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Chinese Medical Journal Nov 2017The aim was to update the genetic and clinical advances of congenital muscular dystrophy (CMD), based on a systematic review of the literature from 1991 to 2017. (Review)
Review
OBJECTIVE
The aim was to update the genetic and clinical advances of congenital muscular dystrophy (CMD), based on a systematic review of the literature from 1991 to 2017.
DATA SOURCES
Articles in English published in PubMed from 1991 to 2017 English were searched. The terms used in the literature searches were CMD.
STUDY SELECTION
The task force initially identified citations for 98 published articles. Of the 98 articles, 52 studies were selected after further detailed review. Three articles, which were not written in English, were excluded from the study. This study referred to all the important and English literature in full.
RESULTS
CMD is a group of early-onset disorders encompassing great clinical and genetic heterogeneity. Patients present with muscle weakness typically from birth to early infancy, delay or arrest of gross motor development, and joint and/or spinal rigidity. The diagnosis of CMD relies on clinical findings, brain and muscle imaging, muscle biopsy histology, muscle and/or skin immunohistochemical staining, and molecular genetic testing.
CONCLUSIONS
Advances in next-generation sequencing and histopathological techniques have enabled the recognition of distinct CMD subtypes supported by specific gene identification. Genetic counseling and multidisciplinary management of CMD play an important role in help patients and their family. Further elucidation of the significant clinical and genetic heterogeneity, therapeutic targets, and the clinical care for patients remains our challenge for the future.
Topics: High-Throughput Nucleotide Sequencing; Humans; Muscle, Skeletal; Muscular Dystrophies; Muscular Dystrophies, Limb-Girdle
PubMed: 29067961
DOI: 10.4103/0366-6999.217091 -
Annali Di Igiene : Medicina Preventiva... 2017Familial hypercholesterolemia (FH) is a genetic disorder that leads to elevated plasma LDL-cholesterol levels and premature coronary heart disease (CHD). An... (Review)
Review
BACKGROUND
Familial hypercholesterolemia (FH) is a genetic disorder that leads to elevated plasma LDL-cholesterol levels and premature coronary heart disease (CHD). An understanding of the mutations responsible for FH and the effectiveness of statins in lowering the risk of CHD in FH patients has increased interest in genetic screening strategies to improve FH diagnosis. In this study, we aimed to evaluate the cost-effectiveness of such strategies.
METHODS
We performed a systematic review of full economic evaluations that assessed the cost-effectiveness of FH genetic screening strategies. We used relevant search terms to investigate Medline, Scopus, Web of Science, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment Database, and the National Health Service Economic Evaluation Database. Data extraction and assessment of the quality of the studies were performed independently by two reviewers. The key features of the included studies are summarized in a narrative synthesis.
RESULTS
We included seven economic evaluations that assessed the cost-effectiveness of genetic screening for FH, published mainly in Europe between 2002 and 2015. Most studies had a no-screening strategy as a comparator, focused on relatives of index cases with genetic or clinical diagnosis of FH (cascade screening), considered a lifetime horizon and adopted a health care payer viewpoint. Cascade screening, based on genetic testing of relatives of an index case with confirmed clinical or genetic diagnosis of FH, was shown to be cost-effective in most settings.
CONCLUSIONS
Our review confirms the cost-effectiveness of cascade genetic screening for the diagnosis of FH. Further research may be needed to assess the cost-effectiveness of cascade screening following the introduction of newly recommended therapeutic regimes and next-generation sequencing.
Topics: Cost-Benefit Analysis; Databases, Factual; Family Health; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Hyperlipoproteinemia Type II; Mass Screening
PubMed: 28715059
DOI: 10.7416/ai.2017.2178 -
European Journal of Human Genetics :... Apr 2017Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat... (Meta-Analysis)
Meta-Analysis
Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.
Topics: Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Male; Middle Aged; Mutation; Polymorphism, Single Nucleotide; RNA Splicing; Siblings
PubMed: 28176767
DOI: 10.1038/ejhg.2016.204 -
In Vivo (Athens, Greece) Jan 2017Mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain (TKD) are associated with response and resistance to targeted therapy. The EGFR mutation... (Review)
Review
BACKGROUND
Mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain (TKD) are associated with response and resistance to targeted therapy. The EGFR mutation status in patients with advanced oral and oropharyngeal squamous cell carcinoma (OOSCC) was evaluated. A systematic literature review was undertaken to summarize current evidence and estimate the overall prevalence of EGFR TKD mutations in patients with head and neck squamous cell carcinoma (HNSCC).
