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Molecular Neurodegeneration Nov 2022The family of VPS10p-Domain (D) receptors comprises five members named SorLA, Sortilin, SorCS1, SorCS2 and SorCS3. While their physiological roles remain incompletely... (Review)
Review
The family of VPS10p-Domain (D) receptors comprises five members named SorLA, Sortilin, SorCS1, SorCS2 and SorCS3. While their physiological roles remain incompletely resolved, they have been recognized for their signaling engagements and trafficking abilities, navigating a number of molecules between endosome, Golgi compartments, and the cell surface. Strikingly, recent studies connected all the VPS10p-D receptors to Alzheimer's disease (AD) development. In addition, they have been also associated with diseases comorbid with AD such as diabetes mellitus and major depressive disorder. This systematic review elaborates on genetic, functional, and mechanistic insights into how dysfunction in VPS10p-D receptors may contribute to AD etiology, AD onset diversity, and AD comorbidities. Starting with their functions in controlling cellular trafficking of amyloid precursor protein and the metabolism of the amyloid beta peptide, we present and exemplify how these receptors, despite being structurally similar, regulate various and distinct cellular events involved in AD. This includes a plethora of signaling crosstalks that impact on neuronal survival, neuronal wiring, neuronal polarity, and synaptic plasticity. Signaling activities of the VPS10p-D receptors are especially linked, but not limited to, the regulation of neuronal fitness and apoptosis via their physical interaction with pro- and mature neurotrophins and their receptors. By compiling the functional versatility of VPS10p-D receptors and their interactions with AD-related pathways, we aim to further propel the AD research towards VPS10p-D receptor family, knowledge that may lead to new diagnostic markers and therapeutic strategies for AD patients.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Depressive Disorder, Major; Protein Transport; Nerve Growth Factors
PubMed: 36397124
DOI: 10.1186/s13024-022-00576-2 -
Journal of Atherosclerosis and... 2015Familial hypercholesterolemia is a genetic disorder associated with elevated LDL-cholesterol and high lifetime cardiovascular risk. Both clinical and molecular cascade... (Review)
Review
Familial hypercholesterolemia is a genetic disorder associated with elevated LDL-cholesterol and high lifetime cardiovascular risk. Both clinical and molecular cascade screening programs have been implemented to increase early definition and treatment. In this systematic review, we discuss the main issues found in 65 different articles related to cascade screening and familial hypercholesterolemia, covering a range of topics including different types/strategies, considerations both positive and negative regarding cascade screening in general and associated with the different strategies, cost and coverage consideration, direct and indirect contact with patients, public policy around life insurance and doctor-patient confidentiality, the "right to know," and public health concerns regarding familial hypercholesterolemia.
Topics: Adolescent; Adult; Cardiology; Cardiovascular Diseases; Child; Child, Preschool; Cholesterol, LDL; Cost-Benefit Analysis; Databases, Factual; Family Health; Female; Health Policy; Humans; Hyperlipidemias; Hyperlipoproteinemia Type II; Infant; Male; Mass Screening; Pathology, Molecular; Risk Factors; Workforce; Young Adult
PubMed: 26194978
DOI: 10.5551/jat.31237 -
JAMA Network Open Nov 2023Exome sequencing (ES) has been established as the preferred first line of diagnostic testing for certain neurodevelopmental disorders, such as global developmental delay... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Exome sequencing (ES) has been established as the preferred first line of diagnostic testing for certain neurodevelopmental disorders, such as global developmental delay and autism spectrum disorder; however, current recommendations are not specific to or inclusive of congenital hydrocephalus (CH).
OBJECTIVE
To determine the diagnostic yield of ES in CH and whether ES should be considered as a first line diagnostic test for CH.
DATA SOURCES
PubMed, Cochrane Library, and Google Scholar were used to identify studies published in English between January 1, 2010, and April 10, 2023. The following search terms were used to identify studies: congenital hydrocephalus, ventriculomegaly, cerebral ventriculomegaly, primary ventriculomegaly, fetal ventriculomegaly, prenatal ventriculomegaly, molecular analysis, genetic cause, genetic etiology, genetic testing, exome sequencing, whole exome sequencing, genome sequencing, microarray, microarray analysis, and copy number variants.
STUDY SELECTION
Eligible studies included those with at least 10 probands with the defining feature of CH and/or severe cerebral ventriculomegaly that had undergone ES. Studies with fewer than 10 probands, studies of mild or moderate ventriculomegaly, and studies using genetic tests other than ES were excluded. A full-text review of 68 studies was conducted by 2 reviewers. Discrepancies were resolved by consensus.
