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Journal of Medical Genetics Apr 2023Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the gene. Patients with BHD syndrome have an... (Review)
Review
BACKGROUND
Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the gene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series.
METHODS
A comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in . Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of pathogenic variants.
RESULTS
Our final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of the variant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers.
CONCLUSIONS
These updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.
Topics: Humans; Male; Female; Aged; Birt-Hogg-Dube Syndrome; Penetrance; Colonic Polyps; Proto-Oncogene Proteins; Tumor Suppressor Proteins; Kidney Neoplasms; Carcinoma, Renal Cell
PubMed: 36849229
DOI: 10.1136/jmg-2022-109104 -
Journal of Clinical Immunology Apr 2021Mendelian autoinflammatory diseases characterized by constitutive activation of the type I interferon pathway, the so-called type I interferonopathies, constitute a... (Review)
Review
Mendelian autoinflammatory diseases characterized by constitutive activation of the type I interferon pathway, the so-called type I interferonopathies, constitute a rapidly expanding group of inborn errors of immunity. Among the type I interferonopathies, STING-associated vasculopathy with onset in infancy (SAVI) and COPA syndrome were described in the last 6 years, both manifesting a major inflammatory lung component associated with significant morbidity and increased mortality. There is striking clinical and histopathological overlap between SAVI and COPA syndrome, although distinct features are also present. Of note, there is a remarkably high frequency of clinical non-penetrance among individuals harboring pathogenic COPA mutations. SAVI is caused by, principally heterozygous, gain-of-function mutations in STING1 (previously referred to as TMEM173) encoding STING, a key adaptor of the interferon signaling pathway induced by DNA. COPA syndrome results from heterozygous dominant-negative mutations in the coatomer protein subunit alpha, forming part of a complex involved in intracellular cargo protein transport between the Golgi and the endoplasmic reticulum (ER). Of importance, a role for COPA in regulating the trafficking of STING, an ER-resident protein which translocates to the Golgi during the process of its activation, was recently defined, thereby possibly explaining some aspects of the phenotypic overlap between SAVI and COPA syndrome. Here, we review the expanding phenotype of these diseases, highlighting common as well as specific features, and recent advances in our understanding of STING biology that have informed therapeutic decision-making in both conditions. Beyond these rare Mendelian disorders, DNA sensing through STING is likely relevant to the pathology of several diseases associated with lung inflammation, including systemic lupus erythematosus, dermatomyositis, environmental toxin exposure, and viral infection.
Topics: Animals; Autoimmunity; Biomarkers; Disease Management; Disease Susceptibility; Endoplasmic Reticulum; Gene Expression Regulation; Genetic Predisposition to Disease; Golgi Apparatus; Humans; Membrane Proteins; Mutation; Penetrance; Phenotype; Pneumonia; Protein Transport; Signal Transduction; Syndrome
PubMed: 33532887
DOI: 10.1007/s10875-021-00974-z -
Advances in Experimental Medicine and... 2021Susceptibility genes involved in disease etiology and prognosis are categorized into two groups: high penetrance genes (i.e., BRCA1, CHEK2, ATM, etc.) and low penetrance...
Susceptibility genes involved in disease etiology and prognosis are categorized into two groups: high penetrance genes (i.e., BRCA1, CHEK2, ATM, etc.) and low penetrance genes (i.e., NATs, GSTs, CYPs, etc., and variants identified by genome-wide association studies). Since low penetrance genes have high population attributable risk, the usefulness of those genes to research on breast cancer prevention is not small. In this chapter, the previous studies on low-penetrance genetic susceptibility through a candidate gene approach and genome-wide association of breast cancer were summarized. The contribution of low-penetrance susceptibility genes to the breast cancer risk prediction models will also be discussed on the utility in clinical or public health application.
Topics: Breast Neoplasms; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Penetrance
PubMed: 33983592
DOI: 10.1007/978-981-32-9620-6_22 -
Nature Communications Dec 2021Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can...
Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Gain of Function Mutation; Heterozygote; Homozygote; Humans; Interleukin-7 Receptor alpha Subunit; Mice; Penetrance; Precancerous Conditions; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cells, B-Lymphoid; Proto-Oncogene Proteins p21(ras); Signal Transduction
PubMed: 34907175
DOI: 10.1038/s41467-021-27197-5 -
Disease Models & Mechanisms Dec 2022Meckel syndrome, nephronophthisis, Joubert syndrome and Bardet-Biedl syndrome are caused by mutations in proteins that localize to the ciliary transition zone (TZ). The...
