-
Familial Cancer Jan 2018Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome accounting for approximately 1000 cases of colorectal cancer (CRC) in the UK annually.... (Meta-Analysis)
Meta-Analysis
Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome accounting for approximately 1000 cases of colorectal cancer (CRC) in the UK annually. LS is characterised by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. The penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether low penetrance genetic risk factors may result in phenotype modification in LS patients. To conduct a systematic literature review and meta-analysis to assess the association between low penetrance genetic risk modifiers and CRC in LS patients. A systematic review was conducted of the PubMed and HuGENet databases. Eligibility of studies was determined by pre-defined criteria. Included studies were analysed via the per-allele model and assessed by pooled odds ratios and establishing 95% confidence intervals. Study heterogeneity was assessed via Cochrane's Q statistic and I2 values. Publication bias was evaluated with funnel plots. Subgroup analysis was conducted on gender. Statistical software used was the Metafor package for the R programme version 3.1.3. Sixty-four polymorphisms were identified and sufficient data was available for analysis of ten polymorphisms, with between 279 and 1768 CRC cases per polymorphism. None demonstrated association with CRC risk in LS patients. However in sub-group analysis the polymorphism rs16892766 (8q23.3) was significant in males (OR 1.53, 95% CI 1.12-2.10). The variable phenotype presentation of the disease still remains largely unexplained, and further investigation is warranted. Other factors may also be influencing the high variability of the disease, such as environmental factors, copy number variants and epigenetic alterations. Investigation into these areas is needed as well as larger and more definitive studies of the polymorphisms analysed in this study.
Topics: Chromosomes, Human, Pair 8; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Copy Number Variations; DNA Mismatch Repair; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Male; Penetrance; Polymorphism, Single Nucleotide; Sex Factors
PubMed: 28508326
DOI: 10.1007/s10689-017-9995-8 -
Clinical Genetics Jan 2019Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by germline TP53 mutations. Genetic testing is not routinely offered in... (Review)
Review
Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by germline TP53 mutations. Genetic testing is not routinely offered in asymptomatic children at risk of the condition as the benefits are debatable and the attitudes of families and health care professionals (HCPs) may vary. This review assessed the attitudes of families and HCPs towards offering genetic testing to children for LFS, with a focus on perceived advantages and disadvantages and involvement of children in the decision-making process. We searched three key databases (Medline, PsycINFO and EMBASE) to identify quantitative and qualitative studies. We screened 729 articles identifying eight studies for detailed review. Most parents perceived TP53 genetic testing to be beneficial in childhood, despite previous lack of surveillance guidelines. Parents raised some concerns, including decreased insurability and diminishing the child's autonomy. Most children tested reported no negative emotional concerns after testing, even if tested positive. Despite generally positive interest clinicians remain hesitant. Most families saw the value in involving children in decision-making. Families' acceptance of TP53 testing in childhood was high. This review highlights the need for research on the long-term psychosocial impacts of testing and the attitudes of families to be reflected in professional guidelines.
Topics: Attitude of Health Personnel; Decision Making; Genetic Predisposition to Disease; Genetic Testing; Genotype; Germ-Line Mutation; Health Personnel; Humans; Li-Fraumeni Syndrome; Parents
PubMed: 30191952
DOI: 10.1111/cge.13442 -
Developmental Neurobiology May 2018The prevalence of autism spectrum disorders (ASD) and the number of identified ASD-related genes have increased in recent years. The SETD5 gene encodes a... (Review)
Review
The prevalence of autism spectrum disorders (ASD) and the number of identified ASD-related genes have increased in recent years. The SETD5 gene encodes a SET-containing-domain 5 protein, a likely reader enzyme. Genetic evidences suggest that SETD5 malfunction contributes to ASD phenotype, such as on intellectual disability (ID) and facial dysmorphism. In this review, we mapped the clinical phenotypes of individuals carrying mutations on the SETD5 gene that are associated with ASD and other chromatinopathies (mutation in epigenetic modifiers that leads to the development of neurodevelopmental disorders such as ASD). After a detailed systematic literature review and analysis of public disease-related databank, we found so far 42 individuals carrying mutations on the SETD5 gene, with 23.8% presenting autistic-like features. Furthermore, most of mutations occurred between positions 9,480,000-9,500,000 bp on chromosome 3 (3p25.3) at the SETD5 gene locus. In all males, mutations in SETD5 presented high penetrance, while in females the clinical phenotype seems more variable with two reported cases showing normal female carriers and not presenting ASD or any ID-like symptoms. At the molecular level, SETD5 interacts with proteins of PAF1C and N-CoR complexes, leading to a possible involvement with chromatin modification pathway, which plays important roles for brain development. Together, we propose that mutations on the SETD5 gene could lead to a new syndromic condition in males, which is linked to 3p25 syndrome, and can leads to ASD-related intellectual disability and facial dysmorphism. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 500-518, 2018.