MATERIALS AND METHODS
Genomic DNA was extracted from formalin-fixed, paraffin-embedded tumor samples of 113 patients with OOSCC. Pyrosequencing was performed to investigate mutations in EGFR exons 18 to 21. Medline databases were searched for relevant studies. Studies reporting mutations in the EGFR TKD in HNSCC were eligible for inclusion in the systematic review.
RESULTS
No mutations in the EGFR TKD were observed in 113 samples of OOSCC. A total of 53 eligible studies were included in the systematic review. In total, from the review, 117 patients harboring a total of 159 EGFR TKD mutations were reported among 4122 patients with HNSCC. The overall prevalence of EGFR TKD mutations in HNSCC was 2.8%.
CONCLUSION
Large-scale studies are warranted to provide further evidence regarding the mutation status of EGFR in patients with HNSCC.
Topics: Carcinoma, Squamous Cell; ErbB Receptors; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mutation; Neoplasm Staging; Polymerase Chain Reaction; Prognosis; Retrospective Studies; Survival Rate
PubMed: 28064216
DOI: 10.21873/invivo.11020 -
Clinical Epigenetics 2016Multiple studies have investigated global DNA methylation profiles and gene-specific DNA methylation in blood-based DNA to develop powerful screening markers for cancer.... (Review)
Review
Multiple studies have investigated global DNA methylation profiles and gene-specific DNA methylation in blood-based DNA to develop powerful screening markers for cancer. This systematic review summarizes the current evidence on methylation studies that investigated methylation level of blood-derived DNA of breast cancer (BC) patients in comparison to healthy controls by conducting a systematic literature review in PubMed and Web of Science. Essential results, such as methylation levels of BC cases and healthy controls, values, and odds ratios, were extracted from these studies by two investigators independently. Overall, 45 publications met the inclusion criteria for this review. DNA from whole blood, as well as cell-free DNA (cfDNA) from serum or plasma, was used in these studies. The most common method used for measuring global DNA methylation was the investigation of repetitive elements as surrogates and the application of array-based genome-wide methylation analysis. For measuring gene-specific methylation level, methylation-specific PCR and pyrosequencing were the most frequently used methods. Epigenome-wide blood DNA hypomethylation in BC patients were reported in several studies; however, the evidence is still not conclusive. The most frequently investigated gene in whole blood was , which was found more frequently methylated in patients compared to controls. was the most widely investigated gene in cfDNA of serum or plasma, which was also found more frequently methylated in patients compared to controls. Several of the eligible studies reported the associations of global hypomethylation and increased BC risk. Studies investigated associations between gene-specific methylation and BC risk, while got heterogeneous results. But two studies reported that hypermethylation of gene was associated with increased BC risk, which suggest the potential use of this gene for BC risk stratification. Overall, our review suggests the possibility of using blood-based DNA methylation marker as promising marker for BC risk stratification, as several studies found associations between certain methylation level in blood and BC risk. However, so far, the evidence is still quite limited. Optimal markers are yet to be developed and promising results needed to be validated in prospective study cohorts and tested in large screening populations.
Topics: Biomarkers, Tumor; Breast Neoplasms; Cell-Free System; DNA Methylation; DNA, Neoplasm; Early Detection of Cancer; Female; Genomics; Humans; Mass Screening; Odds Ratio
PubMed: 27895805
DOI: 10.1186/s13148-016-0282-6 -
BMC Medical Genomics Aug 2016Whole-exome sequencing (WES) consists in the capture, sequencing and analysis of all exons in the human genome. Originally developed in the research context, this... (Review)
Review
BACKGROUND
Whole-exome sequencing (WES) consists in the capture, sequencing and analysis of all exons in the human genome. Originally developed in the research context, this technology is now increasingly used clinically to inform patient care. The implementation of WES into healthcare poses significant organizational, regulatory, and ethical hurdles, which are widely discussed in the literature.
