Objective:To explore the clinical manifestations of two fetuses harboring heterozygous deletions of the SHOX gene. Methods:Two pregnant women who had presented at the Prenatal Diagnosis Center of Nanjing Drum Tower Hospital respectively on June 24, 2022 and July 27, 2022 were selected as the study subjects. In case 1, prenatal ultrasonography had shown short femur and intrauterine growth retardation of the fetus. Case 2 had a history of spontaneous abortions due to structural chromosomal aberrations. Fetus 1 had undergone a test for the FGFR3 gene, and both fetuses were subjected to single nucleotide polymorphism-based microarray (SNP array) analysis. Results:Affter excluding the influence of FGFR3 gene Fetus 1 was found to harbor a heterozygous 883 kb deletion at Xpter or Ypter, whilst fetus 2 was found to harbor a 5.75 Mb deletion in the Xpter region. Both deletions have encompassed the SHOX gene. The origin of the deletion in fetus 1 was unknown, whilst that in fetus 2 was inherited from its mother. Fetus 1 has been delivered at term with a normal phenotype, and fetus 2 was not born yet. Conclusion:The intrauterine and postnatal phenotypes of fetuses may be predicted by combining the ultrasound finding, parental phenotype and results of CMA, variant, and the results can facilitate genetic counseling and decision making over the pregnancy.

Objective:To explore the genetic characteristics of three fetuses with regions of homozygosity (ROH).Methods:Three fetuses with ROH diagnosed at Nanjing Drum Tower Hospital on December 2, 2020, March 19, 2021, and May 27, 2022, respectively were selected as the study subjects. Clinical data of the fetuses were collected. Chromosomal microarray analysis (CMA) was used to detect the ROH, and tandem repeat sequences (STR)-based multiplex PCR assay was used to identify the mosaicism status in fetus 1.Results:Partial maternal isodisomy (iUPD) (16) was found in fetus 1, for which trisomy rescue may be accountable. Meanwhile, the fetus also has confined placental mosaicism (CPM) but not true mosaicism. The formation mechanism of ROH for fetus 2 was identity by descent. Partial maternal iUPD (7) was found in fetus 3, which may be due to gametic recombination.Conclusion:The ROH of the three fetuses were inherited from both parents or the mother. Above findings suggested that it is justified to detect ROH on imprinting disorder-related chromosomes when potential uniparental disomy is suspected.

Objectives:To report the sexual functional outcomes of vaginal dilation therapy in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome patients.Methods:From March 2020 to February 2023, 97 MRKH syndrome patients performed vaginal dilation therapy with guidance from Peking Union Medical College Hospital, and 45 of them engaged in penetrative intercourse and were included in this prospective cohort study. The Chinese version of female sexual function index (FSFI) was used to assess sexual function. Functional success was defined as FSFI>23.45. Forty age-matched healthy women were selected as controls. Kaplan-Meier survival analysis was used to calculate the median time to success. Pearson correlation analysis was used to explore the relationship between neovagina length and sexual function. Complications were collected using follow-up questionnaires.Results:The functional success rate of vaginal dilation therapy was 89% (40/45) with a median time to success of 4.3 months (95% CI: 3.0-6.1 months). Compared to controls, MRKH syndrome patients had significantly lower scores in the orgasm domain (4.72±1.01 vs 4.09±1.20; P=0.013) and pain domain (5.03±0.96 vs 4.26±0.83; P<0.001). However, there were no significant differences in the FSFI total score (26.77±2.70 vs 26.70±2.33; P=0.912), arousal domain (4.43±0.77 vs 4.56±0.63; P=0.422) and satisfaction domain (4.88±0.98 vs 4.65±0.86; P=0.269) between MRKH syndrome patients and controls. MRKH syndrome patients had significantly higher scores in the desire domain (3.33±0.85 vs 3.95±0.73; P<0.001) and lubrication domain (4.37±0.56 vs 5.20±0.67; P<0.001). The prevalence of sexual dysfunction in MRKH patients was non-inferior to controls: low desire [3% (1/40) vs 23% (9/40); P=0.007], arousal disorder [3% (1/40) vs 3% (1/40); P>0.999], lubrication disorder [5% (2/40) vs 25% (10/40); P=0.012], orgasm disorder [40% (16/40) vs 20% (8/40); P=0.051], sexual pain [30% (12/40) vs 15% (6/40); P=0.108]. Conclusions:MRKH syndrome patients undergoing non-invasive vaginal dilation therapy could achieve satisfactory sexual life. Given its high functional success rate and slight complication, vaginal dilation therapy should be recommended as the first-line option, reducing the need for unnecessary surgeries.

