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Orphanet Journal of Rare Diseases Jul 2022Primary ciliary dyskinesia (PCD) represents a highly heterogenous disorder with extensive clinical and genetic patterns among populations of different geographic... (Review)
Review
BACKGROUND
Primary ciliary dyskinesia (PCD) represents a highly heterogenous disorder with extensive clinical and genetic patterns among populations of different geographic location and ethnic origin. However, data about Chinese patients are limited. We aimed to summarize the clinical and genetic spectrum of Chinese PCD patients based on all available literatures.
METHODS
We searched Embase, Pubmed, Web of Science and Chinese databases including CNKI, SinoMed and Wanfang from 1981 to 2021, to identify articles reporting patients with PCD in China, which had included information about transmission electron microscopy and/or genetic testing.
RESULTS
A total of 244 Chinese PCD patients in 52 articles were included. Of these patients, the mean age was 13.1 years, and 55 patients (22.5%) were diagnosed with PCD after 18 years old. Compared with patients diagnosed with PCD in childhood or infancy, patients diagnosed with PCD in adulthood had a higher prevalence of chronic wet cough, sinusitis, Pseudomonas aeruginosa (PA) isolation and radiological bronchiectasis as well as worse lung function. 25 PCD-related genes were identified in 142 patients, and DNAH5, DNAH11, CCDC39 and CCDC40 were the most frequently detected mutations. More than half of genetic variants were loss-of-function mutations, and the majority of these variants were seen only once. Correlations between PCD phenotype, genotype and ciliary ultrastructure were also evidenced.
CONCLUSIONS
Diagnostic delay and under-recognition of PCD remain a big issue in China, which contributes to progressive lung disease and PA infection indicating worse outcome. Specialist equipment and expertise are urgently required to facilitate the early diagnosis and treatment of PCD.
TRIAL REGISTRY
PROSPERO; No.: CRD42021257804; URL: www.crd.york.ac.uk/prospero/.
Topics: Cilia; Ciliary Motility Disorders; Delayed Diagnosis; Genotype; Humans; Kartagener Syndrome; Mutation; Phenotype
PubMed: 35854386
DOI: 10.1186/s13023-022-02427-1 -
European Journal of Cancer (Oxford,... Sep 2021There are limited data comparing the OncotypeDX© Recurrence Score (RS) among BRCA mutation carriers and patients with sporadic breast cancer. (Meta-Analysis)
Meta-Analysis
INTRODUCTION
There are limited data comparing the OncotypeDX© Recurrence Score (RS) among BRCA mutation carriers and patients with sporadic breast cancer.
AIM
To compare RS results among BRCA mutation carriers and patients with sporadic breast cancer in oestrogen receptor positive (ER+), human epidermal growth factor receptor-2 negative (HER2-) breast cancer.
METHODS
A systematic review was performed in accordance with PRISMA and MOOSE guidelines. Retrospective cohort studies comparing RS in BRCA mutation carriers and cases of sporadic cancer were included. Dichotomous variables were pooled as odds ratios (ORs) and associated 95% confidence intervals (CIs) using the Mantel-Haenszel method.
RESULTS
Five studies involving 4286 patients were included with a mean age of 60 years (range 22-85). Overall, 7.8% were BRCA mutation carriers (333/4286). The mean RS was 18.0 (range 0-71), and the mean RS in BRCA carriers was 25 (range 10-71) versus 18.4 in cases of sporadic disease (range 0-62). Patients with sporadic cancers were more likely to have RS < 18 (OR 0.27, 95% CI 0.14-0.51, P = 0.010). BRCA mutation carriers were more likely to have RS 18-30 (OR 1.74, 95% CI 1.28-2.37, P < 0.001) and RS > 30 (OR 3.71, 95% CI 2.55-5.40, P < 0.001).
CONCLUSION
There is an increased likelihood of high-risk RS among patients with known germline BRCA mutations when compared to patients developing sporadic ER+/HER2-early breast cancer. This study offers insight into genomic testing results within BRCA mutation carriers which may be useful in counselling patients with BRCA mutations in future practice.
Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Female; Genes, BRCA1; Genes, BRCA2; Heterozygote; Humans; Middle Aged; Mutation; Receptor, ErbB-2; Receptors, Estrogen; Young Adult
PubMed: 34284256
DOI: 10.1016/j.ejca.2021.06.032 -
BMC Cancer Apr 2016Brain metastases (BM) from colorectal cancer (CRC) are a rare event. However, the implications for affected patients are severe, and the incidence has been reported to... (Review)
Review
BACKGROUND
Brain metastases (BM) from colorectal cancer (CRC) are a rare event. However, the implications for affected patients are severe, and the incidence has been reported to be increasing. For clinicians, knowledge about the characteristics associated with BM is important and could lead to earlier diagnosis and improved survival.