METHODS
In order to inform future policy decisions on the integration of WES into standard clinical practice, we performed a systematic literature review to identify the most important challenges directly reported by technology users.
RESULTS
Out of 2094 articles, we selected and analyzed 147 which reported a total of 23 different challenges linked to the production, analysis, reporting and sharing of patients' WES data. Interpretation of variants of unknown significance, incidental findings, and the cost and reimbursement of WES-based tests were the most reported challenges across all articles.
CONCLUSIONS
WES is already used in the clinical setting, and may soon be considered the standard of care for specific medical conditions. Yet, technology users are calling for certain standards and guidelines to be published before this technology replaces more focused approaches such as gene panels sequencing. In addition, a number of infrastructural adjustments will have to be made for clinics to store, process and analyze the amounts of data produced by WES.
Topics: Exome; Genomics; High-Throughput Nucleotide Sequencing; Humans; Sequence Analysis, DNA
PubMed: 27514372
DOI: 10.1186/s12920-016-0213-6 -
Asia-Pacific Journal of Ophthalmology... 2016Retinitis pigmentosa is the most common form of hereditary retinal degeneration causing blindness. Great progress has been made in the identification of the causative... (Review)
Review
Retinitis pigmentosa is the most common form of hereditary retinal degeneration causing blindness. Great progress has been made in the identification of the causative genes. Gene diagnosis will soon become an affordable routine clinical test because of the wide application of next-generation sequencing. Gene-based therapy provides hope for curing the disease. Investigation into the molecular pathways from mutation to rod cell death may reveal targets for developing new treatment. Related progress with existing systematic review is briefly summarized so that readers may find the relevant references for in-depth reading. Future trends in the study of retinitis pigmentosa are also discussed.
Topics: Animals; Clinical Trials as Topic; Cone-Rod Dystrophies; Disease Management; Disease Models, Animal; Gene Expression Profiling; Genetic Therapy; High-Throughput Nucleotide Sequencing; Humans; Mutation; Retinal Degeneration; Retinitis Pigmentosa; Stem Cell Transplantation
PubMed: 27488069
DOI: 10.1097/APO.0000000000000227 -
BMC Infectious Diseases Jun 2016The outcome of leishmaniasis is an interplay between Leishamania and the host. Identifying contributory host genetic factors is complicated by the variability in... (Review)
Review
BACKGROUND
The outcome of leishmaniasis is an interplay between Leishamania and the host. Identifying contributory host genetic factors is complicated by the variability in phenotype, ethnicity and parasite species. Leishmaniasis is caused exclusively by L. donovani in Sri Lanka with localized cutaneous leishmaniasis (LCL) being the predominant form. We report here an association study of human leucocyte antigen (HLA) class I and II genes with LCL in Sri Lanka, the first on HLA associations in cutaneous leishmaniasis in a South Asian population.
METHODS
An existing DNA repository of 200 each of patients and controls was typed for HLA-DQ by PCR-SSP. Next generation sequencing-based typing for HLA-A, HLA-B and HLA-DRB1 alleles was done in a subset of 280 samples. Association tests were performed on 28,489 genotyped and imputed SNPs spanning a region of 1.4 Mb across the HLA genes. To compare our results with similar studies, we carried out a systematic review to document all HLA associations reported to-date for cutaneous and muco-cutaneous leishmaniasis.
RESULTS
DRB1*04 DQB1*02 (P = 0.03; Pc = 0.09), DRB1*07 DQB1*02 (P = 0.03; Pc = 0.09) haplotypes were absent in patients. B*07 (P = 0.007; Pc = 0.13; OR = 0.36; 95 % CI = 0.17-0.77) allele and DRB1*15 DQB1*06 (P = 0.00; Pc < 0.01; OR = 0.3; 95 % CI = 0.2-.0.6) haplotype were over represented in controls and DRB1*15 (P = 0.002; Pc = 0.01) allele was over represented in patients. Two SNPs (rs281864595/rs1050517) in the antigen recognition region of HLA-B, comprised a haplotype more frequent in controls (P = 0.04). The alleles identified by the systematic review to predispose or to protect from cutaneous/mucocutaneous leishmaniasis remained highly heterogeneous in different populations studied.
