[Efficiency of CNV-seq in detecting fetal DMD gene deletion or duplication in prenatal diagnosis].

Objective: To evaluate the diagnostic efficiency of copy number variation sequencing (CNV-seq) to detect the deletion or duplication of DMD gene in prenatal diagnosis. Methods: A retrospective analysis was carried out on the CNV-seq results of 34 544 fetuses diagnosed in the First People's Hospital of Yunnan Province from January 2018 to July 2023. A total of 156 cases of fetuses were collected, including Group 1:125 cases with family history of Duchenne muscular dystrophy or Becker muscular dystrophy (DMD/BMD), and Group 2:31 cases with no family history but a DMD gene deletion or duplication was detected unexpectedly by CNV-seq. Multiplex ligation-dependent probe amplification (MLPA) was used as a standard method to detect the deletion or duplication. Consistency test was carried out basing on the results of CNV-seq and MLPA of all 156 cases. Results: Comparing to MLPA, CNV-seq had a coincidence rate of 92.3% (144/156) for DMD gene deletion or duplication, with a sensitivity and positive predictive value of 88.2%, with a specificity and negative predictive value of 94.3%, a missed detection rate of 3.8%, and a Kappa value of 0.839. CNV-seq missed 4 cases with deletions and 2 with duplications due to involved fragments less than 100 Kb, among 20 cases of deletions and 6 cases of duplications detected by MLPA in Group 1. In Group 2, the deletions and duplications detected by CNV-seq were 42% (13/31) and 58% (18/31), respectively, in which the percentage of duplication was higher than that in Group 1. Among those 18 cases with duplications, 3 cases with duplication locating in exon 42~67 were likely pathogenic; while 9 cases with duplication covering the 5' or 3' end of the DMD gene, containing exon 1 or 79 and with only one breakpoint within the gene, along with the last 6 cases with duplications locating at chrX: 32650635_32910000 detected only by CNV-seq, which might be judged as variants of uncertain significance. Conclusions: CNV-seq has a good efficiency to detect fetal DMD gene deletion or duplication in prenatal diagnosis, while a further verification test by MLPA is recommended. The duplications on chrX: 32650635_32910000, 5' or 3' end of DMD gene detected by CNV-seq should be carefully verified and assessed because those variants appear to be nonpathogenic polymorphisms.

Diagnosis of single umbilical artery and risk of foetal congenital malformations by prenatal ultrasound: a retrospective study.

BACKGROUND: Single umbilical artery (SUA) is strongly associated with foetal structural abnormalities; however, the exact pattern of this association has not been described. We aimed to investigate the occurrence of malformations in singleton pregnancies with SUA in China and to study the association between the absent side of the umbilical artery and foetal malformations. METHODS: This was a retrospective study of singleton pregnancies for which routine first-trimester anatomical screening was performed at 11+ 0-13+ 6 gestational weeks and, if the pregnancy continued, a second-trimester scan was performed at 20+ 0-24+ 0 weeks. Data were extracted from records at the referral centre, the Obstetrics and Gynecology Hospital of Fudan University, between January 2011 and April 2019 (n = 47,894). Using logistic regression, the odds ratios (OR) with 95% confidence intervals (CIs) were calculated for malformations associated with SUA. RESULTS: The incidence of SUA in our study was 2.0% (970/47,894). Of all foetuses with SUA, 387 (39.9%) had structural malformations. The malformation type varied, with cardiovascular complications being the most common. A robust association was observed between SUA and oesophageal stenosis or atresia (OR: 25.33), followed by cardiovascular (OR: 9.98-24.02), scoliosis (OR: 18.62), genitourinary (OR: 2.45-15.66), and brain malformations (OR: 4.73-9.12). The absence of the left umbilical artery (n = 445, 45.9%) was consistent with that of the right umbilical artery (n = 431, 44.4%). Furthermore, a significantly higher rate of an absent right than the left umbilical artery (p<0.01) was observed in SUA with foetal abnormalities than in SUA with no malformations. CONCLUSIONS: Overall, we observed a higher risk of various specific malformations in foetuses with SUA, and a strong association between SUA and oesophageal stenosis or atresia. The absence of the right umbilical artery was most common in foetuses with SUA and structural malformations. This study provides a reference for ultrasonographers in conducting foetal structural screening for pregnant women with SUA.