METHOD
In this paper, we describe the incidence as well as characteristics associated with BM based on a systematic review of the current literature, following the PRISMA guidelines.
RESULTS
We show that the incidence of BM in CRC patients ranges from 0.6 to 3.2%. BM are a late stage phenomenon, and young age, rectal primary and lung metastases are associated with increased risk of developing BM. Molecular markers such as KRAS, BRAF, NRAS mutation as well as an increase in CEA and CA19.9 levels are suggested predictors of brain involvement. However, only KRAS mutations are reasonably well investigated and associated with an increased risk of BM.
CONCLUSION
The incidence of BM from CRC is 0.6 to 3.2% and did not seem to increase over time. Development of BM is associated with young age, lung metastases, rectal primary and KRAS mutation. Increased awareness of brain involvement in patients with these characteristics is necessary.
Topics: Age Factors; Brain Neoplasms; Colorectal Neoplasms; Female; GTP Phosphohydrolases; Genetic Association Studies; Humans; Lung Neoplasms; Male; Membrane Proteins; Mutation; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Risk Factors
PubMed: 27037031
DOI: 10.1186/s12885-016-2290-5 -
Understanding Mutations in Human SARS-CoV-2 Spike Glycoprotein: A Systematic Review & Meta-Analysis.Viruses Mar 2023Genetic variant(s) of concern (VoC) of SARS-CoV-2 have been emerging worldwide due to mutations in the gene encoding spike glycoprotein. We performed comprehensive... (Meta-Analysis)
Meta-Analysis Review
Genetic variant(s) of concern (VoC) of SARS-CoV-2 have been emerging worldwide due to mutations in the gene encoding spike glycoprotein. We performed comprehensive analyses of spike protein mutations in the significant variant clade of SARS-CoV-2, using the data available on the Nextstrain server. We selected various mutations, namely, A222V, N439K, N501Y, L452R, Y453F, E484K, K417N, T478K, L981F, L212I, N856K, T547K, G496S, and Y369C for this study. These mutations were chosen based on their global entropic score, emergence, spread, transmission, and their location in the spike receptor binding domain (RBD). The relative abundance of these mutations was mapped with global mutation D614G as a reference. Our analyses suggest the rapid emergence of newer global mutations alongside D614G, as reported during the recent waves of COVID-19 in various parts of the world. These mutations could be instrumentally imperative for the transmission, infectivity, virulence, and host immune system's evasion of SARS-CoV-2. The probable impact of these mutations on vaccine effectiveness, antigenic diversity, antibody interactions, protein stability, RBD flexibility, and accessibility to human cell receptor ACE2 was studied in silico. Overall, the present study can help researchers to design the next generation of vaccines and biotherapeutics to combat COVID-19 infection.
Topics: Humans; Spike Glycoprotein, Coronavirus; COVID-19; SARS-CoV-2; Mutation; Protein Binding
PubMed: 37112836
DOI: 10.3390/v15040856 -
Journal of Human Genetics May 2015Mutations in APP, PSEN1 and PSEN2 as the genetic causes of familial Alzheimer's disease (FAD) have been found in various ethnic populations. A substantial number of FAD... (Meta-Analysis)
Meta-Analysis Review
Mutations in APP, PSEN1 and PSEN2 as the genetic causes of familial Alzheimer's disease (FAD) have been found in various ethnic populations. A substantial number of FAD pedigrees with mutations have been reported in the Japanese population; however, it remains unclear whether the genetic and clinical features of FAD in the Japanese population differ from those in other populations. To address this issue, we conducted a systematic review and meta-analysis of Japanese FAD and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) by literature search. Using this analysis, we identified 39 different PSEN1 mutations in 140 patients, 5 APP mutations in 35 patients and 16 MAPT mutations in 84 patients. There was no PSEN2 mutation among Japanese patients. The age at onset in Japanese FAD patients with PSEN1 mutations was significantly younger than that in patients with APP mutations. Kaplan-Meier analysis revealed that patients with MAPT mutations showed a shorter survival than patients with PSEN1 or APP mutations. Patients with mutations in different genes exhibit characteristic clinical presentations, suggesting that mutations in causative genes may modify the clinical presentations. By collecting and cataloging genetic and clinical information on Japanese FAD and FTDP-17, we developed an original database designated as Japanese Familial Alzheimer's Disease Database, which is accessible at http://alzdb.bri.niigata-u.ac.jp/.
