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Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... May 2020To summarize newborn screening for methionine adenosyltransferase I/III (MAT I/III) deficiency in Quanzhou region of Fujian Province.
OBJECTIVE
To summarize newborn screening for methionine adenosyltransferase I/III (MAT I/III) deficiency in Quanzhou region of Fujian Province.
METHODS
A total of 364 545 neonates were screened for inherited metabolic diseases by tandem mass spectrometry. High-throughput next generation sequencing combined with Sanger sequencing was used to detect potential variants in newborns with MAT I/III deficiency. Pathogenicity of suspected variants was predicted by using MutationTaster and HSF software.
RESULTS
Three newborns were identified with MAT I/III deficiency by newborn screening, which yielded an incidence rate of 1 in 121 515. Amino acid and acylcarnitine analysis suggested that the serum methionine of the three patients have increased to various extents. All patients showed normal growth and development during follow-up, and were found to carry MAT1A gene variants including two missense variants [c.776C>T (p.Ala259Val) and c.791G>A (p.Arg264His)] and a synonymous variant [c.360C>T (p.Cys120Cys)]. Among these, c.776C>T (p.Ala259Val) and c.791G>A (p.Arg264His) were known to be pathogenic, whereas c.360C>T (p.Cys120Cys) was a novel variant. Bioinformatics analysis suggested that this variant may alter RNA splicing and affect the structure and function of the MAT1A protein.
CONCLUSION
A systematic review of newborn screening for MAT I/III deficiency was provided. Discovery of the novel variant has enriched the variant profile of the MAT1A gene and provided a basis for the diagnosis of this disease.
Topics: Amino Acid Metabolism, Inborn Errors; China; Genetic Variation; Humans; Infant, Newborn; Methionine Adenosyltransferase; Neonatal Screening
PubMed: 32335878
DOI: 10.3760/cma.j.issn.1003-9406.2020.05.008 -
European Urology Focus Jul 2018Androgen receptor splice variant 7 (AR-V7) may be associated with resistance to next-generation androgen receptor signaling (ARS) inhibitors in castration-resistant... (Meta-Analysis)
Meta-Analysis
Prognostic Value of Androgen Receptor Splice Variant 7 in the Treatment of Castration-resistant Prostate Cancer with Next generation Androgen Receptor Signal Inhibition: A Systematic Review and Meta-analysis.
CONTEXT
Androgen receptor splice variant 7 (AR-V7) may be associated with resistance to next-generation androgen receptor signaling (ARS) inhibitors in castration-resistant prostate cancer (CRPC) sensitive to chemotherapy.
OBJECTIVE
To evaluate the prognostic value of AR-V7 for prostate specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) among CRPC patients treated with ARS inhibitors or chemotherapy.
EVIDENCE ACQUISITION
A search of PubMed, Embase, and Web of Science databases was performed using the keywords "prostate cancer", "prostate tumor", "prostate neoplasm", "prostate carcinoma"; "AR-V7", "AR3", "androgen receptor splicing variant-7" and "androgen receptor-3". Fourteen trials published up to August 2016 were selected.
EVIDENCE SYNTHESIS
A significantly greater proportion of CRPCs than newly diagnosed prostate cancers were AR-V7-positive (odds ratio [OR] 8.29, 95% confidence interval [CI] 5.06-13.57; p<0.001). AR-V7-positive patients treated with ARS inhibitors had a significantly lower PSA response than those who were AR-V7-negative (OR 0.05, 95% CI 0.02-0.16; p<0.001).The difference was not significant in chemotherapy-treated patients (OR 0.64, 95% CI 0.3-1.33; p=0.23). Both PFS (hazard ratio [HR] 4.05, 95% CI 1.91-8.59; p=0.0003) and OS (HR 4.79, 95% CI 2.14-10.72; p<0.001) were better in AR-V7-negative than AR-V7-positive CRPC patients treated with ARS inhibitors. In chemotherapy patients, AR-V7 status had no significant effect on PFS (HR 1.26, 95% CI 0.80-2.00; p=0.32).However, AR-V7-negative patients had significantly better OS (HR 2.82, 95% CI 1.72-4.62; p<0.001). The limitations of our meta-analysis were differences in study sample size and design, AR-V7 assay, and disease characteristics.
CONCLUSIONS
AR-V7 positivity was associated with poorer PSA response and PFS prognosis in CRPC patients treated with ARS inhibitors, but did not affect outcomes except OS for those treated with chemotherapy. Additional studies are warranted to confirm these findings.
PATIENT SUMMARY
We concluded from several studies that androgen receptor splice variant 7 (AR-V7) could predict the outcomes of prostate cancer. AR-V7-positive patients have poorer outcomes when treated with abiraterone or enzalutamide, but relatively better outcomes when treated by chemotherapy.