OBJECTIVE: To analyze the prognosis of fetuses identified with de novo variants of unknown significance (VOUS) by chromosome microarray analysis (CMA). METHODS: A total of 6 826 fetuses who underwent prenatal CMA detection at the Prenatal Diagnosis Center of Drum Tower Hospital from July 2017 to December 2021 were selected as the study subjects. The results of prenatal diagnosis, and outcome of fetuses identified with VOUS of de novo origin were followed up. RESULTS: Among the 6 826 fetuses, 506 have carried VOUS, of which 237 were detected for the parent-of-origin and 24 were found to be de novo. Among the latters, 20 were followed up for 4 to 24 months. Four couples had opted elective abortion, 4 had developed clinical phenotypes after birth, and 12 were normal. CONCLUSION Fetuses with VOUS should be continuously follow-up, in particular those carrying de novo VOUS, in order to clarify their clinical significance.
Pregnancy ; Female ; Humans ; DNA Copy Number Variations ; Follow-Up Studies ; Prenatal Diagnosis/methods* ; Chromosomes ; Microarray Analysis/methods* ; Fetus ; Chromosome Aberrations

OBJECTIVE: To explore the genetic etiology and related factors in 1 065 women with spontaneous abortions. METHODS: All patients have presented at the Center of Prenatal Diagnosis of Nanjing Drum Tower Hospital from January 2018 to December 2021. Chorionic villi and fetal skin samples were collected, and the genomic DNA was assayed by chromosomal microarray analysis (CMA). For 10 couples with recurrent spontaneous abortions but normal CMA results for abortive tissues, non-in vitro fertilization-embryo transfer (IVF-ET) pregnancies and no previous history of live births and no structural abnormalities of the uterus, peripheral venous blood samples were collected. Genomic DNA was subjected to trio-whole exome sequencing (trio-WES). Candidate variants were verified by Sanger sequencing and bioinformatics analysis. Multifactorial unconditional logistic regression analysis was carried out to analyze the factors that may affect chromosomal abnormality in spontaneous abortions, such as the age of the couple, number of previous spontaneous abortions, IVF-ET pregnancy and history of live birth. The incidence of chromosomal aneuploidies in spontaneous abortions during the first trimester was compared in young or advanced-aged patients by chi-square test for liner trend. RESULTS: Among the 1 065 spontaneous abortion patients, 570 cases (53.5%) of chromosomal abnormalities were detected in spontaneous abortion tissues, which included 489 cases (45.9%) of chromosomal aneuploidies and 36 cases (3.4%) of pathogenic/likely pathogenic copy number variations (CNVs). Trio-WES results have revealed one homozygote variant and one compound heterozygote variants in two pedigrees, both of which were inherited from the parents. One likely pathogenic variant was detected in the patient from two pedigrees. Multifactorial unconditional Logistic regression analysis suggested that age of patient was an independent risk factor of chromosome abnormalities (OR = 1.122, 95%CI: 1.069-1.177, P < 0.001), the number of previous abortions and IVF-ET pregnancy were independent protective factors for chromosomal abnormalities (OR = 0.791, 0.648; 95%CI: 0.682-0.916, 0.500-0.840; P = 0.002, 0.001), whilst the age of husband and history of live birth were not (P > 0.05). The incidence of aneuploidies in the abortive tissues has decreased with the number of previous spontaneous abortions in young patients (χ² = 18.051, P < 0.001), but was not significantly correlated with the number of previous spontaneous abortions in advanced-aged patients with spontaneous abortions (P > 0.05). CONCLUSION Chromosomal aneuploidy is the main genetic factor for spontaneous abortion, though CNVs and genetic variants may also underlie its genetic etiology. The age of patients, number of previous abortions and IVF-ET pregnancy are closely associated with chromosome abnormalities in abortive tissues.
Pregnancy ; Humans ; Female ; Aged ; Abortion, Spontaneous/genetics* ; DNA Copy Number Variations ; Chromosome Aberrations ; Chromosome Disorders/genetics* ; Aneuploidy ; Abortion, Habitual/genetics*