Monochorionic triplet pregnancy complicated by conjoined twins and early twin-twin transfusion syndrome.

BACKGROUND: The condition of monozygotic, monochorionic triplet fetuses with a pair of conjoined twins is extremely rare (close to one in a million births), presents challenges in its management, and with poor prognosis. CASE REPORT: We report a case of monochorionic diamniotic triplet pregnancy, ultrasound at 14 weeks shows a pair of conjoined thoracopagus fetuses, sharing heart, liver, and umbilical cord, in addition to omphalocele. The third fetus, without malformations, presents signs of early heart failure compatible with twin-to-twin transfusion syndrome. It was decided to carry out expectant management where at 18 weeks, intrauterine death of the three fetuses occurs. An abortion is performed by hysterotomy. CONCLUSIONS: The treatment in these cases is discussed, three management options have been proposed: expectant management, selective reduction of the conjoined fetuses, or termination of the pregnancy. A review of the literature found only 12 cases with this combination of pathologies, in which only 3 normal fetuses (25%) survived and none of the conjoined twins survived. To our knowledge, this case is the first of a monochorionic triplet pregnancy with conjoined fetuses complicated with early twin-to-twin transfusion.

Genetic testing for fetal loss of heterozygosity using single nucleotide polymorphism array and whole-exome sequencing.

The study explored the clinical significance of fetal loss of heterozygosity (LOH) identified by single-nucleotide polymorphism array (SNP array). We retrospectively reviewed data from pregnant women who underwent invasive diagnostic procedures at prenatal diagnosis centers in southeastern China from December 2016 to December 2021. SNP array was performed by the Affymetrix CytoScan 750 K array platform. Fetuses with LOH were further identified by parental verification, MS-MLPA, and/or trio whole-exome sequencing (trio-WES). The genetic results, fetal clinical manifestations, and perinatal outcome were analyzed. Of 11,062 fetuses, 106 (0.96%) had LOH exhibiting a neutral copy number, 88 (83.0%) had LOH in a single chromosome, whereas 18 (17.0%) had multiple LOHs on different chromosomes. Sixty-six fetuses had ultrasound anomalies (UAs), most frequently fetal growth restriction (18/66 (27.3%)). Parental SNP array verification was performed in 21 cases and trio-WES in 21 cases. Twelve cases had clinically relevant uniparental disomy, five had pathogenic variants, four had likely pathogenic variants, six had variants of unknown significance, and eight had identity by descent. The rate of adverse pregnancy outcomes in fetuses with LOH and UAs (24/66 (36.4%)) was higher than in those without UAs (6/40 (15.0%)) (p < 0.05). LOH is not uncommon. Molecular genetic testing techniques, including parental SNP array verification, trio-WES, methylation-specific multiplex ligation-dependent probe amplification, regular and systematic ultrasonic monitoring, and placental study, can accurately assess the prognosis and guide the management of the affected pregnancy.

Prenatal diagnosis and molecular cytogenetic characterization of fetuses with central nervous system anomalies using chromosomal microarray analysis: a seven-year single-center retrospective study.

Few existing reports have investigated the copy number variants (CNVs) in fetuses with central nervous system (CNS) anomalies. To gain further insights into the genotype-phenotype relationship, we conducted chromosomal microarray analysis (CMA) to reveal the pathogenic CNVs (pCNVs) that were associated with fetal CNS anomalies. We enrolled 5,460 pregnant women with different high-risk factors who had undergone CMA. Among them, 57 subjects with fetal CNS anomalies were recruited. Of the subjects with fetal CNS anomalies, 23 were given amniocentesis, which involved karyotype analysis and CMA to detect chromosomal abnormalities. The other 34 cases only underwent CMA detection using fetal abortive tissue. In this study, we identified five cases of chromosome aneuploid and nine cases of pCNVs in the fetuses, with a chromosomal aberration detection rate of 24.56% (14/57). In the 23 cases that were given both karyotype and CMA analysis, one case with trisomy 18 was detected by karyotyping. Moreover, CMA revealed a further three cases of pCNVs, including the 1p36.33p36.31, 7q11.23, and 1q21.1q21.2 microdeletions, with a 13.04% (3/23) increase in CMA yield over the karyotype analysis. Additionally, three cases of trisomy 13, one case of trisomy 21, and six cases of pCNVs were detected in the other 34 fetuses where only CMA was performed. Furthermore, a higher chromosomal aberration detection rate was observed in the extra CNS anomaly group than in the isolated CNS anomaly group (40.91% vs 14.29%). In conclude, several pathogenic CNVs were identified in the fetuses with CNS anomalies using CMA. Among the detected CNVs, ZIC2, GNB1, and NSUN5 may be the candidate genes that responsible for fetal CNS anomalies. Our findings provides an additional reference for genetic counseling regarding fetal CNS anomalies and offers further insight into the genotype-phenotype relationship.

