Report content and prenatal diagnosis of non-invasive prenatal testing for sex chromosome aneuploidy / 中华妇产科杂志

Objective: To analyze the report content, the methods and results of prenatal diagnosis of high risk of sex chromosome aneuploidy (SCA) in non-invasive prenatal testing (NIPT). Methods: A total of 227 single pregnancy pregnant women who received genetic counseling and invasive prenatal diagnosis at Drum Tower Hospital Affiliated to the Medical School of Nanjing University from January 2015 to April 2022 due to the high risk of SCA suggested by NIPT were collected. The methods and results of prenatal diagnosis were retrospectively analyzed, and the results of chromosome karyotype analysis and chromosome microarray analysis (CMA) were compared. The relationship between NIPT screening and invasive prenatal diagnosis was analyzed. Results: (1) Prenatal diagnosis methods for 277 SCA high risk pregnant women included 73 cases of karyotyping, 41 cases of CMA and 163 cases of karyotyping combined with CMA, of which one case conducted amniocentesis secondly for further fluorescence in situ hybridization (FISH) testing. Results of invasive prenatal diagnosis were normal in 166 cases (59.9%, 166/277), and the abnormal results including one case of 45,X (0.4%, 1/277), 18 cases of 47,XXX (6.5%, 18/277), 36 cases of 47,XXY (13.0%, 36/277), 20 cases of 47,XYY (7.2%, 20/277), 1 case of 48,XXXX (0.4%, 1/277), 20 cases of mosaic SCA (7.2%, 20/277), 5 cases of sex chromosome structural abnormality or large segment abnormality (1.8%, 5/277), and 10 cases of other abnormalities [3.6%, 10/277; including 9 cases of copy number variation (CNV) and 1 case of balanced translocation]. Positive predictive value (PPV) for SCA screening by NIPT was 34.7% (96/277). (2) Among the 163 cases tested by karyotyping combined with CMA, 11 cases (6.7%, 11/163) showed inconsistent results by both methods, including 5 cases of mosaic SCA, 1 case of additional balanced translocation detected by karyotyping and 5 cases of additional CNV detected by CMA. (3) NIPT screening reports included 149 cases of "sex chromosome aneuploidy"(53.8%, 149/277), 54 cases of "number of sex chromosome increased" (19.5%, 54/277), and 74 cases of "number of sex chromosome or X chromosome decreased" (26.7%, 74/277). The PPV of "number of sex chromosome increased" and "number of sex chromosome or X chromosome decreased" were 72.2% (39/54) and 18.9% (14/74), respectively, and the difference was statistically significant (χ2=34.56, P<0.01). Conclusions: NIPT could be served as an important prenatal screening technique of SCA, especially for trisomy and mosaicism, but the PPV is comparatively low. More information of NIPT such as the specific SCA or maternal SCA might help improving the confidence of genetic counseling and thus guide clinic management. Multi technology platforms including karyotyping, CMA and FISH could be considered in the diagnosis of high risk of SCA by NIPT.

Identification TRIM46 as a Potential Biomarker and Therapeutic Target for Clear Cell Renal Cell Carcinoma Through Comprehensive Bioinformatics Analyses.

Background: Tripartite motif containing 46 was initially identified as the oncogene in several human tumors. However, the clinical value and potential functions of tripartite motif containing 46 (TRIM46) in clear cell renal cell carcinoma (ccRCC) remained largely unclear. Methods: The expressing patterns, clinical involvement, and prognostic values of TRIM46 were analyzed using the data obtained from TCGA and GEO databases. A nomogram was constructed to examine the outcome of patients with ccRCC. We estimated the association between TRIM46 with tumor immunity in ccRCC. Results: Tripartite motif containing 46 was highly expressed in ccRCC, and its upregulation revealed an unfavorable prognosis. A nomogram based on TRIM46 expressions and other independent prognostic factors could robustly predict the overall survival of tumor patients. TRIM46 has a strong positive correlation with NUMBL, CACNB1, THBS3, ROBO3, MAP3K12, ANKRD13D, PIF1, PRELID3A, ANKRD13B, and PCNX2. Mechanically, TRIM46 displayed regulatory functions in ccRCC progression via several tumor-associated pathways. Besides, we observed that TRIM46 was distinctly related to tumor immunity in ccRCC. Conclusions: Our findings provide a novel tumor promotive role regarding TRIM46 function in the malignant progression of ccRCC.

