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Brain : a Journal of Neurology Jan 2020Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk...
Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.
Topics: Age of Onset; Case-Control Studies; Cathepsin B; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Glucosylceramidase; Humans; Induced Pluripotent Stem Cells; Lewy Body Disease; Neurogenesis; Neurons; Parkinson Disease; Penetrance; Polymorphism, Single Nucleotide; RNA, Messenger; Risk Factors; Whole Genome Sequencing; alpha-Synuclein
PubMed: 31755958
DOI: 10.1093/brain/awz350 -
JAMA Jan 2022Population-based assessment of disease risk associated with gene variants informs clinical decisions and risk stratification approaches.
IMPORTANCE
Population-based assessment of disease risk associated with gene variants informs clinical decisions and risk stratification approaches.
OBJECTIVE
To evaluate the population-based disease risk of clinical variants in known disease predisposition genes.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study included 72 434 individuals with 37 780 clinical variants who were enrolled in the BioMe Biobank from 2007 onwards with follow-up until December 2020 and the UK Biobank from 2006 to 2010 with follow-up until June 2020. Participants had linked exome and electronic health record data, were older than 20 years, and were of diverse ancestral backgrounds.
EXPOSURES
Variants previously reported as pathogenic or predicted to cause a loss of protein function by bioinformatic algorithms (pathogenic/loss-of-function variants).
MAIN OUTCOMES AND MEASURES
The primary outcome was the disease risk associated with clinical variants. The risk difference (RD) between the prevalence of disease in individuals with a variant allele (penetrance) vs in individuals with a normal allele was measured.
RESULTS
Among 72 434 study participants, 43 395 were from the UK Biobank (mean [SD] age, 57 [8.0] years; 24 065 [55%] women; 2948 [7%] non-European) and 29 039 were from the BioMe Biobank (mean [SD] age, 56 [16] years; 17 355 [60%] women; 19 663 [68%] non-European). Of 5360 pathogenic/loss-of-function variants, 4795 (89%) were associated with an RD less than or equal to 0.05. Mean penetrance was 6.9% (95% CI, 6.0%-7.8%) for pathogenic variants and 0.85% (95% CI, 0.76%-0.95%) for benign variants reported in ClinVar (difference, 6.0 [95% CI, 5.6-6.4] percentage points), with a median of 0% for both groups due to large numbers of nonpenetrant variants. Penetrance of pathogenic/loss-of-function variants for late-onset diseases was modified by age: mean penetrance was 10.3% (95% CI, 9.0%-11.6%) in individuals 70 years or older and 8.5% (95% CI, 7.9%-9.1%) in individuals 20 years or older (difference, 1.8 [95% CI, 0.40-3.3] percentage points). Penetrance of pathogenic/loss-of-function variants was heterogeneous even in known disease predisposition genes, including BRCA1 (mean [range], 38% [0%-100%]), BRCA2 (mean [range], 38% [0%-100%]), and PALB2 (mean [range], 26% [0%-100%]).
CONCLUSIONS AND RELEVANCE
In 2 large biobank cohorts, the estimated penetrance of pathogenic/loss-of-function variants was variable but generally low. Further research of population-based penetrance is needed to refine variant interpretation and clinical evaluation of individuals with these variant alleles.
Topics: Aged; Biological Specimen Banks; Cohort Studies; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Loss of Function Mutation; Male; Mutation; Penetrance; United Kingdom
PubMed: 35076666
DOI: 10.1001/jama.2021.23686 -
Clinical and Experimental Dermatology Apr 2021Vascular malformations (VMs) are caused by localized defects of vascular development. Most VMs are due to sporadic, postzygotic mutations, while some are the result of... (Review)
Review
Vascular malformations (VMs) are caused by localized defects of vascular development. Most VMs are due to sporadic, postzygotic mutations, while some are the result of autosomal dominant germline mutations. Genotype-phenotype correlation is influenced by many factors. Individual genes can induce different phenotypes (pleiotropy), and similar phenotypes can be due to different genes/mutations (redundancy). The phenotypic spectrum of somatic mutations is wide, and depends on variant allele frequency, timing during embryogenesis, cell type(s) involved and type of mutation. The phenotype of germline mutations is determined by penetrance and expressivity, and is influenced by epigenetic factors (DNA methylation, histone modification) or 'second-hit' somatic mutations. Except for disorders with pathognomonic phenotypes such as Proteus syndrome or a characteristic constellation of symptoms such as CLOVES [congenital lipomatous (fatty) overgrowth, vascular malformations, epidermal naevi and scoliosis/skeletal/spinal anomalies] or PIK3CA-related overgrowth spectrum syndrome, differential diagnosis of VM is therefore difficult. It will be greatly facilitated with increasing analytic sensitivity of sequencing techniques such as next-generation sequencing. High-sensitivity molecular techniques are a prerequisite for targeted pharmacotherapy, i.e. selective therapeutic inhibition of activating mutations underlying VM, which has shown promising results in preliminary studies.