A genetic variant in the MAST1 gene is associated with mega-corpus-callosum syndrome with hypoplastic cerebellar vermis, in a fetus.

BACKGROUND: Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations is a rare neurological disorder that is associated with typical clinical and imaging features. The syndrome is caused by pathogenic variants in the MAST1 gene, which encodes a microtubule-associated protein that is predominantly expressed in postmitotic neurons in the developing nervous system. METHODS: Fetal DNA from umbilical cord blood samples and genomic DNA from peripheral blood lymphocytes were subjected to whole-exome sequencing. The potential causative variants were verified by Sanger sequencing. RESULTS: A 26-year-old primigravid woman was referred to our prenatal center at 25 weeks of gestation due to abnormal ultrasound findings in the brain of the fetus. The brain abnormalities included wide cavum septum pellucidum, shallow and incomplete bilateral lateral fissure cistern, bilateral dilated lateral ventricles, hyperplastic corpus callosum, lissencephaly, and cortical dysplasia. No obvious abnormalities were observed in the brainstem or cerebellum hemispheres, but the cerebellum vermis was small. Whole-exome sequencing identified a de novo, heterozygous missense variant, c.695T>C(p.Leu232Pro), in the MAST1 gene and a genetic diagnosis of mega-corpus-callosum syndrome was considered. CONCLUSION: This study is the first prenatal case of MAST1-related disorder reported in the Chinese population and has expanded the mutation spectrum of the MAST1 gene.

Fetal hyperechoic kidneys: Diagnostic considerations and genetic testing strategies.

Isolated bilateral hyperechoic kidneys (HEK) on prenatal ultrasound presents diagnostic, prognostic, and counseling challenges. Prognosis ranges from normal outcome to lethal postnatally. Presence/absence of extra-renal malformations, gestational age at presentation, amniotic fluid volume, and renal size may distinguish underlying etiologies and thereby prognosis, as prognosis is highly dependent upon underlying etiology. An underlying genetic diagnosis, clearly impactful, is determined in only 55%-60% of cases. We conducted a literature review of chromosomal (aneuploidies, copy number variants [CNVs]) single genes and other etiologies of fetal bilateral HEK, summarized how this information informs prognosis and recurrence risk, and critically assessed laboratory testing strategies. The most commonly identified etiologies are autosomal recessive and autosomal dominant polycystic kidney disease and microdeletions at 17q12 involving HNF1b. With rapid gene discovery, alongside advances in prenatal imaging and fetal phenotyping, the growing list of single gene diagnoses includes ciliopathies, overgrowth syndromes, and renal tubular dysgenesis. At present, microarray and gene panels or whole exome sequencing (WES) are first line tests employed for diagnostic evaluation. Whole genome sequencing (WGS), with the ability to detect both single nucleotide variants (SNVs) and CNVs, would be expected to provide the highest diagnostic yield.

Prenatal diagnosis of polycystic renal diseases: diagnostic yield, novel disease-causing variants, and genotype-phenotype correlations.