DATA EXTRACTION AND SYNTHESIS
Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Meta-Analysis of Observational Studies in Epidemiology guidelines were used by 2 reviewers to extract data. Data were synthesized using a random-effects model of single proportions. Data analysis occurred in April 2023.
MAIN OUTCOMES AND MEASURES
The primary outcome was pooled diagnostic yield. Additional diagnostic yields were estimated for specific subgroups on the basis of clinical features, syndromic presentation, and parental consanguinity. For each outcome, a 95% CI and estimate of interstudy heterogeneity (I2 statistic) was reported.
RESULTS
From 498 deduplicated and screened records, 9 studies with a total of 538 CH probands were selected for final inclusion. The overall diagnostic yield was 37.9% (95% CI, 20.0%-57.4%; I2 = 90.1). The yield was lower for isolated and/or nonsyndromic cases (21.3%; 95% CI, 12.8%-31.0%; I2 = 55.7). The yield was higher for probands with reported consanguinity (76.3%; 95% CI, 65.1%-86.1%; I2 = 0) than those without (16.2%; 95% CI, 12.2%-20.5%; I2 = 0).
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis of the diagnostic yield of ES in CH, the diagnostic yield was concordant with that of previous recommendations for other neurodevelopmental disorders, suggesting that ES should also be recommended as a routine diagnostic adjunct for patients with CH.
Topics: Female; Pregnancy; Humans; Autism Spectrum Disorder; Exome Sequencing; Pathology, Molecular; Patients; Hydrocephalus
PubMed: 37991765
DOI: 10.1001/jamanetworkopen.2023.43384 -
Current Pediatric Reviews 2023Silver-Russell syndrome (SRS) is a developmental disorder involving extreme growth failure, characteristic facial features and underlying genetic heterogeneity. As the...
BACKGROUND
Silver-Russell syndrome (SRS) is a developmental disorder involving extreme growth failure, characteristic facial features and underlying genetic heterogeneity. As the clinical heterogeneity of SRS makes diagnosis a challenging task, the worldwide incidence of SRS could vary from 1:30,000 to 1:100,000. Although various chromosomal, genetic, and epigenetic mutations have been linked with SRS, the cause had only been identified in half of the cases.
MATERIAL AND METHODS
To have a better understanding of the SRS clinical presentation and mutation/ epimutation responsible for SRS, a systematic review of the literature was carried out using appropriate keywords in various scientific databases (PROSPERO protocol registration CRD42021273211). Clinical features of SRS have been compiled and presented corresponding to the specific genetic subtype. An attempt has been made to understand the recurrence risk and the role of model organisms in understanding the molecular mechanisms of SRS pathology, treatment, and management strategies of the affected patients through the analysis of selected literature.
RESULTS
156 articles were selected to understand the clinical and molecular heterogeneity of SRS. Information about detailed clinical features was available for 228 patients only, and it was observed that body asymmetry and relative macrocephaly were most prevalent in cases with methylation defects of the 11p15 region. In about 38% of cases, methylation defects in ICRs or genomic mutations at the 11p15 region have been implicated. Maternal uniparental disomy of chromosome 7 (mUPD7) accounts for about 7% of SRS cases, and rarely, uniparental disomy of other autosomes (11, 14, 16, and 20 chromosomes) has been documented. Mutation in half of the cases is yet to be identified. Studies involving mice as experimental animals have been helpful in understanding the underlying molecular mechanism. As the clinical presentation of the syndrome varies a lot, treatment needs to be individualized with multidisciplinary effort.
CONCLUSION
SRS is a clinically and genetically heterogeneous disorder, with most of the cases being implicated with a mutation in the 11p15 region and maternal disomy of chromosome 7. Recurrence risk varies according to the molecular subtype. Studies with mice as a model organism have been useful in understanding the underlying molecular mechanism leading to the characteristic clinical presentation of the syndrome. Management strategies often need to be individualized due to varied clinical presentations.
Topics: Humans; Animals; Mice; Mice, Inbred ICR; Silver-Russell Syndrome; Uniparental Disomy; Genomic Imprinting
PubMed: 35293298
DOI: 10.2174/1573396318666220315142542 -
JAMA Neurology Dec 2022There are many known acquired risk factors for cerebral palsy (CP), but in some cases, CP is evident without risk factors (cryptogenic CP). Early CP cohort studies... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
There are many known acquired risk factors for cerebral palsy (CP), but in some cases, CP is evident without risk factors (cryptogenic CP). Early CP cohort studies report a wide range of diagnostic yields for sequence variants assessed by exome sequencing (ES) and copy number variants (CNVs) assessed by chromosomal microarray (CMA).
