Prenatal exome sequencing in fetuses with congenital heart defects

Li, Ru; Fu, Fang; Yu, Qiuxia; Wang, Dan; Jing, Xiangyi; Zhang, Yongling; Li, Fucheng; Li, Fatao; Han, Jin Hee; Pan, Min; Li, Zhen; Li, Dong-Zhi; Liao, Can

doi:10.1111/cge.13774

Cited by 35 publications

(40 citation statements)

References 26 publications

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“…Ultrasound scans showed a range of abnormalities including increased nuchal translucency, pleural effusion, cardiac anomaly, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. Similar antenatal presentations were also noted in the recent large case series and published case reports 8–40 . More than half of the cases were diagnosed after birth by clinical assessment and molecular testing.…”

Section: Discussionsupporting

confidence: 78%

Prenatal phenotype of Kabuki syndrome: A case series and literature review

Luk

Cheung

et al. 2021

Prenatal Diagnosis

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Objectives Kabuki syndrome (KS) is a genetic disorder characterized by intellectual disability, facial dysmorphism and congenital anomalies. We aim to investigate the prenatal features of fetuses with KS and to provide a comprehensive review of the literature on prenatal sonographic abnormalities associated with KS. Methods We retrospectively reviewed the prenatal ultrasound findings of all mothers of children with molecularly confirmed KS in Hong Kong, between 1991 and 2019. We also performed systematic review of the literature to identify studies on the prenatal findings in KS. Results We identified 11 cases with KS with detectable fetal ultrasound findings ranging from no detectable abnormalities to a variety of non‐specific findings including increased nuchal translucency, pleural effusion, cardiac anomalies, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. In combining our cases with the 77 cases published, 42 (50.6%) of them had more than one abnormal antenatal ultrasound finding. The most frequent ultrasound features observed were cardiac anomalies (49.4%), followed by polyhydramnios (28.9%), genitourinary anomalies (26.5%), single umbilical artery (15.7%), intrauterine growth restriction (14.5%) and hydrops fetalis/pleural effusion/ascites (12.0%). Conclusions These cases demonstrate the prenatal phenotypic heterogeneity associated with KS. Although the ultrasound abnormalities are non‐specific, KS should be considered in the differential diagnosis when these fetal findings following normal microarray analysis/karyotyping.

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Section: Discussionsupporting

confidence: 78%

Prenatal phenotype of Kabuki syndrome: A case series and literature review

Luk

Cheung

et al. 2021

Prenatal Diagnosis

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“…Overall, the yield of the CMA test in our study was consistent with previously published data. However, the detection rate of our pathogenic sequence variants is higher than that reported in the literature [23][24][25] . In conclusion, we suggest CMA as a rst-tier test in fetuses with CHD, and that WES can be offered sequentially if CMA results are negative.…”

Section: Discussioncontrasting

confidence: 70%

“…Similar results have been obtained in previously published data. Wang et al reported that among 602 cases of CHD detected by CMA, the most common chromosomal abnormalities were observed in fetuses with AVSD (73.7%) 23 . Although the subgroup size of our cohort was small, we got very similar results with Wang's study.…”

Section: Discussionmentioning

confidence: 99%

Estimate the Frequency of Causal Genetic Variants in Fetuses With Congenital Heart Defects: a Chinese Cohort Study

Xue

Zhang

et al. 2021

Preprint

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Purpose: This cohort study was designed to assess the prevalence of chromosomal abnormalities in fetuses with different types of congenital heart defects (CHD).Methods: In a cohort of 200 fetuses with CHD, we performed prenatal chromosome microarray analysis (CMA) firstly, and then WES analysis was carried out on some fetuses with negative CMA results. Meanwhile, we conducted a systematic literature search on hot spot pathogenic copy number variations (CNVs) related to CHD in the Chinese population.Results: Chromosomal abnormalities were detected in 49 (24.5%) fetuses after prenatal CMA detection, including 23(11.5%) with aneuploidies and 26 (13.0%) with significant clinical CNVs. The additional diagnostic yield diagnosed by followed WES was 11.5% (6/52). The incidence of total chromosomal abnormality in the non-isolated CHD group (31.8%) was higher than that in the isolated CHD group (20.9%), mainly because the incidence of aneuploidy was significantly increased when CHD combined with extracardial structural abnormalities or soft markers. The chromosome abnormal rate of complex CHD group was higher than that of the simple CHD group, but the difference was not statistically significant (31.8% vs. 23.6%, P = 0.398). The most common CNVs detected in CHD fetuses was the 22q11.2 deletions, followed by deletions of 5p15.33p15.31, deletions of 15q13.2q13.3, deletions of 11q24.2q25, deletions of 17p13.3p13.2, duplications of 17q12.Conclusion: CMA is the recommended initial examination for cases of CHD in the prenatal setting, whether it is simple heart defects or isolated heart defect. For cases with negative CMA results, the follow-up application of WES will offer a considerable proportion of additional detection of clinical significance.

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“…A random-effects model was used to estimate the yield for isolated and multisystem CHD and the yield overall using RevMan version 5.3.4 (Review Manager, The Cochrane Collaboration, Copenhagen, Denmark) 22 . This model pooled our findings with those of 18 studies of 1557 fetuses, based on the analysis of Mone et al 5 and including two more recent studies 4,17 . It allowed for treatment effects to vary across studies and used a simple non-iterative method to estimate the interstudy treatment effect variance.…”

Section: Statistical Analysesmentioning

confidence: 86%

“…Pathogenic CNVs have been detected in 7-36% of fetuses with isolated CHD or CHD associated with other structural anomalies but normal karyotype 6,8 . Next-generation sequencing, especially exome sequencing (ES), enables analysis of single nucleotide variations (SNV) and insertions and deletions (indels) of gene-coding regions, and has facilitated in CHD patients discovery of novel causative genes 4,[14][15][16][17] which are indefinable through traditional genomic methods. However, previous fetal studies have focused on chromosomal abnormalities and sequence variants separately.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive evaluation of genetic variants using chromosomal microarray analysis and exome sequencing in fetuses with congenital heart defect

Qiao

Wang

Zhang

et al. 2021

Ultrasound in Obstet & Gyne

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What are the novel findings of this work?Using chromosomal microarray analysis (CMA) and exome sequencing in 360 unselected fetuses with congenital heart defect (CHD), positive genetic diagnoses were made in 84 (23.3%) cases, including 60 (16.7%) cases with chromosomal abnormalities detected by CMA and a further 24 (6.7%) cases with sequence variants detected by exome sequencing. The prevalence of a genetic defect was highest in fetuses with an atrioventricular septal defect (36.8%), ventricular septal defect with or without atrial septal defect (28.4%), conotruncal defect (22.2%) or right ventricular outflow tract obstruction (20.0%). We also identified two novel missense mutations and a new phenotype caused by variants in PLD1. What are the clinical implications of this work?These findings may facilitate prenatal diagnosis and provide a basis for genetic counseling in pregnancies with fetal CHD. Exome sequencing should be offered to all CHD fetuses without chromosomal abnormality or pathogenic copy number variation identified by CMA.

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Prenatal exome sequencing in fetuses with congenital heart defects

Cited by 35 publications

References 26 publications

Prenatal phenotype of Kabuki syndrome: A case series and literature review

Prenatal phenotype of Kabuki syndrome: A case series and literature review

Estimate the Frequency of Causal Genetic Variants in Fetuses With Congenital Heart Defects: a Chinese Cohort Study

Comprehensive evaluation of genetic variants using chromosomal microarray analysis and exome sequencing in fetuses with congenital heart defect

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