OBJECTIVE: To assess the value of chromosomal microarray analysis (CMA) for the diagnosis of fetuses with anomalies of the central nervous system (CNS) and summarize the outcome of the pregnancies and follow-up. METHODS: A total of 636 fetuses from June 2014 to December 2020 who were referred to the Prenatal Diagnosis Center of Nanjing Drum Tower Hospital due to abnormal CNS prompted by ultrasound were selected as the research subjects. Based on the ultrasound findings, the fetuses were divided into ventricular dilatation group (n = 441), choroid plexus cyst group (n = 41), enlarged posterior fossa group (n = 42), holoprosencephaly group (n = 15), corpus callosum hypoplasia group (n = 22), and other anomaly group (n = 75). Meanwhile, they were also divided into isolated (n = 504) and non-isolated (n = 132) groups based on the presence of additional abnormalities. Prenatal samples (amniotic fluid/chorionic villi/umbilical cord blood) or abortus tissue were collected for the extraction of genomic DNA and CMA assay. Outcome of the pregnancies and postnatal follow-up were summarized and subjected to statistical analysis. RESULTS: In total 636 fetuses with CNS anomalies (including 89 abortus tissues) were included, and 547 cases were followed up. The overall detection rate of CMA was 11.48% (73/636). The detection rates for the holoprosencephaly group, ACC group, choroid plexus cyst group, enlarged posterior fossa group, ventricular dilatation group and other anomaly group were 80% (12/15), 31.82% (7/22), 19.51% (8/41), 14.29% (6/42), 7.48% (33/441) and 9.33% (7/75), respectively. Compared with the isolated CNS anomaly group, the detection rate for the non-isolated CNS anomaly group was significantly higher (6.35% vs. 31.06%) (32/504 vs. 41/132) (χ² = 62.867, P < 0.001). Follow up showed that, for 52 fetuses with abnormal CMA results, 51 couples have opted induced labor, whilst 1 was delivered at full term with normal growth and development. Of the 434 fetuses with normal CMA results, 377 were delivered at full term (6 had developmental delay), and 57 couples had opted induced labor. The rate of adverse pregnancy outcome for non-isolated CNS abnormal fetuses was significantly higher than that of isolated CNS abnormal fetuses (26.56% vs. 10.54%) (17/64 vs. 39/370) (χ² = 12.463, P < 0.001). CONCLUSION Fetuses with CNS anomaly should be tested with CMA to determine the genetic cause. Most fetuses with negative CMA result have a good prognosis, but there is still a possibility for a abnormal neurological phenotype. Fetuses with CNS abnormalities in conjunct with other structural abnormalities are at increased risk for adverse pregnancy outcomes.
Female ; Pregnancy ; Humans ; Holoprosencephaly ; Prenatal Diagnosis/methods* ; Central Nervous System ; Fetus/abnormalities* ; Nervous System Malformations/genetics* ; Microarray Analysis ; Central Nervous System Diseases ; Cysts ; Chromosome Aberrations ; Ultrasonography, Prenatal/methods*

Objective:To detect pathological variant in a Chinese pedigree affected with oral-facial-digital syndrome type 1 (OFD1).Methods:Whole-exome sequencing was used to scan the whole exome of the proband. Potential variant of the OFD1 gene was also detected in all members of the pedigree and 100 healthy controls by Sanger sequencing. X chromosome inactivation analysis was performed. With the determination of the genotype, prenatal diagnosis was carried out by amniotic fluid sampling. Results:A c. 1189_1192delAATC(p.Q398Lfs*2) variant was identified in the OFD1 gene of the proband, other patients from this pedigree, as well as the fetus. The same variant was not found among healthy members from this pedigree and the 100 healthy controls. X chromosome inactivation analysis identifies the pregnant woman and her younger sister both had a non-random inactivation, other women patients had a random inactivation. Conclusion:The c. 1189_1192delAATC(p.Q398Lfs*2) variant of the OFD1 gene probably underlies the pathogenesis in this case. The new variant has enriched pathological spectrum of the OFD1 gene. The reason of intrafamilial clinical variability still need to be further confirmed.