OBJECTIVE
To synthesize the emerging CP genetics literature and address the question of what percentage of individuals with CP have a genetic disorder via ES and CMA.
DATA SOURCES
Searched articles were indexed by PubMed with relevant queries pertaining to CP and ES/CMA (query date, March 15, 2022).
STUDY SELECTION
Inclusion criteria were as follows: primary research study, case series with 10 or more nonrelated individuals, CP diagnosis, and ES and/or CMA data used for genetic evaluation. Nonblinded review was performed.
DATA EXTRACTION AND SYNTHESIS
Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for assessing data quality and validity. Data were extracted by a single observer.
MAIN OUTCOMES AND MEASURES
A separate meta-analysis was performed for each modality (ES, CMA). The primary outcome was proportion/molecular diagnostic yield (number of patients with a discovered genetic disorder divided by the total number of patients in the cohort), evaluated via meta-analysis of single proportions using random-effects logistic regression. A subgroup meta-analysis was conducted, using risk factor classification as a subgroup. A forest plot was used to display diagnostic yields of individual studies.
RESULTS
In the meta-analysis of ES yield in CP, the overall diagnostic yield of ES among the cohorts (15 study cohorts comprising 2419 individuals from 11 articles) was 23% (95% CI, 15%-34%). The diagnostic yield across cryptogenic CP cohorts was 35% (95% CI, 27%-45%), compared with 7% (95% CI, 4%-12%) across cohorts with known risk factors (noncryptogenic CP). In the meta-analysis of CMA yield in CP, the diagnostic yield of CMA among the cohorts (5 study cohorts comprising 294 individuals from 5 articles) was 5% (95% CI, 2%-12%).
CONCLUSIONS AND RELEVANCE
Results of this systematic review and meta-analysis suggest that for individuals with cryptogenic CP, ES followed by CMA to identify molecular disorders may be warranted.
Topics: Humans; Pathology, Molecular; Cerebral Palsy; Microarray Analysis; Exome Sequencing; DNA Copy Number Variations
PubMed: 36279113
DOI: 10.1001/jamaneurol.2022.3549 -
Critical Reviews in Clinical Laboratory... 2016Accurate diagnosis of malaria is essential for identification and subsequent treatment of the disease. Currently, microscopy and rapid diagnostic tests are the most... (Meta-Analysis)
Meta-Analysis Review
Accurate diagnosis of malaria is essential for identification and subsequent treatment of the disease. Currently, microscopy and rapid diagnostic tests are the most commonly used diagnostics, next to treatment based on clinical signs only. These tests are easy to deploy, but have a relatively high detection limit. With declining prevalence in many areas, there is an increasing need for more sensitive diagnostics. Molecular tools may be a suitable alternative, although costs and technical requirements currently hamper their implementation in resource limited settings. A range of (near) point-of-care diagnostics is therefore under development, including simplifications in sample preparation, amplification and/or read-out of the test. Accuracy data, in combination with technical characteristics, are essential in determining which molecular test, if any, would be the most promising to be deployed. This review presents a comprehensive overview of the currently available molecular malaria diagnostics, ranging from well-known tests to platforms in early stages of evaluation, and systematically evaluates their published accuracy. No important difference in accuracy was found between the most commonly used PCR-based assays (conventional, nested and real-time PCR), with most of them having high sensitivity and specificity, implying that there are no reasons other than practical ones to choose one technique over the other. Loop-mediated isothermal amplification and other (novel) diagnostics appear to be highly accurate as well, with some offering potential to be used in resource-limited settings.
Topics: Humans; Malaria; Microscopy; Pathology, Molecular; Polymerase Chain Reaction; Reference Standards; Sensitivity and Specificity
PubMed: 26376713
DOI: 10.3109/10408363.2015.1084991 -
Critical Reviews in Oncology/hematology May 2023Pancreato-biliary and gynecological adenocarcinomas need better tools to predict clinical outcome. Potential prognostic mesenchymal(-like) transcriptome-based subtypes... (Review)
Review
Pancreato-biliary and gynecological adenocarcinomas need better tools to predict clinical outcome. Potential prognostic mesenchymal(-like) transcriptome-based subtypes have been identified in these cancers. In this systematic review, we include studies into molecular subtyping and summarize biological and clinical features of the subtypes within and across sites of origin, searching for suggestions to improve classification and prognostication. PubMed and Embase were searched for original research articles describing potential mesenchymal(-like) mRNA-based subtypes in pancreato-biliary or gynecological adenocarcinomas. Studies limited to supervised clustering were excluded. Fourty-four studies discussing cholangiocarcinomas, gallbladder, ampullary, pancreatic, ovarian, and endometrial adenocarcinomas were included. There was overlap in molecular and clinical features in mesenchymal(-like) subtypes across all adenocarcinomas. Approaches including microdissection were more likely to identify prognosis-associated subtypes. To conclude, molecular subtypes in pancreato-biliary and gynecological adenocarcinomas share biological and clinical characteristics. Furthermore, separation of stromal and epithelial signals should be applied in future studies of biliary and gynecological adenocarcinomas.
