Dataset Information

The prevalence of genetic diagnoses in fetuses with severe congenital heart defects.

ABSTRACT:

Purpose

Congenital heart defects (CHD) are associated with genetic syndromes. Rapid aneuploidy testing and chromosome microarray analysis (CMA) are standard care in fetal CHD. Many genetic syndromes remain undetected with these tests. This cohort study aims to estimate the frequency of causal genetic variants, in particular structural chromosome abnormalities and sequence variants, in fetuses with severe CHD at mid-gestation, to aid prenatal counselling.

Methods

Fetuses with severe CHD were extracted from the PRECOR registry (2012-2016). We evaluated pre- and postnatal genetic testing results retrospectively to estimate the frequency of genetic diagnoses in general, as well as for specific CHDs.

Results

919 fetuses with severe CHD were identified. After exclusion of 211 cases with aneuploidy, a genetic diagnosis was found in 15.7% (111/708). These comprised copy number variants in 9.9% (70/708). In 4.5% (41/708) sequence variants were found that would have remained undetected with CMA. Interrupted aortic arch, pulmonary atresia with ventricular septal defect and atrioventricular septal defect were most commonly associated with a genetic diagnosis.

Conclusion

In case of normal CMA results, parents should be offered exome sequencing sequentially, if time allows for it, especially if the CHD is accompanied by other structural malformations due to the large variety in genetic syndromes.

SUBMITTER: van Nisselrooij AEL

PROVIDER: S-EPMC7332415 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

The prevalence of genetic diagnoses in fetuses with severe congenital heart defects.

van Nisselrooij Amber E L AEL Lugthart Malou A MA Clur Sally-Ann SA Linskens Ingeborg H IH Pajkrt Eva E Rammeloo Lukas A LA Rozendaal Lieke L Blom Nico A NA van Lith Jan M M JMM Knegt Alida C AC Hoffer Mariëtte J V MJV Aten Emmelien E Santen Gijs W E GWE Haak Monique C MC

Genetics in medicine : official journal of the American College of Medical Genetics 20200428 7

<h4>Purpose</h4>Congenital heart defects (CHD) are associated with genetic syndromes. Rapid aneuploidy testing and chromosome microarray analysis (CMA) are standard care in fetal CHD. Many genetic syndromes remain undetected with these tests. This cohort study aims to estimate the frequency of causal genetic variants, in particular structural chromosome abnormalities and sequence variants, in fetuses with severe CHD at mid-gestation, to aid prenatal counselling.<h4>Methods</h4>Fetuses with sever ...[more]

PMID: 32341573

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Project description:AimsFetuses affected by congenital heart defects (CHD) are considered to be at increased risk of fetal growth restriction and intrauterine demise. Whether these risks are a direct consequence of fetal CHD or a result of associated uteroplacental dysfunction is not evident from the data of recent studies. The aim of this study was to investigate the prevalence of uteroplacental dysfunction reflected by abnormal uterine artery Doppler indices and reduced fetal growth in CHD pregnancies.MethodsThis is a retrospective case-control study including singleton pregnancies referred for detailed fetal cardiac assessment subsequently diagnosed with or without CHD. Mid-trimester uterine artery Doppler assessment at 20-24 weeks as well as third trimester fetal biometry and arterial Doppler pulsatility indices (PI) were performed. All fetal biometry were converted into centiles and Doppler values to multiples of median (MoM) to adjust for physiological changes with gestation.ResultsThe study included 811 pregnancies including 153 cases where the fetus was diagnosed with CHD. Mid-pregnancy uterine artery PI was significantly higher in women with fetal CHD compared to controls (0.90MoM vs 0.83MoM; p = 0.006). In the third trimester, median centiles for fetal head circumference (45.4 vs 57.07; p<0.001), abdominal circumference (51.17 vs 55.71; p = 0.014), estimated fetal weight (33.6 vs 56.7; p<0.001) and cerebroplacental ratio (CPR: 0.84MoM vs 0.95MoM; p<0.001) were significantly lower in fetuses with CHD compared to controls. The percentage of small for gestational age births <10th centile (24.0% vs 10.7%; <0.001) and low CPR <0.6MoM (11.7% vs 2.5%; p<0.001) were significantly higher in the fetal CHD cohort.ConclusionsMid-pregnancy uterine artery resistance is increased and subsequent fetal biometry reduced in pregnancies with CHD fetuses. These findings suggest that fetal CHD are associated with uteroplacental dysfunction, secondary to impaired maternal uteroplacental perfusion resulting in relative fetal hypoxaemia and reduced fetal growth.