Topics: Epigenesis, Genetic; Genes, Dominant; Genotype; Germ-Line Mutation; Humans; Mutation; Penetrance; Phenotype; Vascular Malformations
PubMed: 33368487
DOI: 10.1111/ced.14513 -
Journal of the American Society of... Sep 2021The reported prevalence of Alport syndrome varies from one in 5000 to one in 53,000 individuals. This study estimated the frequencies of predicted pathogenic variants...
BACKGROUND
The reported prevalence of Alport syndrome varies from one in 5000 to one in 53,000 individuals. This study estimated the frequencies of predicted pathogenic variants in sequencing databases of populations without known kidney disease.
METHODS
Predicted pathogenic variants were identified using filtering steps based on the ACMG/AMP criteria, which considered collagen IV 3-5 position 1 Gly to be critical domains. The population frequencies of predicted pathogenic variants were then determined per mean number of sequenced alleles. Population frequencies for compound heterozygous and digenic combinations were calculated from the results for heterozygous variants.
RESULTS
variants resulting in position 1 Gly substitutions were confirmed to be associated with hematuria (for each, <0.001). Predicted pathogenic variants were found in at least one in 2320 individuals. p.(Gly624Asp) represented nearly half (16 of 33, 48%) of the variants in Europeans. Most variants (54 of 59, 92%) had a biochemical feature that potentially mitigated the clinical effect. The predicted pathogenic heterozygous and variants affected one in 106 of the population, consistent with the finding of thin basement membrane nephropathy in normal donor kidney biopsy specimens. Predicted pathogenic compound heterozygous variants occurred in one in 88,866 individuals, and digenic variants in at least one in 44,793.
CONCLUSIONS
The population frequencies for Alport syndrome are suggested by the frequencies of predicted pathogenic variants, but must be adjusted for the disease penetrance of individual variants and for the likelihood of already diagnosed disease and non-Gly substitutions. Disease penetrance may depend on other genetic and environmental factors.
Topics: Autoantigens; Collagen Type IV; Databases, Genetic; Female; Humans; Male; Mutation; Nephritis, Hereditary; Penetrance; Prevalence
PubMed: 34400539
DOI: 10.1681/ASN.2020071065 -
Genes Oct 2020Inherited retinal diseases (IRDs) are a diverse and variable group of rare human disorders [...].
Inherited retinal diseases (IRDs) are a diverse and variable group of rare human disorders [...].
Topics: Gene Expression; Genetic Association Studies; Genetic Variation; Genetics, Population; Genotype; Humans; Penetrance; Phenotype; Retinal Diseases
PubMed: 33137882
DOI: 10.3390/genes11111274 -
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 -
Nature Communications Dec 2023Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and...
Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and COL4A-associated nephropathy (COL4A-AN) represent the most common forms of monogenic kidney diseases. These disorders have incomplete penetrance and variable expressivity, and we hypothesize that polygenic factors explain some of this variability. By combining SNP array, exome/genome sequence, and electronic health record data from the UK Biobank and All-of-Us cohorts, we demonstrate that the genome-wide polygenic score (GPS) significantly predicts CKD among ADPKD monogenic variant carriers. Compared to the middle tertile of the GPS for noncarriers, ADPKD variant carriers in the top tertile have a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile have only a 3-fold increased risk of CKD. Similarly, the GPS significantly predicts CKD in COL4A-AN carriers. The carriers in the top tertile of the GPS have a 2.5-fold higher risk of CKD, while the risk for carriers in the bottom tertile is not different from the average population risk. These results suggest that accounting for polygenic risk improves risk stratification in monogenic kidney disease.
