Aetiology of CHD

Among the 200 foetuses included in the CMA test, 134 presented with isolated CHD and 66 presented with non-isolated CHD, including structural anomalies (n = 28), soft markers (n = 22), and structural anomalies and soft markers (n = 16). Of the 200 foetuses, 178 presented with simple CHD and 22 with complex CHD. Further, according to the anatomical classification proposed by Botto et al. [14], participants were divided into eight main groups. Among them, the three most common heart abnormalities were septal defects (60/200, 30.0%), conotruncal defects (49/200, 24.5%), and left ventricular outflow tract defects (29/200, 14.5%).

After prenatal CMA testing, chromosomal abnormalities were detected in 49 foetuses, the prevalence was 24.5% (49/200). Among them, 23 cases (11.5%) were of aneuploidies, including 8 cases of trisomy 21, 9 of trisomy 18, and 6 of trisomy 13. Additionally, clinically significant CNVs were detected in 26 (13%) cases, including 20 (10.0%) pathogenic (P) CNVs and 6 (3.0%) likely pathogenic (LP) CNVs. Further, CNVs which were variants of unknown significance (VOUS) were detected in 8 (4%) cases; the other 143 foetuses were reported to presented with negative CMA results. Finally, 52 cases were recalled and received WES testing after genetic counselling, of which 6 (11.5%) were found to have P or LP sequence variants. The process and brief results of the study are shown in Fig. 1.

Fig. 1
figure1

Flow chart of the study and results overview. CHD: congenital heart disease; CMA: Chromosomal microarray analysis; CNVs, copy number variations; VOUS, variants of uncertain significance

Subgroup analysis of different types of CHD

Next, we evaluated the relationship between chromosomal abnormalities and CHD types. Compared with the isolated CHD group, the chromosomal abnormality rate and aneuploidy rate of the non-isolated CHD group were higher (31.8% vs 20.9%). However, the clinically significant CNVs rate was lower (Table 1, 12.1% vs 13.4%). It is worth noting that the higher rate of chromosomal abnormality in the non-isolated CHD group was mainly because the incidence of aneuploidy was significantly increased when CHD was combined with extracardiac structural abnormalities or soft markers (19.7% vs 7.5%).

Table 1 Distribution of genetic variants in different group

Further, the chromosomal abnormality rate of the complex CHD group was higher than that of the simple CHD group (31.8% vs. 23.6%), including aneuploidy rates (13.6% vs. 11.2%) and clinically significant CNV rates (18.2% vs. 12.4%). Also, the incidence of foetal chromosomal abnormality was highest in foetuses with atrioventricular septal defects (AVSD) (54.5%). The chromosomal abnormality rates of different subgroups of CHD are shown in Table 2.

Table 2 Types of congenital heart disease and frequencies for fetuses with chromosomal abnormalities

Subsequently, we evaluated the association between the incidence of chromosomal abnormalities and extracardiac structural abnormalities. A total of 44 foetuses with extracardiac structural abnormalities were included, including 36 with single extracardiac structural abnormality and 8 with multiple extracardiac structural abnormalities. Overall, the incidence of chromosomal abnormality was 34.1% (15/44), aneuploidies were found in 18.2% (8/44), and clinically significant CNVs were found in 15.9% (7/44). Additionally, we found that there was no statistical difference between single extracardiac structural abnormality and multiple extracardiac structural anomalies (33.3% vs. 37.5%, p > 0.05). Moreover, among these cases of CHD with extracardiac structural abnormalities, those with central nervous system abnormalities presented with a high probability of chromosomal abnormalities. Table 3 summarizes the detection of chromosomal abnormalities in cases of CHD with different types of extracardiac structural abnormalities.

Table 3 Detection rates of chromosomal abnormalities in fetuses with CHD plus additional structural anomalies

Finally, among the 38 cases of CHD with soft markers, 34 presented with single soft markers and 4 with multiple soft markers. CHD combined with single umbilical artery and absent/shortened nasal bone were the most common. The incidence rate of chromosomal abnormality was 45.7% (13/38) in CHD foetuses with soft markers. The incidence of aneuploidy was (26.3%, 10/38) higher than that of clinically significant CNVs (7.9%, 3/38) in CHD foetuses with soft markers. Our data suggest that there was a high chance of detecting aneuploidies in CHD foetuses with soft markers, especially those with absent or shortened nasal bone (71.4%, 5/7). Moreover, combining multiple soft markers did not increase the chromosomal abnormalities (35.3% vs. 25%, p > 0.05). The chromosomal abnormalities of CHD with soft markers are shown in Table 4. In addition, no significant difference was observed in the chromosomal abnormality rates between CHD with extracardiac structural anomalies and CHD with soft markers groups (34.1% vs. 45.7%, p = 0.991). Notably, the chromosomal abnormality rates of the CHD combined with only soft markers group, the CHD combined with only structural anomalies group, and the CHD combined with both soft markers and structural anomalies group were 27.3%, 28.6%, and 43.8%, respectively. This suggests that the incidence of chromosomal abnormality was greatly increased in CHD foetuses presenting with both soft markers and additional structural anomalies (Table 1).

Table 4 Detection rates of chromosomal abnormalities in fetuses with CHD plus soft markers

WES analysis

After informed consent was obtained, 52 CHD foetuses with negative CMA tests were further analysed using WES, including 44 cases of isolated CHD and 8 cases of non-isolated CHD. As shown in Table 5, a total of 18 cases with 22 sequence variants which fulfilled the filtering criteria were detected. Three (5.8%) cases with pathogenic sequence variants and 3 (5.8%) cases with likely pathogenic sequence variants. The additional diagnostic yield of clinically significant sequence variants by WES testing for foetuses with CHD was 11.5% (6/52). Frequently encountered genes included NOTCH1, GLI3, DNAH, SCN5A.

Table 5 Detection of variants in fetuses with CHD using WES

Hotspot significant CNVs related to CHD in the Chinese population

In order to explore the characteristics of clinically significant CNVs associated with CHD in the Chinese population, we also conducted a systematic literature review. Five papers which met our criteria were selected for a detailed full-text review.

We summarized and analysed CMA data from 200 cases in our study and 1,385 cases reported in 5 other literature reports (Table 6). A total of 161 P or LP CNVs were found in 9.0% of cases (143/1585). All chromosomes, except 14, 19, and Y, presented with clinically significant CNVs, and the clinically significant CNVs on chromosomes 22, 16, and 15 were the most common. Deletion of 22q11.2 was the most common clinically significant CNV, accounting for 27.3% (44/161). In foetuses with 22q11.2 deletion, the most common heart defects were Tetralogy of Fallot (52.3%, 23/44), ventricular septal defect (27.3%, 12/44), and interrupted aortic arch (18.2%, 8/44). The other 5 most commonly recurrent CNVs loci related to CHD were deletions of 5p15.33p15.31 (Cri du chat syndrome), deletions of 15q13.2q13.3 (Angelman/Prader–Willi syndrome), deletions of 11q24.2q25 (Jacobsen syndrome), deletions of 17p13.3p13.2 (Miller–Diekers syndrome), and duplications of 17q12. In addition, Fig. 2 showed all of the clinically significant CNVs from our study and the literatures. All CNVs found using the CMA in this cohort are listed in Table 7.

Table 6 The comparison of studies in prevalence of genetic variants identified in CHD fetuses by CMA
Fig. 2
figure2

Hotspot significant CNVs related to CHD detected in 1585 Chinese by CMA. Dup: duplication; Del: deletion

Table 7 Pathogenic or likely pathogenic CNVs found in the cohort

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