Luming Sun

Clinicalapplicationofmassivelyparallelsequencing-basedprenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11105 pregnancies with mixed risk factors

To report the performance of massively parallel sequencing (MPS) based prenatal noninvasive fetal trisomy test based on cell‐free DNA sequencing from maternal plasma in a routine clinical setting in China.

Targeted gene panel sequencing prenatally detects two novel mutations of DYNC2H1 in a fetus with increased biparietal diameter and polyhydramnios

BACKGROUNDnGenetic skeletal disorders (GSDs) are clinically and genetically heterogeneous with more than 350 genes accounting for the diversity of disease phenotypes. Prenatal diagnosis of these disorders has been challenging because of the limited but variable prenatal phenotypes, highlighting the need of a novel genetic approach. Short-rib polydactyly syndrome (SRPS) Type III is an autosomal recessive GSD characterized by extreme narrowness of the thorax, severely shortened tubular bones, polydactyly and multiple malformations.nnnMETHODSnCytogenetic and molecular analyses using GTG-banding, single nucleotide polymorphism array and a novel GSDs targeted gene panel sequencing were performed in a 24 weeks fetus with increased biparietal diameter (BPD), short limbs, narrow thorax and polyhydramnios.nnnRESULTSnNo chromosomal abnormalities and pathogenic copy number variations (CNVs) were detected in the fetus. Two novel compound heterozygous mutations c.2992Cu2009>u2009T and c.12836Gu2009>u2009C in the DYNC2H1 gene were identified by targeted genes panel sequencing. A literature review was performed to delineate the prenatal phenotype of SRPS Type III.nnnCONCLUSIONnThis is the first report of prenatal diagnosis of DYNC2H1 mutations causing SRPS Type III in a fetus with increased BPD associated with polyhydramnios in China. Our findings expand the mutation spectrum of DYNC2H1 in this rare disease and demonstrate that targeted gene panel capture followed by next-generation sequencing (NGS) is an efficient and cost-effective method to perform a molecular prenatal diagnosis of a rare genetic skeletal disorder.

Clinical outcomes after assisted reproductive technology in twin pregnancies: chorionicity-based comparison

The chorionicity–based evaluation of the perinatal risk in twin pregnancies after assisted reproductive technology (ART) is lacking. A retrospective review was performed of all twin pregnancies monitored prenatally and delivered at our hospital between 2010 and 2014. Chorionicity was diagnosed by ultrasound examination at first trimester and confirmed by postnatal pathology. Pregnancy and perinatal outcomes were prospectively recorded. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were calculated in a logistic regression model. A total of 1153 twin pregnancies were analyzed. The occurrence of preterm premature rupture of membranes (PPROM) was 3 times as frequent in monochorionic diamniotic (MCDA) twin pregnancies after ART as in those spontaneous counterparts (aOR 3.0; 95%CI 1.1–3.2). The prevalence of intrahepatic cholestasis of pregnancies (ICP) was significantly higher in dichorionic diamniotic (DCDA) twin pregnancies following ART compared to spontaneous DCDA pregnancies (aOR 3.3; 95%CI 1.3–5.6). Perinatal outcomes did not differ between two conception methods, either in MCDA or DCDA twin pregnancies. Based on differentiation of chorionicity, ART is associated with the increased risk of PPROM in MCDA twin pregnancies and with a higher rate of ICP in DCDA twin gestations. ART does not increase adversity of perinatal outcomes in twin pregnancies.

Noninvasive prenatal testing for fetal trisomy 9 mosaicism by maternal plasma DNA sequencing

Abstract Maternal plasma DNA sequencing based noninvasive prenatal testing (NIPT) has been proven to be highly accurate in the detection of trisomy 21, 18, 13, X and Y, however, few reports have been made on its detection efficiency of rare complex aneuploidies. Here, we report a case of fetal trisomy 9 mosaicism identified by using NIPT, which may provide useful information for the further integration of NIPT into prenatal screening and diagnosis practice.

Prenatal diagnosis of skeletal dysplasias using a targeted skeletal gene panel

This study aimed to perform an accurate and precise diagnosis for fetuses with suspected skeletal anomalies based on an incomplete and limited ultrasound phenotype.

Risk factors for fetal death after radiofrequency ablation for complicated monochorionic twin pregnancies

Radiofrequency ablation (RFA) is a management alternative for complicated monochorionic twin pregnancies. The purpose of this study is to evaluate risk factors for fetal death after RFA.