BACKGROUND: Polycystic renal disease is a frequent congenital anomaly of the kidneys, but research using chromosomal microarray analysis and exome sequencing in fetuses with polycystic renal disease remains sparse, with most studies focusing on the multisystem or genitourinary system. OBJECTIVE: This study aimed to assess the detection rate of detectable genetic causes of fetal polycystic renal disease at different levels, novel disease-causing variants, and genotype-phenotype correlations. STUDY DESIGN: This study included 220 fetal polycystic renal disease cases from January 2014 to June 2022. Cases were divided into the following 3 groups: isolated multicystic dysplastic kidneys, nonisolated multicystic dysplastic kidneys, and suspected polycystic kidney disease group. We reviewed data on maternal demographics, ultrasonographic results, chromosomal microarray analysis/exome sequencing results, and pregnancy outcomes. RESULTS: In our cohort, chromosomal microarray analysis identified 19 (8.6%) fetuses carrying chromosomal abnormalities, and the most common copy number variation was 17q12 microdeletion (7/220; 3.2%). Furthermore, 94 families chose to perform trio-exome sequencing testing, and 21 fetuses (22.3%) were found to harbor pathogenic/likely pathogenic variants. There was a significant difference in the live birth rate among the 3 groups (91/130 vs 46/80 vs 1/10; P<.001). Among 138 live birth cases, 106 (78.5%) underwent postnatal ultrasound review, of which 95 (89.6%) had a consistent prenatal-postnatal ultrasound diagnosis. CONCLUSION: For both isolated and nonisolated polycystic renal disease, our data showed high detection efficiency with both testing tools. The detection of novel pathogenic variants expands the known disease spectrum of polycystic renal disease-associated genes while enriching our understanding of the genotype-phenotype correlation. Therefore, we consider it feasible to perform chromosomal microarray analysis+exome sequencing testing in fetal polycystic renal disease. Moreover, prenatal-postnatal ultrasound concordance was greater, the live birth rate was higher, and prognosis was better when known genetic disorders were excluded, indicating that genetic testing results significantly influenced pregnancy decisions.

Trust in prenatal exome sequencing for expectant families facing unexplained fetal anomalies.

OBJECTIVE: Despite exome sequencing (ES) becoming increasingly incorporated into the prenatal setting, few studies have elucidated motivations for and trust in ES and genomic research among a diverse cohort of patients and their partners. METHODS: This is a qualitative study that involved semi-structured interviews with pregnant or recently pregnant individuals and their partners, interviewed separately, in the setting of ES performed through research for a fetal structural anomaly. All interview transcripts were coded thematically and developed by a multidisciplinary team. RESULTS: Thirty-five individuals participated, the majority of whom (66%) self-identified as a racial or ethnic group underrepresented in genomic research. Many patients and their partners expressed trust in the healthcare system and research process and appreciated the extensive testing for information and closure. There were nonetheless concerns about data privacy and protection for individuals, including those underrepresented, who participated in genomic testing and studies. CONCLUSION: Our findings illustrate important elements of motivation, trust and concern related to prenatal ES performed in the research setting, taking into account the perspectives not only of diverse and underrepresented study participants but also partners of pregnant individuals.

A novel NONO nonsense variant in a fetus with renal abnormalities.

At 16 + 6-weeks a fetal scan performed in the second pregnancy of a 42 y.o. woman identified a right multicystic dysplastic kidney, left renal agenesis, absent urinary bladder, myocardial hypertrophy, increased nuchal fold, a single umbilical artery, and oligohydramnios. Trio exome sequencing analysis detected a novel pathogenic NONO variant. Postmortem examination after the termination of pregnancy confirmed the ultrasound findings and also revealed pulmonary hypoplasia, retrognathia and low-set ears. The variant was a novel de novo hemizygous pathogenic loss-of-function variant in NONO [NM_007363.5], associated with a rare X-linked recessive neurodevelopmental disorder, named intellectual developmental disorder, X-linked syndromic 34 (OMIM#300967). The postnatal characteristic features of this disorder include intellectual disability, developmental delay, macrocephaly, structural abnormalities involving the corpus callosum and/or cerebellum, left ventricular noncompaction and other congenital heart defects. In the prenatal setting, the phenotype has been poorly described, with all described cases presenting with heart defects. This case highlights the need of further clinical delineation to include renal abnormalities in the prenatal phenotype spectrum.

Fetal cystic and solid tumor of the atrioventricular node: Autopsy diagnosis at 12 weeks of gestational age.