Topics: Age of Onset; Alzheimer Disease; Chromosomes, Human, Pair 17; Frontotemporal Dementia; Genetic Predisposition to Disease; Humans; Mutation
PubMed: 25694106
DOI: 10.1038/jhg.2015.15 -
Prenatal Diagnosis Feb 2023The aim was to determine the accuracy of cell-free DNA testing (cfDNA) for detecting sex chromosome aneuploidies (SCA) in singleton pregnancies. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The aim was to determine the accuracy of cell-free DNA testing (cfDNA) for detecting sex chromosome aneuploidies (SCA) in singleton pregnancies.
METHODS
A systematic review and meta-analysis was performed to assess cfDNA accuracy for prenatal detection of 45,X, 47,XXY, 47,XXX and 47,XYY. Inclusion was restricted to studies published between January 2010 and December 2021 reporting both cfDNA and confirmatory diagnostic test results.
RESULTS
For 45,X, the sensitivity was 98.8% (95%CI 94.6%-100%), specificity 99.4% (95%CI 98.7%-99.9%) and positive predictive value (PPV) 14.5% (95%CI 7.0%-43.8%). For 47,XXY, the sensitivity was 100% (95%CI 99.6%-100%), specificity 100% (95%CI 99.9%-100%) and PPV 97.7% (95%CI 78.6%-100%). For 47,XXX, the sensitivity was 100% (95%CI 96.9%-100%), specificity 99.9% (95%CI 99.7%-100%) and PPV 61.6% (95%CI 37.6%-95.4%). For 47,XYY, the sensitivity was 100% (95%CI 91.3%-100%), specificity 100% (95% CI 100%-100%) and PPV 100% (95%CI 76.5%-100%). All four SCAs had estimated negative predictive values (NPV) exceeding 99.99%, though false negatives were reported.
CONCLUSIONS
This analysis suggests that cfDNA is a reliable screening test for SCA, though both false negatives and false positives were reported. These estimates of test performance are derived from pregnancies at high pretest risk for aneuploidy, limiting the generalisability to average risk pregnancies.
Topics: Pregnancy; Female; Humans; Cell-Free Nucleic Acids; Sex Chromosome Aberrations; Aneuploidy; Chromosomes, Human, X; Prenatal Diagnosis
PubMed: 36588186
DOI: 10.1002/pd.6298 -
Kidney International Sep 2022Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated...
Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, mitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.
Topics: Ataxia; Genetic Association Studies; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Steroids; Ubiquinone
PubMed: 35483523
DOI: 10.1016/j.kint.2022.02.040 -
Journal of the Chinese Medical... Mar 2015A systematic review of genetic studies of thyroid disorders in Taiwan identified studies of gene mutations involved in the synthesis and binding of thyroid hormone, as... (Review)
Review
A systematic review of genetic studies of thyroid disorders in Taiwan identified studies of gene mutations involved in the synthesis and binding of thyroid hormone, as well as mutations of proto-oncogenes and tumor suppressor genes in thyroid cancer. Studies related to gene polymorphisms in patients with autoimmune thyroid disease (AITD) and thyroid cancer were also reviewed. The most prevalent mutations in the Han-Chinese population were c.2268insT in the thyroid peroxidase (TPO) gene and c.919-2A>G in the Pendred syndrome (PDS) gene. Additional mutations have also been revealed in the genes encoding TPO (n = 5), thyroglobulin (TG; n = 6), pendrin (n = 2), and thyroxine-binding globulin (TBG; n = 2), which were novel at the time they were reported. The prevalence of various somatic mutations in differentiated thyroid cancer was similar in Taiwan and Western countries, with the RAS kinase mutation and tyrosine receptor kinase (TRK) and rearranged during transfection (RET) proto-oncogenes being detected in lower frequencies and the B-type RAF kinase (BRAF) mutation accounting for the majority of cases. Recent microRNA analysis revealed an association between miR146b and the BRAF mutation, which was associated with poor prognosis of papillary thyroid carcinoma (PTC). Susceptibility to Graves' disease (GD) was linked to the human leukocyte antigen (HLA) region. The associated alleles were different in Han-Chinese and Caucasians; HLA-DPB1*0501, the major allele in Taiwan, has a low frequency in the West. By contrast, a high frequency of HLA-DRB1*0301 was detected in Caucasians but not Han-Chinese. In addition to the HLA region, cytotoxic T lymphocyte-associated molecule-4 (CTLA4) gene polymorphisms +49G>A and +6230G>A (CT60) were positively associated with GD. The GG genotype and G allele of single nucleotide polymorphism (SNP) +49G>A were also related to relapse of Graves' hyperthyroidism after antithyroid drug withdrawal. Differences in the genetic patterns between Han-Chinese and Caucasians for some thyroid disorders suggest the importance of variable genetic influences in different populations.