Topics: Humans; Pancreatic Neoplasms; Adenocarcinoma; Prognosis; Bile Duct Neoplasms; Bile Ducts, Intrahepatic
PubMed: 37004743
DOI: 10.1016/j.critrevonc.2023.103982 -
Acta Tropica Mar 2023It has been tested and proven that vaccination is still the best strategy to combat infectious diseases. However, to date, there are still no vaccines against human... (Review)
Review
It has been tested and proven that vaccination is still the best strategy to combat infectious diseases. However, to date, there are still no vaccines against human soil-transmitted helminthic diseases, despite their high prevalence globally, particularly in developing countries and rural areas with tropical climates and poor sanitation. The development of vaccines against helminths is riddled with obstacles. Helminths have a complex life cycle, multiple stages within the same host with stage-specific antigen expression, and the ability to regulate host immune reactions to evade the immune response. These elements contribute to the main challenge of helminthic vaccines: the identification of effective vaccine candidates. Therefore, this article reviews the current progress and potential future direction of soil-transmitted helminthic vaccines, particularly against Trichuris trichiura, Ascaris lumbricoides, Strongyloides stercoralis, Necator americanus and Ancylostoma duodenale. The study design employed was a systematic review, using qualitative meta-summary synthesis. Preclinical studies and clinical trials on the development of protein subunit vaccines against the five soil-transmitted helminths were searched on PubMed and Scopus. Effectiveness was indicated by a reduction in worm burden or larval output, an increase in specific IgG levels, or an increase in cytokine production. Our findings show that only the hookworm vaccine against N. americanus is in the clinical trial phase, while the rest is still in exploratory research and pre-clinical development phase.
Topics: Animals; Humans; Soil; Hookworm Infections; Ascaris lumbricoides; Ancylostomatoidea; Necator americanus; Vaccines; Helminthiasis; Feces
PubMed: 36586174
DOI: 10.1016/j.actatropica.2022.106796 -
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 -
Gene Dec 2023Identification of genetic risk factors for PCOS susceptibility. (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
Identification of genetic risk factors for PCOS susceptibility.
OBJECTIVE
To identify genetic risk variants of the genes involved in metabolic or inflammatory pathways.
DATA SOURCES
Relevant literature was identified and extracted from PubMed, Central Cochrane Library, Google Scholar, and Science Direct by using a set of keywords related to pre-determined genes up to 06 May 2023. Study selection and synthesis: PRISMA guidelines were followed to design the protocol which is registered in PROSPERO (CRD42023422501). Pooled odds ratio (OR) and 95% confidence interval (95% CI) for different gene variants were calculated under different genetic models (dominant model, recessive model, additive model, and allele model) by using Review Manager software 4.2.
MAIN OUTCOMES
Metabolic genetic variants FTO rs9939609, IL-6 rs1800795 and CAPN10 rs3842570, rs2975760, and RAB5B rs705702 are associated with PCOS risk.
RESULTS
Forty-four relevant articles have been identified for genes involved in metabolic (n = 23) or inflammatory pathways (n = 21). There is a significant association (p < 0.05) of IL-6 rs1800795 and FTO rs9939609 with increased risk.CAPN10 rs2975760 Ins allele is suggested as a protective factor among only the non-Asian population. Also, a significant association of CAPN10 rs2975760 and RAB5B rs705702 with increased risk among the Asian population is suggested. However, no significant association could be found between CAPN10 rs3792267, rs5030952, and SUMO1P1 rs2272046, and the risk of PCOS in any of the subpopulations analysed. In silico analysis suggests the deleterious effect of IL-6 rs1800795.
CONCLUSION
and relevance: The study suggests the role of various genetic variants for genetic predisposition to PCOS among different subpopulations.
Topics: Female; Humans; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Genetic Predisposition to Disease; Interleukin-6; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 37714276
DOI: 10.1016/j.gene.2023.147796