Primary cardiac tumors are uncommon clinical entities with an incidence of 0.0017% to 0.03% of all autopsies. Cystic tumor of the atrioventricular node (CTAVN) comprises of 2.7% of cardiac tumors causing sudden death associated with complete heart block. CTAVN is a congenital benign cystic and solid mass located in the triangle of Koch in atrioventricular nodal region of the heart. It has been described from infancy to adulthood, most often as an incidental finding at autopsy, but has been not yet described in fetuses. We report a case of late spontaneous abortion detected during the first ultrasound follow-up consultation at 12w+1d of gestation in a healthy 23-year-old pregnant woman, gravida 2 para 0 and one previous termination of pregnancy. Pathological study of abortion product was request. No abnormalities were detected on gross examination, but microscopically, characteristics features of cardiac cystic and solid tumor of the atrioventricular node were identified. We present the first case described in literature of a congenital benign CTAVN in a non-macerate, normal, female fetus with an appropriate growth and development for 12w+1d of gestational age. There are many reasons for performing a fetal post-mortem autopsy foremost of which is identifying an accurate cause of death.

Comprehensive phenotyping of fetuses with trisomy 18: a perinatal center experience.

Trisomy 18 is the second most common aneuploidy after trisomy 21. It presents with varying degrees of heterogeneous clinical phenotypes involving multiple organ systems, with a high mortality rate. Clinical assessment of fetal trisomy 18 is always challenging. In this study, we describe the phenotypes of the fetuses with trisomy 18 from a perinatal cohort. We reviewed fetuses with trisomy 18 in referrals for perinatal autopsy over the period of 15 years. A detailed phenotyping of the fetuses with trisomy 18 was executed by perinatal autopsy. Appropriate fetal tissues were obtained to perform genomic testing. We observed trisomy 18 in 16 fetuses (2%) in our cohort of 784 fetal/neonatal losses and a perinatal autopsy was performed on all of them. Abnormal facial profile was the most frequent anomaly (10/16, 62%) followed by anomalies of the extremities (9/16, 56%), and cardiac defects (6/16, 37%). We also observed esophageal atresia, diaphragmatic hernia, and neural tube defect. The study represents one of the largest cohorts of trisomy 18 from a perinatal center from a developing country and highlights the clinical heterogeneity attributed to trisomy 18. We also report a recurrence of trisomy 18 in a family.

Residual risk of clinically significant copy number variations in fetuses with nasal bone absence or hypoplasia after excluding non-invasive prenatal screening-detectable findings.

BACKGROUND: It remains controversial whether prenatal screening or diagnostic testing should be offered to fetuses with nasal bone (NB) absence or hypoplasia, and there are no studies comparing the yield of chromosomal microarray analysis (CMA) to non-invasive prenatal screening (NIPS). The aim of this study was to evaluate the residual risk of clinically significant copy number variations (CNVs) in fetuses with NB absence or hypoplasia after excluding theoretically NIPS-detectable abnormalities, and to assess their clinical outcomes. METHODS: This prospective study encompassed 400 fetuses with NB absence or hypoplasia undergoing CMA testing between 2015 and 2022. Clinically significant CMA findings were categorized into three subgroups, including three-NIPS-detectable (trisomies 21, 18 and 13), five-NIPS-detectable (trisomies 21, 18 and 13 and sex chromosome aneuploidies) and genome-wide NIPS-detectable (variants over 7 Mb). We calculated the theoretical residual risk and compared it with the results of a control cohort of low-risk pregnancies. We further evaluated their clinical outcomes. RESULTS: The overall diagnostic yield in our cohort was 7.8% (31/400). The detection rate of clinically significant CMA findings in fetuses with non-isolated NB absence or hypoplasia was significantly higher than that in fetuses with isolated NB absence or hypoplasia (20.0% vs. 6.6%, P =.005). The theoretical residual risks in all NIPS models were significantly higher when compared with the control cohort. The normal infant rate in fetuses with normal CMA results was 97.9% (323/330), and a significant higher incidence was observed in fetuses with isolated NB absence or hypoplasia compared with non-isolated NB absence or hypoplasia (98.4% vs. 91.7%, P =.028). CONCLUSIONS: The residual risk of clinically significant CNVs in fetuses with NB absence or hypoplasia following the exclusion of theoretically NIPS-detectable findings was higher than that in low-risk pregnancies. This risk should be considered in genetic counseling to make a more comprehensive and precise choice regarding prenatal genetic testing.