Should kidney volume be used as an indicator of surgical occasion for patients with autosomal dominant polycystic kidney disease?

To investigate the best surgical occasion of laparoscopic cyst decortications (LCDs) in patients with autosomal dominant polycystic kidney disease (ADPKD), in accordance with the renal volume (RV). We retrospectively analyzed 135 (65 male and 70 female) patients with ADPKD who underwent LCD between June 2011 and October 2015. Patients were divided into 4 groups according to the volume of the operated kidney measured from computed tomography scans: group A (28 patients, RV < 500 mL), group B (63 patients, RV = 500-1000 mL), group C (30 patients, RV = 1000-1500 mL), and group D (14 patients, RV > 1500 mL). We studied postoperative indicators at least 1-year follow-up. For each RV group, therapeutic responses of LCD in these patients with ADPKD were assessed by improvement of clinical parameters and manifestations. A significant glomerular filtration rate (GFR) improvement was found in RV group B (31.8 ±â€Š11.1 mL/min; final GFR 36.9 ±â€Š12.7 mL/min; P < 0.01), and RV group C (21.1 ±â€Š8.7 mL/min; final GFR 27.4 ±â€Š9.2 mL/min; P < 0.01). RV group C had much higher GFR improvements than did RV group B (P < 0.01). In addition, refractory pain in patients of RV groups B, C, and D was much relieved by LCD treatment. Compared with other RV groups, blood pressures in patients with ADPKD of RV group D were also improved (P < 0.01). Our study indicates that RV could be used to evaluate LCD clinical outcomes in patients with ADPKD. The results of LCD for patients with ADPKD with RV between 500 and 1500 mL were encouraging, especially with regards to renal function improvement and pain relief. Therefore, RV may become a useful marker to predict the timing of LCD surgery in patients with ADPKD.

The association between metabolic syndrome and the risk of prostate cancer, high-grade prostate cancer, advanced prostate cancer, prostate cancer-specific mortality and biochemical recurrence.

BACKGROUND: Although a previous meta-analysis reported no association between metabolic syndrome (MetS) and prostate cancer risk, a number of studies suggest that MetS may be associated with the aggressiveness and progression of prostate cancer. However, these results have been inconsistent. This systematic review and meta-analysis investigated the nature of this association. METHODS: We systematically searched MEDLINE, EMBASE and bibliographies of retrieved studies up to January 2013 using the keywords "metabolic syndrome" and "prostate cancer". We assessed relative risks (RRs) of the prostate cancer, several parameters of prostate cancer aggressiveness and progression associated with MetS using 95% confidence intervals (95% CIs). RESULTS: The literature search produced 547 hits from which 19 papers were extracted for the meta-analysis. In cancer-free population with and without MetS, the combined adjusted RR (95% CI) of prostate cancer risk and prostate cancer-specific mortality in longitudinal cohort studies is 0.96 (0.85 ~ 1.09) and 1.12 (1.02 ~ 1.23) respectively. In the prostate cancer patients with and without MetS, the combined unadjusted OR (95% CI) of high grade Gleason prostate cancer is 1.44 (1.20 ~ 1.72), the OR of advanced prostate cancer is 1.37 (1.12 ~ 1.68) and the OR of biochemical recurrence is 2.06 (1.43 ~ 2.96). CONCLUSIONS: The overall analyses revealed no association between MetS and prostate cancer risk, although men with MetS appear more likely to have high-grade prostate cancer and more advanced disease, were at greater risk of progression after radical prostatectomy and were more likely to suffer prostate cancer-specific death. Further primary studies with adjustment for appropriate confounders and larger, prospective, multicenter investigations are required.

