a total of 39 Hox genes divided into 4 separate clusters. Of these, mutations in 10 Hox genes have been found to cause human disorders with significant variation in their inheritance patterns, penetrance, expressivity and mechanism of pathogenesis. This review aims to describe the various phenotypes caused by germline mutation in these 10 Hox genes that cause a human phenotype, with specific emphasis paid to the genotypic and phenotypic differences between allelic disorders. As clinical whole exome and genome sequencing is increasingly utilized in the future, we predict that additional Hox gene mutations will likely be identified to cause distinct human phenotypes. As the known human phenotypes closely resemble gene-specific murine models, we also review the homozygous loss-of-function mouse phenotypes for the 29 Hox genes without a known human disease. This review will aid clinicians in identifying and caring for patients affected with a known Hox gene disorder and help recognize the potential for novel mutations in patients with phenotypes informed by mouse knockout studies.
Topics: Animals; Congenital Abnormalities; Disease Models, Animal; Exome; Genes, Homeobox; Genetic Diseases, Inborn; Genetic Variation; Genome, Human; Genotype; Germ-Line Mutation; Humans; Mice; Molecular Biology; Multigene Family; Penetrance; Phenotype; Syndrome; Vertebrates
PubMed: 24239177
DOI: 10.1016/j.ymgme.2013.10.012 -
Genetics in Medicine : Official Journal... Jan 2020
Topics: Alleles; Penetrance; Repressor Proteins; Transcription Factors
PubMed: 31395943
DOI: 10.1038/s41436-019-0621-z -
The New England Journal of Medicine Apr 2011
Review
Topics: Cardiomyopathies; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Desmosomes; Diabetic Cardiomyopathies; Humans; Mutation; Myocardium; Penetrance; Phenotype; Sarcomeres
PubMed: 21524215
DOI: 10.1056/NEJMra0902923 -
Molecular Oncology Jun 2010Genetic and lifestyle/environmental factors are implicated in the aetiology of breast cancer. This review summarizes the current state of knowledge on rare high... (Review)
Review
Genetic and lifestyle/environmental factors are implicated in the aetiology of breast cancer. This review summarizes the current state of knowledge on rare high penetrance mutations, as well as moderate and low-penetrance genetic variants implicated in breast cancer aetiology. We summarize recent discoveries from large collaborative efforts to combine data from candidate gene studies, and to conduct genome-wide association studies (GWAS), primarily in breast cancers in the general population. These findings are compared with results from collaborative efforts aiming to identify genetic modifiers in BRCA1 and BRCA2 carriers. Breast cancer is a heterogeneous disease, and tumours from BRCA1 and BRCA2 carriers display distinct pathological characteristics when compared with tumours unselected for family history. The relationship between genetic variants and pathological subtypes of breast cancer, and the implication of discoveries of novel genetic variants to risk prediction in BRCA1/2 mutation carriers and in populations unselected for mutation carrier status, are discussed.
Topics: Breast Neoplasms; Female; Genes, BRCA1; Genes, BRCA2; Genetic Predisposition to Disease; Genome-Wide Association Study; Heterozygote; Humans; Mutation; Penetrance; Polymorphism, Genetic
PubMed: 20542480
DOI: 10.1016/j.molonc.2010.04.011 -
Journal of the American Heart... Aug 2023
Topics: Humans; Aged; Prealbumin; Penetrance; Amyloidosis; Heart Failure; Health Disparate Minority and Vulnerable Populations
PubMed: 37486081
DOI: 10.1161/JAHA.123.030802 -
Translational Research : the Journal of... Jan 2013Mutations in genes encoding ion channel pore-forming α-subunits and accessory β-subunits as well as intracellular calcium-handling proteins that collectively maintain... (Review)
Review
Mutations in genes encoding ion channel pore-forming α-subunits and accessory β-subunits as well as intracellular calcium-handling proteins that collectively maintain the electromechanical function of the human heart serve as the underlying pathogenic substrate for a spectrum of sudden cardiac death (SCD)-predisposing heritable cardiac arrhythmia syndromes, including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). Similar to many Mendelian disorders, the cardiac "channelopathies" exhibit incomplete penetrance, variable expressivity, and phenotypic overlap, whereby genotype-positive individuals within the same genetic lineage assume vastly different clinical courses as objectively assessed by phenotypic features such electrocardiographic abnormalities and number/type of cardiac events. In this Review, we summarize the current understanding of the global architecture of complex electrocardiographic traits such as the QT interval, focusing on the role of common genetic variants in the modulation of ECG parameters in health and the environmental and genetic determinants of incomplete penetrance and variable expressivity in the heritable cardiac arrhythmia syndromes most likely to be encountered in clinical practice.
Topics: Arrhythmias, Cardiac; Genetic Variation; Humans; Penetrance; Polymorphism, Genetic; Syndrome
PubMed: 22995932
DOI: 10.1016/j.trsl.2012.08.005 -
Annals of Neurology Aug 2022The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available.
METHODS
We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership-Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses.
RESULTS
A higher polygenic resilience score was associated with a lower risk for PD (β = -0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.
INTERPRETATION
The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270-278.
Topics: Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Parkinson Disease; Penetrance; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 35599344
DOI: 10.1002/ana.26416