The Role of Preprocedure Genetic Counseling in Pregnancies Interrupted for Fetal Abnormalities.

OBJECTIVE: Congenital birth defects affect 3 to 5% of pregnancies. Genetic counseling can help patients navigate the testing process and understand results. The study objective was to identify predictors and utility of genetic counseling at the time of pregnancy termination. Additionally, we aimed to see what proportion of patients would benefit from additional testing based on the results of the genetic testing. STUDY DESIGN: This was a retrospective cohort review of all terminations performed for fetal anomalies by an academic center from July 2016 to May 2020. Indications were stratified by abnormal serum screening or types of abnormal ultrasound findings. Data were abstracted regarding uptake of genetic counseling and testing results. Abnormal results that warranted additional testing regarding recurrence risks were noted. Multivariable logistic regression was performed to identify predictors of receipt of genetic counseling and testing. RESULTS: Of 387 patients, 57% (n = 220) received preprocedure genetic counseling and 43% (n = 167) did not. Among patients who received diagnostic testing, 62% (n = 194) had genetic counseling compared with 38% (n = 121) without counseling (adjusted odds ratio 2.46, 95% confidence interval [1.41-4.29], p < 0.001). Among the entire cohort, 38% (n = 148) had suspected aneuploidy based on serum screening. Of these, 89% (n = 132/148) had definitive testing, 92% (n = 122/132) confirming the aneuploidy. Among the other 68% (n = 239) with structural anomalies, 76% (n = 183) had diagnostic testing with 29% (n = 53) yielding an abnormal result. Among those fetuses with structural anomalies, 36% (n = 19/53) of genetic diagnoses warranted additional parental testing because of risk of recurrence compared with only 2% (n = 2/122) of patients with abnormal serum screening results alone. CONCLUSION: Genetic counseling was associated with increased uptake of diagnostic testing, which yielded useful information and prompted additional testing. This is important for determining etiology and recurrence risk and should be offered to patients presenting for termination for fetal indications, as well as providing diagnostic closure for patients. KEY POINTS: · Genetic counseling increases the uptake of diagnostic testing in patients with fetal anomalies.. · Patients with ultrasound anomalies received less diagnostic testing despite actionable results 36% of the time.. · Genetic testing is invaluable for recurrence risk counseling even if patients chose to terminate..

Copy number variants and fetal structural abnormalities in stillborn fetuses: A secondary analysis of the Stillbirth Collaborative Research Network study.

OBJECTIVE: To examine the association of placental and fetal DNA copy number variants (CNVs) with fetal structural malformations (FSMs) in stillborn fetuses. DESIGN: A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network (SCRN) study. SETTING: Multicenter, 59 hospitals in five geographic regions in the USA. POPULATION: 388 stillbirth cases of the SCRN study (2006-2008). METHODS: Fetal structural malformations were grouped by anatomic system and specific malformation type (e.g. central nervous system, thoracic, cardiac, gastrointestinal, skeletal, umbilical cord and craniofacial defects). Single-nucleotide polymorphism array detected CNVs of at least 500 kb. CNVs were classified into two groups: normal, defined as no CNVs >500 kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. MAIN OUTCOME MEASURES: The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without FSMs using the Wald Chi-square test. RESULTS: The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs than among those with normal CNVs (47.5 versus 19.1%; P-value <0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by hydrops, craniofacial defects and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g. CHD1L) and a duplication of 21q22.13 involving four genes (SIM2, CLDN14, CHAF1B, HLCS) were associated with a skeletal and cardiac defect, respectively. CONCLUSION: Specific CNVs involving several genes were associated with FSMs in stillborn fetuses. The findings warrant further investigation and may inform counselling and care surrounding pregnancies affected by FSMs at risk for stillbirth.

Chromosome Microarray Analysis and Exome Sequencing: Implementation in Prenatal Diagnosis of Fetuses with Digestive System Malformations.