Molecular genetics study of ED1 gene for two X-linked hypohidrotic ectodermal dysplasia families / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To provide genetic diagnosis and counseling for patients from two families affected with X-linked hypohidrotic ectodermal dysplasia.</p><p><b>METHODS</b>Potential mutation of the ED1 gene was screened by DNA sequencing. For family 1, multiplex ligation-dependent probe amplification (MLPA) analysis and haplotyping of ED1 gene were also carried out for prenatal diagnosis.</p><p><b>RESULTS</b>For the patient from family 1, deletion of the exon 1 of the ED1 gene and 2 short tandem repeat(STR) sites (DXS8269 and DXS1422) were detected. His daughter was carrier of the deletion. Upon prenatal diagnosis, the fetus was confirmed to be a normal male, for whom the haplotype of ED1 gene has differed from that of the proband. In family 2, a c.463C>T mutation in exon 3 of the ED1 gene was detected in the proband, whose mother was heterozygous for the same mutation.</p><p><b>CONCLUSION</b>The deletion (exon 1) and missense (R155C) mutation in ED1 gene have probably underlied the disease in the two families. During prenatal diagnosis, it may be necessary to obtain precise results through combining mutation detection and haplotype analysis of the ED1 gene.</p>

Mutation analysis and prenatal diagnosis of families affected with Duchenne and Becker muscular dystrophy / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect potential mutations for probands from families affected with Duchenne/Becker muscular dystrophy (DMD/BMD), and to carry out prenatal diagnosis through identification of female carriers.</p><p><b>METHODS</b>A total of 43 DMD/BMD families were recruited. Multiplex PCR was used to analyze 18 exons within hotspots for DMD gene deletions. Multiplex ligation-dependent probe amplification (MLPA) was used to detect potential deletions and duplications of DMD gene for 43 patients and 36 females from 32 families. Prenatal diagnosis was performed for 27 families.</p><p><b>RESULTS</b>Deletional mutations were detected in 26 patients with multiplex PCR. In addition, MLPA has detected 3 deletions and 6 duplicational mutations, and the ranges of mutations were all determined. Among 36 female members, 18 were determined as carriers of deletional mutations, 10 were excluded as mutation carriers. The status of remaining 8 could not be determined. For prenatal diagnosis, 3 out of 18 male fetuses were diagnosed as patients and 1 female fetus was identified as carrier.</p><p><b>CONCLUSION</b>MLPA is an accurate and reliable method for detecting deletional/duplicational mutations of DMD gene as well as for prenatal diagnosis and detection of female carriers.</p>

Reduced folate carrier A80G polymorphism and susceptibility to neural tube defects: a meta-analysis.

The reduced folate carrier (RFC1) plays a crucial role in mediating folate delivery into a variety of cells. RFC1 polymorphism (A80G) has been reported to be associated with increased risk of neural tube defects (NTDs). However, results derived from individually underpowered studies are conflicting. We performed a systematic search of MEDLINE and EMBASE databases and carried out a meta-analysis on the association between RFC1 polymorphism (A80G) and NTDs risk. Overall, a significant correlation between RFC1 A80G polymorphism and NTDs risk was found neither in infants nor in maternal (allele contrast in infants: OR(RE)=1.15, 95% CI: 0.92-1.45; allele contrast in mothers: OR(RE)=1.24, 95% CI: 0.98-1.56). The present meta-analysis failed to support a positive association between RFC1 A80G polymorphism and susceptibility to NTDs. It is important to realize, however, that socio-economic factors, and gene-environment and gene-gene interactions, could have influenced the outcome of our meta-analysis. For this reason, a relationship between the A80G polymorphism and NTD risk cannot be entirely discounted.