Description of the molecular and phenotypic spectrum of Wiedemann-Steiner syndrome in Chinese patients

BackgroundWiedemann–Steiner syndrome (WDSTS) is a rare genetic disorder characterized by facial gestalt, neurodevelopmental delay, skeletal anomalies and growth retardation, which is caused by variation of KMT2A gene. To date, only 2 Chinese WDSTS patients have been reported. Here, we report the phenotypes and KMT2A gene variations in 14 unrelated Chinese WDSTS patients and investigate the phenotypic differences between the Chinese and French cohorts. MethodsNext generation sequencing was performed for each patient, and the variants in the KMT2A gene were validated by Sanger sequencing. The phenotypes of 16 Chinese WDSTS patients were summarized and compared to 33 French patients.ResultsGenetic sequencing identified 13 deleterious de novo KMT2A variants in 14 patients, including 10 truncating, 2 missenses and 1 splicing variants. Of the 13 variants, 11 are novel and two have been reported previously. One of the patients is mosaic in the KMT2A gene. The variation spectra and phenotypic profiles of the Chinese WDSTS patients showed no difference with patients of other ethnicities; however, differ in the frequencies of several clinical features. We demonstrated that variations in the KMT2A gene can lead to both advanced and delayed bone age. We identified 6 novel phenotypes, which include microcephaly, deep palmar crease, external ear deformity, carpal epiphyseal growth retardation, dyslipidemia, and glossoptosis. In addition, patients harbored missense variants in the CXXC zinc finger domain of KMT2A showed more severe neurophenotypes.ConclusionOur study consists of the largest cohort of Chinese WDSTS patients that continues to expand the WDSTS phenotypic and variation spectrum. Our results support the notion that the CXXC zinc finger domain of KMT2A gene is a hotspot for missense variants associated with more severe neurophenotypes.

Outcome of dichorionic triamniotic triplet: the experience from an emerging fetal therapy center

Abstract Objectives: To report a cohort of dichorionic triamniotic (DCTA) triplets with access to contemporary fetal interventions. Design: Prospective study. Setting: A regional referral center for the diagnosis and management of complicated multiple pregnancies. Population: All DCTA triplets receiving consultation and prenatal care at our center from 2010 to 2015. Methods: The following management alternatives for DCTA were offered: 1) expectant management; 2) reduction of one or two fetus of the monochorionic (MC) component using radiofrequency ablation (RFA) after 16 weeks or potassium chloride (KCL) before 16 weeks, respectively; 3) reduction of the isolated fetus using KCL before 16 weeks. Main outcome measure: Survival rate of different management alternatives. Results: A total of 47 DCTA triplets were included in this study. After consultations on possible prognosis and management options, 19 patients chose expectant management, 14 patients opted RFA to reduce one fetus of the MC component, 14 patients required KCL to reduce the MC component. Fetal demise per pregnancy occurred more frequently in the subgroup managed expectantly (53%) compared to subgroups managed with RFA (7%, pu2009=u2009.02) or KCL (0%, pu2009=u2009.02). Overall survival was significantly lower in DCTA triplets managed expectantly (58%) compared to subgroup managed with RFA (93%, pu2009<u2009.01) or KCL (100%, pu2009=u2009.04). Conclusion: Fetal reduction seems to improve perinatal survival in DCTA triplets.

Prenatal diagnosis of Wolf–Hirschhorn syndrome: from ultrasound findings, diagnostic technology to genetic counseling

PurposeWolf–Hirschhorn syndrome (WHS) is a contiguous gene syndrome due to terminal chromosome 4p deletions. We explored prenatal diagnosis of WHS by ultrasound as well as karyotype and single nucleotide polymorphism array (SNP array) to characterize the structural variants of WHS prenatally.MethodsTen prenatal cases of WHS were evaluated for the indication of the invasive testing, the ultrasound features, and cytogenetic and microarray results.ResultsEight cases were diagnosed by karyotyping and SNP array, while two cases were detected only by SNP array. Combining our cases with 37 prenatal cases from the literature, the most common sonographic features were IUGR (97.7%) and typical facial appearance (82.9%). Other less common phenotypes included renal hypoplasia (36.2%), cardiac malformation (29.8%), cleft lip and palate (25.5%), cerebral abnormalities (25.5%), skeletal anomalies (21.3%), and increased nuchal translucency/nuchal fold thickness (NT/NF) (19%).ConclusionsThe most common intrauterine phenotypes of WHS were severe IUGR and typical facial appearance with other less consistent ultrasound findings. Noninvasive prenatal testing (NIPT) is one very promising screening tool for WHS. SNP array can improve diagnostic precision for detecting WHS, especially for the cryptic aberrations that cannot be identified by the traditional karyotyping. Ectopic kidney may be a previously unrecognized phenotype of WHS.