(1) Purpose: Retrospective back-to-back comparisons were performed to evaluate the accuracy, effectiveness, and incremental yield of chromosome microarray analysis (CMA) and exome sequencing (ES) analysis in fetuses with digestive system malformations (DSMs). (2) Methods: In total, 595 women with fetal DSMs who underwent prenatal diagnosis were enrolled. We analyzed the diagnostic yields of CMA and ES and evaluated pregnancy outcomes. Copy number variants (CNVs) were classified according to the American College of Medical Genetics and Genomics guidelines. (3) Results: Pathogenic CNVs were detected in 11/517 (2.12%) fetuses, and variants of unknown significance (VUS) were identified in 69 (13.35%) fetuses using CMA. ES detected 29 pathogenic/likely pathogenic variants in 23/143 (16.08%) fetuses and 26/143 (18.2%) VUS. In those with other ultrasound abnormalities, the detection rate of multiple system structural malformations was 41.2%, followed by skeletal (33.3%), cardiovascular (25.4%), and central nervous system (18.6%) malformations. Of the 391 surviving children, 40 (10.2%) exhibited varying degrees of mental retardation. (4) Conclusion: A correlation exists between DSMs and chromosomal abnormalities. When combined with other systemic abnormalities, the incidence of chromosomal abnormalities increases significantly. Patients with congenital DSM are at risk of developing neurodevelopmental disorders. Combined CMA and ES detection of fetal DSM has good clinical application potential.

Prenatal whole-exome sequencing for fetal structural anomalies: a retrospective analysis of 145 Chinese cases.

BACKGROUND: Whole-exome sequencing (WES) significantly improves the diagnosis of the etiology of fetal structural anomalies. This study aims to evaluate the diagnostic value of prenatal WES and to investigate the pathogenic variants in structurally abnormal fetuses. METHODS: We recruited 144 fetuses with structural anomalies between 14 and 2020 and 15 December 2021 in the study. Genetic screening was performed by WES combined with karyotyping and chromosomal microarray analysis. The molecular diagnostic yield of prenatal WES for each type of fetal structural anomaly and the identified pathogenic genes and mutations were reported. RESULTS: In this study, we retrospectively analyzed the clinical and genetic data of 145 structurally anomalous fetuses. These cases were classified into 9 phenotypic classes based on antenatal ultrasound findings. Thirty-eight pathogenic variants in 24 genes were identified in 35 of the 145 cases, including 14 novel variants in 13 genes (EP300, MYH3, TSC2, MMP9, CPLANE1, INVS, COL1A1, EYA1, TTC21B, MKS1, COL11A2, PDHA1 and L1CAM). Five additional pathogenic variants were classified as incidental findings. Our study showed that the overall diagnosis rate of WES was 28.1% (27/96) in the parent-fetus trio cases and 16.3% (8/49) in the proband-only cases. Fetuses with musculoskeletal anomalies had the highest diagnostic yield (51.4%, 19/37). In addition, FGFR3 and COL1A1 were the most common pathogenic genes. CONCLUSIONS: Our work expands the mutation spectrum of the genes associated with fetal structural anomalies and provides valuable information for future parental genetic counselling and pregnancy management of the structurally anomalous fetuses.

First trimester anatomy ultrasound for patients with obesity: a randomized controlled trial.