Topics: Humans; Penetrance; Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic; Multifactorial Inheritance; Risk Factors
PubMed: 38097619
DOI: 10.1038/s41467-023-43878-9 -
Reviews in Endocrine & Metabolic... Aug 2023Monogenic Forms of Diabetes (MFD) account for about 3% of all diabetes, and their accurate diagnosis often results in life-changing therapeutic reassignment for the... (Review)
Review
Monogenic Forms of Diabetes (MFD) account for about 3% of all diabetes, and their accurate diagnosis often results in life-changing therapeutic reassignment for the patients. Like other Mendelian diseases, reduced penetrance and variable expressivity are often seen in several different types of MFD, where symptoms develop only in a portion of the persons who carry the pathogenic variant or vary widely in symptom severity and age of onset. This complicates diagnosis and disease management in MFD. In addition to its clinical importance, knowledge of genetic modifiers that confer penetrance and expressivity variability opens possibilities to identify protective genetic variants which may help probe the mechanisms of more common forms of diabetes and shed light in new therapeutic strategies. In this review, we will mainly address penetrance and expressivity variation in different types of MFD, factors that confer such variations and opportunities that come with such knowledge. Related literature was searched in PubMed, Medline and Embase. Papers with publication year from 1974 to 2023 are included. Data are either sourced from literatures or from OMIM, Clinvar and 1000 genome browser.
Topics: Humans; Penetrance; Diabetes Mellitus; Mutation
PubMed: 37165203
DOI: 10.1007/s11154-023-09809-1 -
European Journal of Medical Genetics Jun 2024Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants...
PURPOSE
Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants (SNV/MNVs) is usually based on the paradigm of complete penetrance.
METHOD
From 2020 to 2022, we proposed a collaboration study with the French molecular diagnosis for intellectual disability network. The aim was to recruit families for whom the index case, diagnosed with a neurodevelopmental disorder, was carrying a pathogenic or likely pathogenic variant for an OMIM morbid gene and inherited from an asymptomatic parent. Grandparents were analyzed when available for segregation study.
RESULTS
We identified 12 patients affected by a monogenic neurodevelopmental disorder caused by likely pathogenic or pathogenic variant (SNV/MNV) inherited from an asymptomatic parent. These genes were usually associated with de novo variants. The patients carried different variants (1 splice-site variant, 4 nonsense and 7 frameshift) in 11 genes: CAMTA1, MBD5, KMT2C, KMT2E, ZMIZ1, MN1, NDUFB11, CUL3, MED13, ARID2 and RERE. Grandparents have been tested in 6 families, and each time the variant was confirmed de novo in the healthy carrier parent.
CONCLUSION
Incomplete penetrance for SNV and MNV in neurodevelopmental disorders might be more frequent than previously thought. This point is crucial to consider for interpretation of variants, family investigation, genetic counseling, and prenatal diagnosis. Molecular mechanisms underlying this incomplete penetrance still need to be identified.
Topics: Humans; Penetrance; Female; Male; Neurodevelopmental Disorders; Pedigree; Child; Child, Preschool; Adult; Adolescent; Mutation; Infant
PubMed: 38453051
DOI: 10.1016/j.ejmg.2024.104932 -
Advances in Experimental Medicine and... 2021Genetic susceptibility explains 5-10% of all breast cancer cases. High-penetrance breast cancer susceptibility genes deliberate a greater than tenfold relative risk of... (Review)
Review
Genetic susceptibility explains 5-10% of all breast cancer cases. High-penetrance breast cancer susceptibility genes deliberate a greater than tenfold relative risk of breast cancer. BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer, and TP53, PTEN, and SKT11 (LKB1) are rarely present. The prevalence of BRCA1 and BRCA2 genetic alterations differ in various ethnic groups. The Korean Hereditary Breast Cancer (KOHBRA) Study, nationwide-scale study, was established to acquire evidence for the accurate risk assessment and management of hereditary breast and ovarian cancer (HBOC) in Korea prospectively since 2007. In this chapter, we review previous research related to hereditary breast cancer and summarize the present concepts and research results centered on the Korean Hereditary Breast Cancer Research at this time.
Topics: Breast Neoplasms; Female; Genes, BRCA2; Genetic Predisposition to Disease; Humans; Mutation; Ovarian Neoplasms; Penetrance; Republic of Korea
PubMed: 33983595
DOI: 10.1007/978-981-32-9620-6_25