Meckel syndrome, nephronophthisis, Joubert syndrome and Bardet-Biedl syndrome are caused by mutations in proteins that localize to the ciliary transition zone (TZ). The phenotypically distinct syndromes suggest that these TZ proteins have differing functions. However, mutations in a single TZ gene can result in multiple syndromes, suggesting that the phenotype is influenced by modifier genes. We performed a comprehensive analysis of ten zebrafish TZ mutants, including mks1, tmem216, tmem67, rpgrip1l, cc2d2a, b9d2, cep290, tctn1, nphp1 and nphp4, as well as mutants in ift88 and ift172. Our data indicate that variations in phenotypes exist between different TZ mutants, supporting different tissue-specific functions of these TZ genes. Further, we observed phenotypic variations within progeny of a single TZ mutant, reminiscent of multiple disease syndromes being associated with mutations in one gene. In some mutants, the dynamics of the phenotype became complex with transitory phenotypes that are corrected over time. We also demonstrated that multiple-guide-derived CRISPR/Cas9 F0 'crispant' embryos recapitulate zygotic null phenotypes, and rapidly identified ciliary phenotypes in 11 cilia-associated gene candidates (ankfn1, ccdc65, cfap57, fhad1, nme7, pacrg, saxo2, c1orf194, ttc26, zmynd12 and cfap52).
Topics: Animals; Cilia; Zebrafish; Penetrance; Syndrome; Polycystic Kidney Diseases; Biological Variation, Population; Zebrafish Proteins; Vesicular Transport Proteins
PubMed: 36533556
DOI: 10.1242/dmm.049568 -
Endocrine Jun 2020Familial nonmedullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancer cases. FNMTC is divided into two groups: syndromic and nonsyndromic. Nonsyndromic... (Review)
Review
Familial nonmedullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancer cases. FNMTC is divided into two groups: syndromic and nonsyndromic. Nonsyndromic FNMTC is more common as compared with syndromic FNMTC. In syndromic FNMTC, patients are at risk of nonmedullary thyroid cancer (NMTC) and other tumors, and the susceptibility genes are known. In nonsyndromic FNMTC, NMTC is the major feature of the disease and occurs in isolation with an autosomal dominant pattern of inheritance and variable penetrance. New data have emerged on the genetics, clinical characteristics, and outcomes of patients with FNMTC that may have clinical relevance in the management of patients. In this review, we focus on newly characterized syndromic FNMTC entities, criteria for screening and surveillance of nonsyndromic FNMTC, and the classification of nonsyndromic FNMTC as well as the genetic background and heterogeneity of nonsyndromic FNMTC.
Topics: Carcinoma, Papillary; Genetic Predisposition to Disease; Humans; Penetrance; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 32162184
DOI: 10.1007/s12020-020-02250-3 -
Nature Feb 2024Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease. The ZRS is arguably the most well-studied...
Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies.
Topics: Humans; Enhancer Elements, Genetic; Extremities; Gain of Function Mutation; Homeodomain Proteins; Interferon Regulatory Factors; Organ Specificity; Penetrance; Phenotype; Polydactyly; Polymorphism, Single Nucleotide; Protein Binding; Proto-Oncogene Proteins c-ets; Transcription Factor AP-1
PubMed: 38233525
DOI: 10.1038/s41586-023-06922-8 -
Annals of Neurology Nov 2022Parkinson's disease (PD) is a complex neurodegenerative condition in which genetic and environmental factors interact to contribute to its etiology. Remarkable progress... (Review)
Review
Parkinson's disease (PD) is a complex neurodegenerative condition in which genetic and environmental factors interact to contribute to its etiology. Remarkable progress has been made in deciphering disease etiology through genetic approaches, but there is limited data about how environmental and genetic factors interact to modify penetrance, risk, and disease severity. Here, we provide insights into environmental modifiers of PD, discussing precedents from other neurological and non-neurological conditions. Based on these examples, we outline genetic and environmental factors contributing to PD and review potential environmental modifiers of penetrance and clinical variability in monogenic and idiopathic PD. We also highlight the potential challenges and propose how future studies might tackle these important questions. ANN NEUROL 2022;92:715-724.