BACKGROUND: Second-trimester ultrasound is the standard technique for fetal anatomy evaluation in the United States despite international guidelines and literature that suggest that first-trimester timing may be superior in patients with obesity. First-trimester imaging performs well in cohorts of participants with obesity. OBJECTIVE: Our aim was to compare the completion rate of a first-trimester fetal anatomy ultrasound scan with that of a second-trimester fetal anatomy ultrasound scan among pregnant people with a body mass index ≥35 kg/m2. STUDY DESIGN: This randomized controlled trial enrolled participants with a body mass index ≥35 kg/m2 with a singleton gestation and who presented before 14+0/7 weeks of gestation. Participants were randomized to receive an ultrasound assessment of anatomy at either 12+0/7 to 13+6/7 weeks or at 18+0/7 to 22+6/7 weeks. The primary outcome was completion rate (percentage of scans that optimally imaged all the required fetal structures). Secondary outcomes included the necessity of a transvaginal approach, completion rates for each individual view, number of anomalies identified and missed in each group, scan duration, and patient perspectives. A 1-year pilot sample was analyzed using Bayesian methods for the primary outcome with a neutral prior and frequentist analyses for the remaining outcomes. RESULTS: A total of 128 participants were enrolled, and 1 withdrew consent; 62 subjects underwent a first-trimester ultrasound scan and 62 underwent a second-trimester ultrasound scan. A total of 2 participants did not attend the research visits, and 1 sought termination of pregnancy. In the first-trimester group, 66% (41/62) of ultrasound scans were completed in comparison with 53% (33/62) in the second-trimester ultrasound group (Bayesian relative risk, 1.20; 95% credible interval, 0.91-1.73). When compared with a second-trimester scan plus a follow-up ultrasound, a first-trimester ultrasound plus a second-trimester ultrasound was equally successful in completing the anatomy views (76%). First-trimester anatomy ultrasound scans required a transvaginal approach in 63% (39/62) of cases and had a longer duration than a second-trimester ultrasound scan. No anomalies were missed in either group. First-trimester ultrasound participants who responded to a survey described that they were very satisfied with the technique. CONCLUSION: In pregnant subjects with a body mass index ≥35 kg/m2, a single first-trimester anatomy ultrasound scan was more likely to obtain all the recommended anatomic views than a single second-trimester ultrasound scan. An evaluation of anatomy at 12+0/7 to 13+6/7 weeks' gestation plus an evaluation at 18+0/7 to 22+6/7 led to complete anatomic evaluation 4 weeks earlier than 2 second trimester scans. Assessment of ultrasound duration in a clinical setting is needed to ensure feasibility outside of a research setting.

Prenatal whole-exome sequencing in fetuses with increased nuchal translucency.

BACKGROUND: Increased nuchal translucency (NT) is associated with an increased risk for genetic disorders. The aim of this study was to investigate the value of whole-exome sequencing (WES) in detecting genetic abnormalities for fetuses with isolated first-trimester increased NT. METHODS: After the exclusion of aneuploidies and pathogenic copy number variants (CNVs) by quantitative fluorescent polymerase chain reaction (QF-PCR) and chromosomal microarray analysis (CMA), WES was performed on 63 fetuses with isolated first-trimester increased NT (≥3.5 mm). RESULTS: Overall, WES yielded a 4.8% (3/63) diagnostic rate for fetuses with isolated increased NT. Pathogenic variants were identified in 37.5% (3/8) fetuses that developed additional structural anomalies later in gestation, and no pathogenic variants were detected in increased NT that resolved or remained isolated throughout the pregnancy. CONCLUSION: This study provides powerful evidence to offer prenatal WES for increased NT only when additional abnormalities are present. Early detailed ultrasound to detect emerging anomalies can help physicians offer prenatal WES to fetuses with a greater likelihood of diagnosis.

[Clinical phenotype and genetic analysis of a fetus with recombinant chromosome 8 syndrome].

OBJECTIVE: To explore the clinical characteristics and molecular genetic mechanism of a fetus with recombinant chromosome 8 (Rec8) syndrome. METHODS: A fetus who was diagnosed with Rec8 syndrome at the Provincial Hospital Affiliated to Shandong First Medical University on July 20, 2021 due to high risk for sex chromosomal aneuploidy indicated by non-invasive prenatal testing (NIPT) (at 21st gestational week) was selected as the study subject. Clinical data of the fetus was collected. G-banded karyotyping and chromosomal microarray analysis (CMA) were carried out on the amniotic fluid sample. Peripheral blood samples of the couple were also subjected to G banded karyotyping analysis. RESULTS: Prenatal ultrasonography at 23rd gestational week revealed hypertelorism, thick lips, renal pelvis separation, intrahepatic echogenic foci, and ventricular septal defect. The karyotype of amniotic fluid was 46,XX,rec(8)(qter→q22.3::p23.1→qter), and CMA was arr[GRCh37]8p23.3p23.1(158049_6793322)×1, 8q22.3q24.3(101712402_146295771)×3. The karyotype of the pregnant woman was 46,XX,inv(8)(p23.1q22.3), whilst that of her husband was normal. CONCLUSION: The Rec8 syndrome in the fetus may be attributed to the pericentric inversion of chromosome 8 in its mother. Molecular testing revealed that the breakpoints of this Rec8 have differed from previously reported ones.