CONCLUSIONS
Our preliminary findings suggest a role for some class I and class II HLA genes in determining predisposition to LCL in this population which should be corroborated with further studies. The systematic review reiterates this need, as the purported susceptibility or protection gained by certain HLA alleles or haplotypes has rarely been independently verified.
Topics: Adolescent; Adult; Alleles; Asian People; Case-Control Studies; Child; Child, Preschool; Ethnicity; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; HLA-A Antigens; HLA-B Antigens; HLA-DQ beta-Chains; HLA-DRB1 Chains; Haplotypes; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Leishmaniasis, Cutaneous; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Sri Lanka; Young Adult
PubMed: 27301744
DOI: 10.1186/s12879-016-1626-8 -
Journal of Assisted Reproduction and... Jul 2016The purpose of the review was to define the various diagnostic platforms currently available to perform preimplantation genetic testing for aneuploidy and describe in a... (Review)
Review
PURPOSE
The purpose of the review was to define the various diagnostic platforms currently available to perform preimplantation genetic testing for aneuploidy and describe in a clear and balanced manner the various strengths and weaknesses of these technologies.
METHODS
A systematic literature review was conducted. We used the terms "preimplantation genetic testing," "preimplantation genetic diagnosis," "preimplantation genetic screening," "preimplantation genetic diagnosis for aneuploidy," "PGD," "PGS," and "PGD-A" to search through PubMed, ScienceDirect, and Google Scholar from the year 2000 to April 2016. Bibliographies of articles were also searched for relevant studies. When possible, larger randomized controlled trials were used. However, for some emerging data, only data from meeting abstracts were available.
RESULTS
PGS is emerging as one of the most valuable tools to enhance pregnancy success with assisted reproductive technologies. While all of the current diagnostic platforms currently available have various advantages and disadvantages, some platforms, such as next-generation sequencing (NGS), are capable of evaluating far more data points than has been previously possible. The emerging complexity of different technologies, especially with the utilization of more sophisticated tools such as NGS, requires an understanding by clinicians in order to request the best test for their patients..
CONCLUSION
Ultimately, the choice of which diagnostic platform is utilized should be individualized to the needs of both the clinic and the patient. Such a decision must incorporate the risk tolerance of both the patient and provider, fiscal considerations, and other factors such as the ability to counsel patients on their testing results and how these may or may not impact clinical outcomes.
Topics: Aneuploidy; Blastocyst; Female; Fertilization in Vitro; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Pregnancy; Preimplantation Diagnosis; Real-Time Polymerase Chain Reaction
PubMed: 27299602
DOI: 10.1007/s10815-016-0740-2 -
Tuberculosis (Edinburgh, Scotland) May 2016Contact tracing complemented with genotyping is considered an important means of understanding person-to-person transmission of tuberculosis (TB). It still remains... (Review)
Review
Contact tracing complemented with genotyping is considered an important means of understanding person-to-person transmission of tuberculosis (TB). It still remains unclear whether Whole Genome Sequencing (WGS) of Mycobacterium tuberculosis can rule in transmission and how it performs in different human populations, risk groups and across TB lineages. This systematic review aimed to determine the sensitivity and specificity of WGS for detection of recent transmission using conventional epidemiology as the gold standard and investigate if WGS identifies previously undetected transmission events. Systematic review was conducted according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses group. A compound search strategy was developed to identify all relevant studies published between 01/01/2005 and 30/11/2014 using three online databases. Publications satisfying specific criteria have been identified and data extracted. A total of 12 publications were included. We established that WGS has a higher discriminatory power compared to conventional genotyping and detects transmission events missed by epidemiological investigations. A cut-off value of <6 SNPs between isolates may predict recent transmission. None of the studies performed a head-to-head comparison between WGS and conventional genotyping using unselected prospectively collected isolates. Minimum reporting criteria for WGS studies have been proposed and quality control parameters considered.
Topics: Contact Tracing; Disease Outbreaks; Genome, Bacterial; Genotype; High-Throughput Nucleotide Sequencing; Humans; Molecular Epidemiology; Mycobacterium tuberculosis; Phenotype; Tuberculosis
PubMed: 27156621
DOI: 10.1016/j.tube.2016.02.009