Topics: Androgen Receptor Antagonists; Antineoplastic Agents; Disease-Free Survival; Humans; Male; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen
PubMed: 28753843
DOI: 10.1016/j.euf.2017.01.004 -
Gene May 2020Osteogenesis imperfecta (OI) is a rare disease characterized by increased bone fragility and predisposition to fractures, bone deformities and other major signs such as...
Rare splicing mutation in COL1A1 gene identified by whole exomes sequencing in a patient with osteogenesis imperfecta type I followed by prenatal diagnosis: A case report and review of the literature.
BACKGROUND
Osteogenesis imperfecta (OI) is a rare disease characterized by increased bone fragility and predisposition to fractures, bone deformities and other major signs such as dentinogenesis imperfecta, blue sclera and deafness. Over 90% of OI cases are caused by mutations in the COL1A1 and COL1A2 genes and the inheritance is autosomal dominant.
METHODS
We present a case of a couple requesting genetic counseling, because the man was diagnosed with OI on a clinical and radiological basis and the woman was pregnant. Whole exomes sequencing (WES) was performed in order to identify the mutation (s), followed by prenatal diagnosis.
RESULTS
WES identified a rare splicing mutation c.1155 + 1G > C in the COL1A1 gene recognized to be pathogenic and subsequently confirmed by next generation sequencing. The carrier state of the mutation was excluded for the fetus, so the pregnancy was further pursued and a healthy baby was born at term.
CONCLUSIONS
WES is a new and effective technique for detecting pathogenic variants in monogenic diseases and it is preferable to use such a technique in diseases with genetic heterogeneity especially when time does not allow another time-consuming diagnostic technique such classical Sanger sequencing. WES offers possibility to expand the global spectrum of OI pathogenic variants enabling the diagnosis of the disease.
Topics: Adult; Alternative Splicing; Collagen Type I; Collagen Type I, alpha 1 Chain; Exome; Female; Genotype; High-Throughput Nucleotide Sequencing; Humans; Male; Mutation; Osteogenesis Imperfecta; Pedigree; Pregnancy; Prenatal Diagnosis; Protein Isoforms; Exome Sequencing
PubMed: 32165296
DOI: 10.1016/j.gene.2020.144565 -
Annals of Hematology Dec 2019U2 small nuclear RNA auxiliary factor 1 (U2AF1) mutant is the most common molecular biological abnormality in patients with myelodysplastic syndromes. Some studies have... (Meta-Analysis)
Meta-Analysis
U2 small nuclear RNA auxiliary factor 1 (U2AF1) mutant is the most common molecular biological abnormality in patients with myelodysplastic syndromes. Some studies have reported the prognostic impact of U2AF1 mutant in patients with de novo MDS, with discrepant results, so we do a meta-analysis about the relevant literatures to further investigate their prognostic impact on patients with de novo MDS. We conducted a literature search on databases such as PubMed, Embase, and the Cochrane Library to obtain studies on the prognosis of U2AF1 mutant in patients with de novo MDS published up to August 9, 2018. The primary endpoint was overall survival (OS), and the secondary endpoint was acute myeloid leukemia (AML) transformation. We extracted the hazard ratios (HRs) of OS and AML transformation and their 95% confidence intervals (CIs). Meta-analysis was performed by selecting a fixed-effect model or a random-effects model based on the heterogeneity between studies. A total of 14 cohort studies were included in the final meta-analysis, including 3322 patients with de no MDS, in which 390 patients were associated with U2AF1 mutant. The results showed that U2AF1 mutant had an adverse prognostic impact on OS (HR = 1.84, 95% CI: 1.45-2.33, P < 0.00001) and AML transformation (HR = 2.47, 95% CI: 1.50-4.06, P = 0.0004). U2AF1 mutant was associated with shorter OS in subgroup analyses of low- or intermediate-1-IPSS, U2AF1 and U2AF1. Out meta-analysis indicates that U2AF1 mutants are independent, detrimental prognostic factors for OS and AML transformation in patients with de novo MDS, as well as associating with shorter OS in subgroups of low- or intermediate-1-IPSS, U2AF1 and U2AF1. Further prospective studies are needed in the future, and subgroup analysis of U2AF1 subgroups is needed to obtain a more reliable basis for the impact of U2AF1 mutant on the prognosis of de novo MDS.
Topics: Disease-Free Survival; Female; Humans; Leukemia, Myeloid, Acute; Male; Models, Biological; Mutation; Myelodysplastic Syndromes; Neoplasm Proteins; Splicing Factor U2AF; Survival Rate
PubMed: 31754743
DOI: 10.1007/s00277-019-03843-3 -
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