Objective:To examine the correlation between neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR) and neutrophil-monocyte ratio (NMR) for postoperative pneumonia or long-term overall survival in patients with esophageal cancer after neoadjuvant therapy.Methods:The clinical data of 137 patients, including 111 males and 26 females, with the age of ( M( Q R))61(10) years (range: 45 to 75 years), undergoing radical resection of esophageal cancer after neoadjuvant therapy admitted at Department of Thoracic Surgery, West China Hospital from January 2016 to May 2019 were analyzed retrospectively. The blood routine one or two days before surgery and the occurrence of pneumonia after surgery were collected via hospital information system. The absolute count of neutrophils, lymphocytes and monocytes was recorded, to calculate NLR, LMR and NMR. The survival of patients was recorded systematically via follow-up. In the first part, the influencing factors of postoperative inflammation were analyzed, to group the patients into two groups according to the occurrence of postoperative pneumonia. χ 2 test, t-test or rank-sum test were conducted for inter-group comparison. In the second part, cut-off values of inflammatory biomarkers were obtained with the receiver operating characteristic (ROC) curve and grouped, with postoperative pneumonia as endpoint criteria. Independent factors correlated with postoperative pneumonia were determined through univariate and multivariate Logistic regression analysis. In the third part, the analysis on prognosis factors was carried on, with the survival as endpoint criteria. Cut-off values of inflammatory biomarkers were obtained with X-Tile software and grouped. The survival analysis was carried on with univariate and multivariate Cox proportional hazards regression model, and the Kaplan-Meier curve was drawn finally. The results of survival analysis were verified by Log-rank test. Results:Median follow-up time was 614 (299) days (range: 382 to 1 612 days). Cut-off values of NLR, LMR, and NMR obtained via the ROC curve were 3.0, 3.9, and 6.2, respectively. According to the multivariate Logistic regression analysis, NLR>3.0 ( OR=2.740, 95% CI: 1.221 to 6.152, P=0.015) and LMR>3.9 ( OR=0.140, 95% CI: 0.022 to 0.890, P=0.037) were independent prognosis factors for postoperative pneumonia in patients with esophageal cancer after neoadjuvant therapy. Cut-off values of NLR, LMR, and NMR obtained with X-Tile software were 3.3, 4.2, and 7.2, respectively. Through multivariate Cox proportional risk regression analysis, late tumor ypTNM staging (8th AJCC) ( HR=2.087, 95% CI:1.079 to 4.038, P=0.029), poor pathologic response ( HR=2.251, 95% CI: 1.117 to 4.538, P=0.023), and LMR>4.2 ( HR=0.347, 95% CI: 0.127 to 0.946, P=0.039) could be independent prognosis factors for overall survival. Kaplan-Meier survival analysis indicated that the overall survival of patients with LMR ≤4.2 was worse ( P=0.002), with the 1-year overall survival rate of 82.9%, and the 1-year overall survival rate of patients with LMR>4.2 was 94.6%. Conclusion:Preoperative LMR ≤3.9 and NLR>3.0 can be considered as independent prognosis factors for postoperative pneumonia, while LMR≤4.2 as one of independent prognosis factors for overall survival.

Objective:To examine the correlation between neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR) and neutrophil-monocyte ratio (NMR) for postoperative pneumonia or long-term overall survival in patients with esophageal cancer after neoadjuvant therapy.Methods:The clinical data of 137 patients, including 111 males and 26 females, with the age of ( M( Q R))61(10) years (range: 45 to 75 years), undergoing radical resection of esophageal cancer after neoadjuvant therapy admitted at Department of Thoracic Surgery, West China Hospital from January 2016 to May 2019 were analyzed retrospectively. The blood routine one or two days before surgery and the occurrence of pneumonia after surgery were collected via hospital information system. The absolute count of neutrophils, lymphocytes and monocytes was recorded, to calculate NLR, LMR and NMR. The survival of patients was recorded systematically via follow-up. In the first part, the influencing factors of postoperative inflammation were analyzed, to group the patients into two groups according to the occurrence of postoperative pneumonia. χ 2 test, t-test or rank-sum test were conducted for inter-group comparison. In the second part, cut-off values of inflammatory biomarkers were obtained with the receiver operating characteristic (ROC) curve and grouped, with postoperative pneumonia as endpoint criteria. Independent factors correlated with postoperative pneumonia were determined through univariate and multivariate Logistic regression analysis. In the third part, the analysis on prognosis factors was carried on, with the survival as endpoint criteria. Cut-off values of inflammatory biomarkers were obtained with X-Tile software and grouped. The survival analysis was carried on with univariate and multivariate Cox proportional hazards regression model, and the Kaplan-Meier curve was drawn finally. The results of survival analysis were verified by Log-rank test. Results:Median follow-up time was 614 (299) days (range: 382 to 1 612 days). Cut-off values of NLR, LMR, and NMR obtained via the ROC curve were 3.0, 3.9, and 6.2, respectively. According to the multivariate Logistic regression analysis, NLR>3.0 ( OR=2.740, 95% CI: 1.221 to 6.152, P=0.015) and LMR>3.9 ( OR=0.140, 95% CI: 0.022 to 0.890, P=0.037) were independent prognosis factors for postoperative pneumonia in patients with esophageal cancer after neoadjuvant therapy. Cut-off values of NLR, LMR, and NMR obtained with X-Tile software were 3.3, 4.2, and 7.2, respectively. Through multivariate Cox proportional risk regression analysis, late tumor ypTNM staging (8th AJCC) ( HR=2.087, 95% CI:1.079 to 4.038, P=0.029), poor pathologic response ( HR=2.251, 95% CI: 1.117 to 4.538, P=0.023), and LMR>4.2 ( HR=0.347, 95% CI: 0.127 to 0.946, P=0.039) could be independent prognosis factors for overall survival. Kaplan-Meier survival analysis indicated that the overall survival of patients with LMR ≤4.2 was worse ( P=0.002), with the 1-year overall survival rate of 82.9%, and the 1-year overall survival rate of patients with LMR>4.2 was 94.6%. Conclusion:Preoperative LMR ≤3.9 and NLR>3.0 can be considered as independent prognosis factors for postoperative pneumonia, while LMR≤4.2 as one of independent prognosis factors for overall survival.