Topics: Congenital Hypothyroidism; Genetic Predisposition to Disease; HLA Antigens; Humans; Iodide Peroxidase; Membrane Transport Proteins; Mutation; PTEN Phosphohydrolase; Proto-Oncogene Proteins B-raf; Receptors, Thyrotropin; Sulfate Transporters; Thyroid Diseases
PubMed: 25455162
DOI: 10.1016/j.jcma.2014.09.010 -
International Immunopharmacology Nov 2023Tumor mutation burden (TMB) is a complement to traditional biomarkers related to the efficacy of immune checkpoint inhibitors (ICIs). The relationship between TMB and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tumor mutation burden (TMB) is a complement to traditional biomarkers related to the efficacy of immune checkpoint inhibitors (ICIs). The relationship between TMB and the efficacy of ICIs in gastric cancer was controversial. The systematic review and meta-analysis were conducted to investigate the predictive value of TMB on survival of gastric cancer patients treated with ICIs.
METHODS
We searched the databases PubMed, Embase, and Web of Science for articles, then screened eligible articles according to inclusion criteria. The effective data were extracted to calculate the pooled effects of hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS), then perform publication bias, sensitivity analysis, and subgroup analysis by STATA 16.0.
RESULTS
The high TMB patients showed significantly longer survival than the low TMB patients (OS: HR 0.65,95% CI 0.55, 0.77, p < 0.001; PFS: HR 0.51, 95% CI 0.33, 0.77, p = 0.001). In the Asian subgroup, patients with high TMB exhibited better prognosis compared to low TMB (OS: HR 0.56, 95% CI 0.43, 0.72, p < 0.001; PFS: HR 0.45, 95% CI 0.28, 0.72, p = 0.001). In the non-Asian subgroup, the survival benefit was observed to be skewed toward patients with high TMB, but it was not statistically significant (OS:HR 0.61, 95% CI 0.32, 1.16, p = 0.133; PFS:HR 0.68, 95% CI 0.31, 1.48, p = 0.322).
CONCLUSIONS
This meta-analysis demonstrated that gastric cancer patients with high TMB showed significant benefits from ICIs compared to those with low TMB patients, particularly in Asian populations.
Topics: Humans; Immune Checkpoint Inhibitors; Stomach Neoplasms; Databases, Factual; Progression-Free Survival; Mutation
PubMed: 37748223
DOI: 10.1016/j.intimp.2023.110986 -
Annals of Oncology : Official Journal... Oct 2016Somatic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway play a vital role in carcinogenesis. Approximately 15%-20% of colorectal cancers... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Somatic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway play a vital role in carcinogenesis. Approximately 15%-20% of colorectal cancers (CRCs) harbor activating mutations in PIK3CA, making it one of the most frequently mutated genes in CRC. We thus carried out a systematic review and meta-analysis investigating the prognostic significance of PIK3CA mutations in CRC.
MATERIALS AND METHODS
Electronic databases were searched from inception through May 2015. We extracted the study characteristics and prognostic data of each eligible study. The hazard ratio (HR) and 95% confidence interval (CI) were derived and pooled using the random-effects Mantel-Haenszel model.
RESULTS
Twenty-eight studies enrolling 12 747 patients were eligible for inclusion. Data on overall survival (OS) and progression-free survival (PFS) were available from 19 and 10 studies, respectively. Comparing PIK3CA-mutated CRC patients with PIK3CA-wild-type CRC patients, the summary HRs for OS and PFS were 0.96 (95% CI 0.83-1.12) and 1.20 (95% CI 0.98-1.46), respectively. The trim-and-fill, Copas model and subgroup analyses stratified by the study characteristics confirmed the robustness of the results. Five studies reported the CRC prognosis for PIK3CA mutations in exons 9 and 20 separately; neither exon 9 mutation nor exon 20 mutation in PIK3CA was significantly associated with patient survival.
CONCLUSIONS
Our findings suggest that PIK3CA mutation has the neutral prognostic effects on CRC OS and PFS. Evidence was accumulating for the establishment of CRC survival between PIK3CA mutations and patient-specific clinical or molecular profiles.
Topics: Biomarkers, Tumor; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Mutation; Prognosis; Proportional Hazards Models
PubMed: 27436848
DOI: 10.1093/annonc/mdw264