Project description:BackgroundThe contribution of genetic variants to congenital heart defects (CHDs) has been investigated in many postnatal cohorts but described in few prenatal fetus cohorts. Overall, specific genetic variants especially copy number variants (CNVs) leading to CHDs are somewhat diverse among different prenatal cohort studies. In this study, a total of 1118 fetuses with confirmed CHDs were recruited from three units over a 5-year period, composing 961 of singleton pregnancies and 157 of twin pregnancies. We performed chromosomal microarray analysis on all cases to detect numerical chromosomal abnormalities (NCAs) and pathogenic/likely pathogenic CNVs (P/LP CNVs) and employed whole-exome sequencing for some cases without NCAs and P/LP CNVs to detect P/LP sequence variants (P/LP SVs).ResultsOverall, NCAs and P/LP CNVs were identified in 17.6% (197/1118) of cases, with NCA accounting for 9.1% (102/1118) and P/LP CNV for 8.5% (95/1118). Nonisolated CHDs showed a significantly higher frequency of NCA than isolated CHD (27.3% vs. 4.4%, p < 0.001), but there was no significant difference in the frequency of P/LP CNVs between isolated and nonisolated CHD (11.7% vs. 7.7%). A total of 109 P/LP CNVs were identified in 95 fetuses, consisting of 97 (89.0%) de novo, 6 (5.5%) parental inherited and 6 (5.5%) with unavailable parental information. The 16p11.2 proximal BP4-BP5 deletion was detected in 0.9% (10/1118) of all cases, second only to the most common 22q11.21 proximal A-D deletion (2.1%, 23/1118). Most of the 16p11.2 deletions (8/10) detected were de novo, and were enriched in CHD cases compared with a control cohort from a previous study. Additionally, SV was identified in 12.9% (8/62) of cases without NCA and P/LP CNV, most of which were de novo with autosomal dominant inheritance.ConclusionsOur cohort study provides a deep profile of the contribution of genetic variants to CHDs in both singleton and twin fetuses; NCA and P/LP CNV contribute to 9.1% and 8.5% of CHD in fetuses, respectively. We confirmed the 16p11.2 deletion as a CHD-associated hotspot CNV, second only to the 22q11.21 deletion in frequency. Most 16p11.2 deletions detected were de novo. Additionally, P/LP SV was identified in 12.9% (8/62) of fetuses without NCA or P/LP CNV.

