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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 -
The Journal of Clinical Investigation Mar 2021Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial...
Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit-encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.
Topics: Adolescent; Adult; Cell Line; Child, Preschool; Electron Transport Complex I; Female; Gene Knockout Techniques; Genes, Recessive; HSP40 Heat-Shock Proteins; Homozygote; Humans; Male; Middle Aged; Mutation; Optic Atrophy, Hereditary, Leber; Pedigree; Penetrance; Phenotype; Protein Subunits; Reactive Oxygen Species; Young Adult
PubMed: 33465056
DOI: 10.1172/JCI138267 -
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 -
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 -
Genetics in Medicine : Official Journal... Dec 2023Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse...
PURPOSE
Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYK variants.
METHODS
We phenotypically characterized Dstyk knockout mice of 3 separate inbred backgrounds and re-analyzed the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to as "SSV" below). DSTYK loss of function (LOF) and SSVs were annotated in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis vs controls. A phenome-wide association study analysis was also performed using United Kingdom Biobank (UKBB) data.
RESULTS
Results demonstrate ∼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk mice. Phenotypic penetrance increased to ∼40% in C3H/HeJ mutants, with mild-to-moderate severity. Re-analysis of the original family segregating the rare SSV showed low penetrance (43.8%) and no alternative genetic causes for CAKUT. LOF DSTYK variants burden showed significant excess for CAKUT and epilepsy vs controls and an exploratory phenome-wide association study supported association with neurological disorders.
CONCLUSION
These data support causality for DSTYK LOF variants and highlights the need for large-scale sequencing studies (here >200,000 cases) to accurately assess causality for genes and variants to lowly penetrant traits with common population prevalence.
Topics: Animals; Mice; Humans; Penetrance; Mice, Inbred C3H; Mice, Inbred C57BL; Urinary Tract; Urogenital Abnormalities; Kidney; Risk Factors; Epilepsy; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37746849
DOI: 10.1016/j.gim.2023.100983 -
Science Immunology Aug 2021Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very... (Observational Study)
Observational Study
Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such variants ( = 3.5 × 10). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (=2, 5 and 38 years), or moderate (=1, 5 years), severe (=1, 27 years), or critical (=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious variants in the male general population is < 6.5x10 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; COVID-19; Child; Child, Preschool; Genetic Diseases, X-Linked; Humans; Immune System Diseases; Infant; Male; Middle Aged; Pedigree; Penetrance; Toll-Like Receptor 7; Young Adult
PubMed: 34413140
DOI: 10.1126/sciimmunol.abl4348 -
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 -
Current Opinion in Lipidology Apr 2023Not all patients with severe hypertriglyceridemia develop acute pancreatitis. We surveyed recent literature on inter-individual genetic variation in susceptibility to... (Review)
Review
PURPOSE OF REVIEW
Not all patients with severe hypertriglyceridemia develop acute pancreatitis. We surveyed recent literature on inter-individual genetic variation in susceptibility to pancreatitis.
RECENT FINDINGS
Genetic determinants of pancreatitis include: rare Mendelian disorders caused by highly penetrant pathogenic variants in genes involved in trypsinogen activation; uncommon susceptibility variants in genes involved in trypsinogen activation, protein misfolding as well as calcium metabolism and cystic fibrosis, that have variable penetrance and show a range of odds ratios for pancreatitis; and common polymorphisms in many of the same genes that have only a small effect on risk. The role of these genetic variants in modulating pancreatitis risk in hypertriglyceridemia is unclear. However, among genetic determinants of plasma triglycerides, those predisposing to more severe hypertriglyceridemia associated with chylomicronemia appear to have higher pancreatitis risk.
SUMMARY
Currently, among patients with severe hypertriglyceridemia, the most consistent predictor of pancreatitis risk is the triglyceride level. Furthermore, pancreatitis risk appears to be modulated by a higher genetic burden of factors associated with greater magnitude of triglyceride elevation. The role of common and rare genetic determinants of pancreatitis itself in this metabolic context is unclear.
Topics: Humans; Pancreatitis; Acute Disease; Trypsinogen; Hypertriglyceridemia; Triglycerides
PubMed: 36752614
DOI: 10.1097/MOL.0000000000000866 -
European Journal of Neurology Sep 2022Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) variants for Parkinson disease (PD) vary widely. G2385R is one of the most common LRRK2 variants in...
BACKGROUND AND PURPOSE
Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) variants for Parkinson disease (PD) vary widely. G2385R is one of the most common LRRK2 variants in Asian populations, and its penetrance is currently unknown. We aimed to estimate the penetrance of G2385R in the Chinese population.
METHODS
The G2385R variant was tested by Sanger sequencing in 6386 participants older than 50 years, all from the community cohort established by Shanghai Ruijin Hospital in 2009-2011. G2385R carriers and matched noncarriers underwent a brief questionnaire survey (including sex, current age, PD diagnosis, and age at onset) and face-to-face PD assessment during 2020-2021. The penetrance of PD was estimated by the Kaplan-Meier method.
RESULTS
A total of 396 G2385R carriers and 415 noncarriers were included, after excluding those with a baseline diagnosis of PD or unwilling to participate. In G2385R carriers, the penetrance of PD was 1.64% at 70 years, 10.26% at 80 years, and 18.49% at 90 years, and reached 25.90% at 95 years. The penetrance of PD in G2385R carriers was higher than in noncarriers (p = 0.0071). In noncarriers, only 0%, 3.72%, and 9.66% developed parkinsonism by 70, 80, and 90 years of age. Among carriers and noncarriers, there were no statistically significant differences in penetrance comparisons between males and females, or between urban and rural.
CONCLUSIONS
The lifetime penetrance of LRRK2 G2385R in the Chinese population was 25.9%. The penetrance modifier of G2385R in our study was age-related. Further investigation of genetic and environmental modifiers affecting G2385R penetrance is warranted.
Topics: China; Female; Genetic Predisposition to Disease; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Mutation; Parkinson Disease; Penetrance; Protein Serine-Threonine Kinases
PubMed: 35608967
DOI: 10.1111/ene.15417 -
Physiological Genomics Oct 2022Sequencing cancer predisposing genes (CPGs) in evocative patients (i.e., patients with personal and family history of multiple/early-onset/unusual cancers) allows... (Review)
Review
Sequencing cancer predisposing genes (CPGs) in evocative patients (i.e., patients with personal and family history of multiple/early-onset/unusual cancers) allows follow-up in their relatives to be adapted when a causative pathogenic variant is identified. Unfortunately, many evocative families remain unexplained. Part of this "missing heritability" could be due to CPG dysregulations caused by remote noncoding genomic alterations. Transcription levels are regulated through the ability of promoters to physically interact with their distant cis-regulatory elements. Three-dimensional chromatin contacts, mediated by a dynamic loop extrusion process, are uncovered by chromosome conformation capture (3C) and 3C-derived techniques, which have enabled the discovery of new pathological mechanisms in developmental diseases and cancers. High-penetrance cancer predisposition is caused by germline hereditary alterations otherwise found at the somatic level in sporadic cancers. Thus, data from both developmental diseases and cancers provide information about possible unknown cancer predisposition mechanisms. This mini-review aims to deduce from these data whether abnormal chromatin folding can cause high-penetrance cancer predisposition.
Topics: Chromatin; Genome; Humans; Neoplasms; Penetrance; Promoter Regions, Genetic
PubMed: 36036457
DOI: 10.1152/physiolgenomics.00052.2022