Topics: Humans; Parkinson Disease; Penetrance
PubMed: 35913124
DOI: 10.1002/ana.26467 -
BioRxiv : the Preprint Server For... Mar 2023Many pathogenic sequence variants (PSVs) have been associated with increased risk of cancers. Mendelian risk prediction models use Mendelian laws of inheritance to...
Many pathogenic sequence variants (PSVs) have been associated with increased risk of cancers. Mendelian risk prediction models use Mendelian laws of inheritance to predict the probability of having a PSV based on family history, as well as specified PSV frequency and penetrance (agespecific probability of developing cancer given genotype). Most existing models assume penetrance is the same for any PSVs in a certain gene. However, for some genes (for example, BRCA1/2), cancer risk does vary by PSV. We propose an extension of Mendelian risk prediction models to relax the assumption that risk is the same for any PSVs in a certain gene by incorporating variant-specific penetrances and illustrating these extensions on two existing Mendelian risk prediction models, BRCAPRO and PanelPRO. Our proposed BRCAPRO-variant and PanelPRO-variant models incorporate variant-specific BRCA1/2 PSVs through the region classifications. Due to the sparsity of the variant information we classify BRCA1/2 PSVs into three regions; the breast cancer clustering region (BCCR), the ovarian cancer clustering region (OCCR), and an other region. Simulations were conducted to evaluate the performance of the proposed BRCAPRO-variant model compared to the existing BRCAPRO model which assumes the penetrance is the same for any PSVs in BRCA1 (and respectively BRCA2). Simulation results showed that the BRCAPRO-variant model was well calibrated to predict region-specific BRCA1/2 carrier status with high discrimination and accuracy on the region-specific level. In addition, we showed that the BRCAPRO-variant model achieved performance gains over the existing risk prediction models in terms of calibration without loss in discrimination and accuracy. We also evaluated the performance of the two proposed models, BRCAPRO-variant and PanelPRO-variant, on a cohort of 1,961 families from the Cancer Genetics Network (CGN). We showed that our proposed models provide region-specific PSV carrier probabilities with high accuracy, while the calibration, discrimination and accuracy of gene-specific PSV carrier probabilities were comparable to the existing gene-specific models. As more variant-specific PSV penetrances become available, we have shown that Mendelian risk prediction models can be extended to integrate the additional information, providing precise variant or region-specific PSV carrier probabilities and improving future cancer risk predictions.
PubMed: 36945459
DOI: 10.1101/2023.03.06.531363 -
Gastroenterology Apr 2021Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide...
BACKGROUND AND AIMS
Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology.
METHODS
PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets. PRS were then combined using regression to assess which combination of scores best predicted IBD status in European, AJ, Hispanic, and African American cohorts in BioMe. Additionally, rare variants were assessed in genes associated with very early-onset IBD (VEO-IBD), by estimating genetic penetrance in each BioMe population.
RESULTS
Combining risk scores based on association data from distinct ancestral populations improved IBD prediction for every population in BioMe and significantly improved prediction among European ancestry UK Biobank individuals. Lower predictive power for non-Europeans was observed, reflecting in part substantially lower African IBD case-control reference sizes. We replicated associations for two VEO-IBD genes, ADAM17 and LRBA, with high dominant model penetrance in BioMe. Autosomal recessive LRBA risk alleles are associated with severe, early-onset autoimmunity; we show that heterozygous carriage of an African-predominant LRBA protein-altering allele is associated with significantly decreased LRBA and CTLA-4 expression with T-cell activation.
CONCLUSIONS
Greater genetic diversity in African populations improves prediction across populations, and generalizes some VEO-IBD genes. Increasing African American IBD case-collections should be prioritized to reduce health disparities and enhance pathophysiological insight.
Topics: Humans; Age of Onset; Black or African American; Case-Control Studies; Colitis, Ulcerative; Crohn Disease; Europe; Genetic Predisposition to Disease; Genome-Wide Association Study; Hispanic or Latino; Jews; Multifactorial Inheritance; Penetrance; Phenotype; Polymorphism, Single Nucleotide; Prevalence; Race Factors; Risk Assessment; Risk Factors; United States; White People; Network Meta-Analysis
PubMed: 33359885
DOI: 10.1053/j.gastro.2020.12.034