Project description:ImportanceHypospadias is a common birth defect of the male urinary tract that may be isolated or may co-occur with other structural malformations, including congenital heart defects (CHDs). The risk for co-occurring CHDs among boys with hypospadias remains unknown, which limits screening and genetic testing strategies.ObjectiveTo characterize the risk of major CHDs among boys born with hypospadias.Design, setting, and participantsThis retrospective cohort study used data from population-based birth defect surveillance programs on all male infants born in 11 US states from January 1, 1995, to December 31, 2014. Statistical analysis was performed from September 2, 2020, to March 25, 2022.ExposureHypospadias.Main outcomes and measuresDemographic and diagnostic data were obtained from 2 active state-based birth defect surveillance programs for primary analyses, the Texas Birth Defects Registry and the Arkansas Reproductive Health Monitoring System, with validation among 9 additional states in the National Birth Defects Prevention Network (NBDPN). Birth defect diagnoses were identified using the British Pediatric Association coding for hypospadias (exposure) and major CHDs (primary outcomes). Maternal covariates and birth year were also abstracted from the vital records. Poisson regression was used to estimate adjusted prevalence ratios and 95% CIs for major CHDs within Texas and Arkansas and combined using inverse variance-weighted meta-analysis. Findings were validated using the NBDPN.ResultsAmong 3.7 million pregnancies in Texas and Arkansas, 1485 boys had hypospadias and a co-occurring CHD. Boys with hypospadias were 5.8 times (95% CI, 5.5-6.1) more likely to have a co-occurring CHD compared with boys without hypospadias. Associations were observed for every specific CHD analyzed among boys with hypospadias, occurred outside of chromosomal anomalies, and were validated in the NBDPN. An estimated 7.024% (95% CI, 7.020%-7.028%) of boys with hypospadias in Texas and 5.503% (95% CI, 5.495%-5.511%) of boys with hypospadias in Arkansas have a co-occurring CHD. In addition, hypospadias severity and maternal race and ethnicity were independently associated with the likelihood for hypospadias to co-occur with a CHD; boys in Texas with third-degree (ie, more severe) hypospadias were 2.7 times (95% CI, 2.2-3.4) more likely than boys with first-degree hypospadias to have a co-occurring CHD, with consistent estimates in Arkansas (odds ratio, 2.7; 95% CI, 1.4-5.3), and boys with hypospadias born to Hispanic mothers in Texas were 1.5 times (95% CI, 1.3-1.8) more likely to have a co-occurring CHD than boys with hypospadias born to non-Hispanic White mothers.Conclusions and relevanceIn this cohort study, boys with hypospadias had a higher prevalence of CHDs than boys without hypospadias. These findings support the need for consideration of additional CHD screening programs for boys born with hypospadias.

Project description:BackgroundCongenital heart defects (CHDs) are the most common birth defects. Assessment of the incidence, distribution, disease spectrum, and genetic deficits of fetal CHDs in China is urgently needed.MethodsA national echocardiography screening program for fetal CHDs was implemented in 92 prenatal screening-diagnostic centers in China.FindingsA total of 18,171 fetal CHD cases were identified from 2,452,249 pregnancies, resulting in 7·4/1,000 as the national incidence rate of fetal CHD. The incidences of fetal CHD in the six geographical regions, the southern, central, eastern, southwestern, northern, and northwestern, were 7·647 (CI: 7·383-7·915), 7·839 (CI: 7·680-8·000), 7·647 (CI: 7·383-7·915), 7·562 (CI: 7·225-7·907), 5·618 (CI: 5·337-5·906), and 4·716 (CI: 4·341-5·108), respectively, per 1,000 pregnancies. Overall, ventricular septal defect was the most common fetal CHD, accounting for 17.04% of screened pregnancies nationwide, and tetralogy of Fallot, the most common anomaly in the major defect of fetal CHD, was the second most common, accounting for 9.72%. A total of 76.24% cases of fetal CHD were found to be an isolated intracardiac single defect. The remaining 23.76% of cases of fetal CHD had multiple heart defects. Among all extracardiac malformations, the central nervous system (CNS) was the most common tissue with extracardiac anomalies associated with CHD, accounting for 22.89% of fetal CHD cases. Chromosomal karyotyping identified trisomy 18 as the most common chromosomal abnormality in fetal CHD. We also documented that CHD-containing syndromes could be identified with a comprehensive approach integrating prenatal ultrasound, MRI, pathological autopsy, and cytogenetics and molecular genetics.ConclusionImplementation of prenatal echocardiography as a practically feasible platform to screen fetal CHD will reduce the financial and emotional burden of CHD, which may facilitate intrauterine and neonatal intervention of CHD.

Dataset Information

The prevalence of genetic diagnoses in fetuses with severe congenital heart defects.

Purpose

Methods

Results

Conclusion

Publications

The prevalence of genetic diagnoses in fetuses with severe congenital heart defects.

Similar Datasets

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