Topics: Animals; Autism Spectrum Disorder; Genetic Variation; Humans; Methyltransferases
PubMed: 29484850
DOI: 10.1002/dneu.22584 -
DNA repair gene polymorphisms and risk of cutaneous melanoma: a systematic review and meta-analysis.Carcinogenesis Oct 2009Polymorphisms of DNA repair-related genes might modulate cancer predisposition. We performed a systematic review and meta-analysis of the available evidence regarding... (Meta-Analysis)
Meta-Analysis Review
Polymorphisms of DNA repair-related genes might modulate cancer predisposition. We performed a systematic review and meta-analysis of the available evidence regarding the relationship between these polymorphisms and the risk of developing cutaneous melanoma. Relevant studies were searched using PubMed, Medline, Embase, Cancerlit, Cochrane and ISI Web of Knowledge databases. Data were gathered according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. The model-free approach was adopted to perform the meta-analysis of the retrieved data. We identified 20 original reports that describe the relationship between melanoma risk and the single-nucleotide polymorphisms (SNPs) of 16 genes (cases = 4195). For seven SNPs considered in at least two studies, the findings were heterogeneous. Data were suitable for meta-analysis only in the case of the XPD/ERCC2 SNP rs13181 (cases = 2308, controls = 3698) and demonstrated that the variant C allele is associated with increased melanoma risk (odds ratio = 1.12, 95% confidence interval = 1.03-1.21, P = 0.01; population attributable risk = 9.6%). This is the first meta-analysis suggesting that XPD/ERCC2 might represent a low-penetrance melanoma susceptibility gene. Much work is still to be done before definitive conclusions can be drawn on the role of DNA repair alterations in melanomagenesis since for the other genes involved in this highly complex process, the available information is scarce or null.
Topics: DNA Damage; DNA Repair; DNA, Neoplasm; Genetic Predisposition to Disease; Humans; Melanoma; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Risk Factors; Skin Neoplasms; Xeroderma Pigmentosum Group D Protein
PubMed: 19706646
DOI: 10.1093/carcin/bgp207 -
Endocrine-related Cancer Mar 2021Pancreatic neuroendocrine tumors (pNETs) in Von Hippel-Lindau (VHL) disease have a relatively good prognosis. However, a subset of pNETs metastasize and significantly...
Pancreatic neuroendocrine tumors (pNETs) in Von Hippel-Lindau (VHL) disease have a relatively good prognosis. However, a subset of pNETs metastasize and significantly contribute to VHL-related mortality. Evidence-based guidelines are needed for timely detection, management and intervention of these tumors. However, the value of several diagnostic tools is controversial, and evidence-based management strategies are lacking. This systematic review aims to update current literature on diagnostic and management strategies of pNETs in VHL and proposes evidence-based recommendations. The databases of PubMed/Medline, Embase and Web of Science were systematically searched to identify relevant studies. Studies were screened independently and cross-checked by two authors to assess eligibility for inclusion. Eighty-four articles were eligible for full text reading, and thirteen were critically appraised using the modified Quality Assessment of Diagnostic Accuracy Studies or modified Quality in Prognostic Studies tool. Six studies assessed the diagnostic value of imaging modalities, five focused on the optimal timing for surgical intervention, and one article studied the growth rate of pNETs. Quality of the available evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluations tool. Studies recommended CT or MRI as the primary screening modalities for pNETs. For detection of metastases, 68Gallium-DOTATATE/TOC PET/CT is advised. For pNETs <2 cm a watch-and-wait approach is recommended, while for pNETs ≥2.5 cm surgical resection is advised. Due to limited data, no strong recommendations on surveillance could be proposed.
Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radionuclide Imaging; von Hippel-Lindau Disease
PubMed: 33512331
DOI: 10.1530/ERC-20-0469 -
Gastroenterology Research and Practice 2017Environmental factors and genetic mutations have been increasingly recognized as risk factors for chronic pancreatitis (CP). The p.R122H mutation was the first... (Review)
Review
BACKGROUND
Environmental factors and genetic mutations have been increasingly recognized as risk factors for chronic pancreatitis (CP). The p.R122H mutation was the first discovered to affect hereditary CP, with 80% penetrance. We performed here a systematic review and meta-analysis to evaluate the associations of p.R122H mutation with CP of diverse etiology.