Mutation analysis and prenatal diagnosis of EXT1 gene mutations in Chinese patients with multiple osteochondromas / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Multiple osteochondromas (MO), an inherited autosomal dominant disorder, is characterized by the presence of multiple exostoses on the long bones. MO is caused by mutations in the EXT1 or EXT2 genes which encode glycosyltransferases implicated in heparin sulfate biosynthesis.</p><p><b>METHODS</b>In this study, efforts were made to identify the underlying disease-causing mutations in patients from two MO families in China.</p><p><b>RESULTS</b>Two novel EXT1 gene mutations were identified and no mutation was found in EXT2 gene. The mutation c.497T > A in exon 1 of the EXT1 gene was cosegregated with the disease phenotype in family 1 and formed a stop codon at amino acid site 166. The fetus of the proband was diagnosed negative. In family 2, the mutation c.1430-1431delCC in exon 6 of the EXT1 gene would cause frameshift and introduce a premature stop codon after the reading frame being open for 42 amino acids. The fetus of this family inherited this mutation from the father.</p><p><b>CONCLUSIONS</b>Mutation analysis of two MO families in this study demonstrates its further application in MO genetic counseling and prenatal diagnosis.</p>

Molecular genetic study of MECP2 gene for a patient with typical Rett syndrome / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To provide genetic diagnosis and counseling for a 2-year-old girl with typical Rett syndrome through analyzing the methyl-CpG binding protein 2 (MECP2) gene.</p><p><b>METHODS</b>Potential mutation of the MECP2 gene was screened by DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis of members of the family as well as normal controls. Lymphocyte culture for karyotype analysis was carried out for the patient to exclude chromosomal abnormalities.</p><p><b>RESULTS</b>The karyotype of the girl was normal. No variation of the MECP2 gene was detected in the patient by direct sequencing. A heterozygosis variation, c.1072G>A in exon 4 of the MECP2 gene was detected in a normal female control, which was not found in other controls. The son and daughter of the female control were respectively heterozygous and homozygous carriers of the same mutation. By MLPA analysis, a heterozygosis deletion of exon 3 and part of exon 4 was detected in the patient. cDNA amplification and sequencing confirmed the presence of a 1176 bp deletion (c.27-1202del1176). The same deletion was not detected in the parents.</p><p><b>CONCLUSION</b>A large deletion in MECP2 gene was detected with MLPA in a patient featuring typical Rett syndrome. The same deletion was missed by sequencing analysis. With cDNA sequencing, the breakage point of the mutation can be mapped precisely.</p>

Diagnosis of 22q11 deletion and duplication in congenital heart disease by multiplex ligation dependent probe amplification / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the clinical utility of multiplex ligation-dependent probe amplification (MLPA) for detecting 22q11 deletion and duplication in congenital heart disease (CHD) cases and to study the incidence of 22q11 deletion and duplicaton in different kinds of CHD.</p><p><b>METHODS</b>Forty eight probes of which 25 located in 22q11 low copy number region (LCR 22s A-H), 7 in 22q11 surrounding region (CES, 22q13) and 16 in chromosomes 4, 8, 10 and 17 were selected to detect 22q11 deletion and duplication in 181 preoperative children with CHD and 14 fetuses with serious CHD or CHD with multiple malformations. In these cases, karyotype analysis was also performed.</p><p><b>RESULTS</b>MLPA demonstrated that 7 cases had 22q11 deletion [6 cases from CLTCL1 to LZTR1(LCR A-D) and 1 case from CLTCL1 to PCQAP (LCR A-C)] and that 1 case had 22q11 duplication,spanning from ZNF74 to LZTR1(LCR B-D). The phenotypes of heart defect included ventricular septal defect, atrioventricular septal defect, pulmonary stenosis and tetralogy of Fallot. Karyotype analysis showed that 1 case had 21q deletion [46, XY, 21q], 1 case had mosaic trisomy 8 [47,XY, +8/46, XY(1:2)] and 4 cases had trisomy 21. One of the 4 cases with trisomy 21 had concurrent 22q11 duplication.</p><p><b>CONCLUSIONS</b>MLPA is a rapid, sensitive, site specific and relatively inexpensive method for diagnosis of 22q11 deletion and duplication in CHD. 22q11 deletion and duplication may cause various kinds of CHD, suggesting that genetic detection should be performed routinely in CHD patients.</p>