METHODS
The PubMed, EMBASE, and MEDLINE database were reviewed. The pooled odds ratio (OR) with 95% confidence intervals was used to evaluate the association of p.R122H mutation with CP. Initial analysis was conducted with all etiologies of CP, followed by a subgroup analysis for hereditary and nonhereditary CP, including alcoholic or idiopathic CP.
RESULTS
A total of eight case-control studies (1733 cases and 2415 controls) were identified and included. Overall, p.R122H mutation was significantly associated with an increased risk of CP (OR = 4.78[1.13-20.20]). Further analysis showed p.R122H mutation strongly associated with the increased risk of hereditary CP (OR = 65.52[9.09-472.48]) but not with nonhereditary CP, both alcoholic and idiopathic CP.
CONCLUSIONS
Our study showing the differential role of p.R122H mutation in various etiologies of CP indicates that this complex disorder is likely influenced by multiple genetic factors as well as environmental factors.
PubMed: 29118810
DOI: 10.1155/2017/9505460 -
Circulation. Genomic and Precision... Oct 2021The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly...
BACKGROUND
The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly develop a cardiomyopathy (variant transthyretin amyloidosis cardiomyopathy) phenotype. Yet, there are conflicting data on the prevalence and outcomes of p.Val142Ile variant carriers.
METHODS
We performed a systematic review of the prevalence and outcomes of p.Val142Ile variant transthyretin amyloidosis cardiomyopathy among subjects of African descent. We found 62 relevant articles after searching the MEDLINE databases from 1980 to 2020 that reported data for ≈150 000 subjects.
RESULTS
The reported worldwide prevalence of the p.Val142Ile variant is 0.3% to 1.6% in the general population. Among people of African descent, the reported prevalence from all studies ranges from 1.1% to 9.8%, but for studies with >1000 subjects, it is 3% to 3.5%. The prevalence of the p.Val142Ile variant in a region is dependent on the reported percentage of subjects who are of African descent in that region. p.Val142Ile variant transthyretin amyloidosis cardiomyopathy typically presents in the seventh to eighth decade of life and the majority of cases reported were male, with 25% to 38% diagnosed with atrial fibrillation. It was associated with a longitudinally worse quality of life and a lower adjusted survival compared with other types of transthyretin amyloidosis cardiomyopathy.
CONCLUSIONS
The p.Val142Ile variant is the most common variant of the transthyretin gene with most carriers being of African descent. The true penetrance is unknown but the p.Val142Ile variant is associated with increased rates of incident heart failure and portends a lower overall survival. Increased awareness could lead to earlier diagnosis and improved heart failure outcomes among those of African descent, which is of increasing importance given the advent of novel therapeutics for this disease.
Topics: Amino Acid Substitution; Amyloid Neuropathies, Familial; Cardiomyopathies; Female; Humans; Male; Mutation, Missense; Prealbumin; Prevalence; Risk Factors; Sex Factors
PubMed: 34461737
DOI: 10.1161/CIRCGEN.121.003356 -
Movement Disorders : Official Journal... Mar 2023Spinocerebellar ataxia type 17 or ATX-TBP is a CAG/CAA repeat expansion disorder characterized by marked clinical heterogeneity. Reports of affected carriers with... (Review)
Review
Spinocerebellar ataxia type 17 or ATX-TBP is a CAG/CAA repeat expansion disorder characterized by marked clinical heterogeneity. Reports of affected carriers with subthreshold repeat expansions and of patients with Parkinson's disease (PD) with expanded repeats have cast doubt on the established cutoff values of the expansions and the phenotypic spectrum of this disorder. The objective of this systematic review was to explore the genotype-phenotype relationships for repeat expansions in TBP to delineate the ATX-TBP phenotype and reevaluate the pathological range of repeat expansions. The International Parkinson and Movement Disorder Society Genetic Mutation Database (MDSGene) standardized data extraction protocol was followed. Clinically affected carriers of reported ATX-TBP expansions were included. Publications that contained repeat sizes in screened cohorts of patients with PD and/or healthy individuals were included for a separate evaluation of cutoff values. Phenotypic and genotypic data for 346 ATX-TBP patients were curated. Overall, 97.7% of the patients had ≥41 repeats, while 99.6% of patients with PD and 99.9% of healthy individuals had ≤42 repeats, with a gray zone of reduced penetrance between 41 and 45 repeats. Pure parkinsonism was more common in ATX-TBP patients with 41 to 45 repeats than in the group with ≥46 repeats, which conversely more often presented with a complex phenotype with mixed movement disorders. An updated genotype-phenotype assessment for ATX-TBP is provided, and new repeat expansion cutoff values of reduced penetrance (41-45 expanded repeats) and full penetrance (46-66 expanded repeats) are proposed. These adjusted cutoff values will have diagnostic and counseling implications and may guide future clinical trial protocol. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Genetic Association Studies; Parkinson Disease; Spinocerebellar Ataxias; TATA-Box Binding Protein; Trinucleotide Repeat Expansion
PubMed: 36374860
DOI: 10.1002/mds.29278 -
International Journal of Cancer Jul 2012XPA, a zinc-finger DNA-binding protein, play an important role in both global genome and transcription-coupled repair pathways. XPA -4G>A polymorphism was identified in... (Meta-Analysis)
Meta-Analysis Review
XPA, a zinc-finger DNA-binding protein, play an important role in both global genome and transcription-coupled repair pathways. XPA -4G>A polymorphism was identified in the 5' noncoding region, located four nucleotides upstream of the ATG start codon. Previous studies have shown that this polymorphism may affect mRNA tertiary structure and stability and play a role in susceptibility to cancer. However, the results remained controversial. To derive a more precise estimation of association between this polymorphism and risk of different types of cancer, we performed a meta-analysis based on 36 case-control or case-cohort studies, including a total of 11,700 cases and 15,033 controls. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, no significantly elevated cancer risk was found in all genetic models when eligible studies were pooled into the meta-analysis. In the stratified analyses, we found that individuals with A-allele had a higher risk of lung cancer (AA versus GG: OR = 1.25, 95% CI = 1.09-1.43; recessive model: OR = 1.31, 95% CI = 1.16-1.48). When stratified by ethnicity, significantly elevated risks were observed among Asian populations (AA versus GG: OR = 1.31, 95% CI = 1.01-1.70; dominant model: OR = 1.14, 95% CI = 1.00-1.30). This meta-analysis suggests that XPA -4G>A polymorphism is associated with increased lung cancer risk and may be a low-penetrant risk factor in Asian ethnicity for cancer development.
Topics: Asian People; Case-Control Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Lung Neoplasms; Neoplasms; Odds Ratio; Polymorphism, Single Nucleotide; Xeroderma Pigmentosum Group A Protein
PubMed: 21866550
DOI: 10.1002/ijc.26391 -
Clinical Genetics Jan 2020Neurexins are presynaptic cell adhesion molecules critically involved in synaptogenesis and vesicular neurotransmitter release. They are encoded by three genes...
Neurexins are presynaptic cell adhesion molecules critically involved in synaptogenesis and vesicular neurotransmitter release. They are encoded by three genes (NRXN1-3), each yielding a longer alpha (α) and a shorter beta (β) transcript. Deletions spanning the promoter and the initial exons of the NRXN1 gene, located in chromosome 2p16.3, are associated with a variety of neurodevelopmental, psychiatric, neurological and neuropsychological phenotypes. We have performed a systematic review to define (a) the clinical phenotypes most associated with mono-allelic exonic NRXN1 deletions, and (b) the phenotypic features of NRXN1 bi-allelic deficiency due to compound heterozygous deletions/mutations. Clinically, three major conclusions can be drawn: (a) incomplete penetrance and pleiotropy do not allow reliable predictions of clinical outcome following prenatal detection of mono-allelic exonic NRXN1 deletions. Newborn carriers should undergo periodic neuro-behavioral observations for the timely detection of warning signs and the prescription of early behavioral intervention; (b) the presence of additional independent genetic risk factors should always be sought, as they may influence prognosis; (c) children with exonic NRXN1 deletions displaying early-onset, severe psychomotor delay in the context of a Pitt-Hopkins-like syndrome 2 phenotype, should undergo DNA sequencing of the spared NRXN1 allele in search for mutations or very small insertions/deletions.
Topics: Calcium-Binding Proteins; Cell Adhesion Molecules, Neuronal; Genetic Predisposition to Disease; Humans; Intellectual Disability; Mental Disorders; Mutation; Nervous System Diseases; Neural Cell Adhesion Molecules; Neurodevelopmental Disorders; Phenotype
PubMed: 30873608
DOI: 10.1111/cge.13537