Correlation between types of Ventricular Septal Defect and chromosomal abnormalities in Low-Risk Non-Invasive Prenatal Testing

doi:10.21203/rs.3.rs-3794576/v1

Objective

The aim of this study was to examine whether there is any association between various types of ventricular septal defect (VSD) and chromosomal abnormalities in the low-risk environment of non-invasive prenatal testing (NIPT) and to evaluate the prognosis of fetuses with different types of VSD.

Methods

From May 2017 to May 2022, Tianjin Central Obstetrics and Gynecology Hospital collected cases of prenatal diagnosis of fetal VSD by amniocentesis. Those with NIPT high-risk, such as chromosomal number abnormalities, fragment deletions or duplications, and polymorphisms, were excluded from the study. Data collected included ultrasound classification of VSD, prenatal NIPT results, copy number variations (CNVs) results, and neonatal outcomes.

Results

This study investigated the prevalence of pathogenic copy number variations (CNVs) in 74 cases, including 45 isolated ventricular septal defects (VSDs) (9 of which were muscular and 36 non-muscular) and 29 non-isolated VSDs (10 with intracardiac and 19 with extra-cardiac structural anomalies). Results revealed that the incidence of pathogenic CNVs was lower in isolated VSDs than in non-isolated VSDs in a low-risk NIPT condition (χ2 = 9.344, P = 0.002). There was no significant difference in the prevalence of pathogenic CNV between VSDs with intracardiac and extra-cardiac structural anomalies (P = 0.541). Moreover, VSDs associated with intracardiac structural anomalies had the highest rate of surgical intervention.

Conclusions

When NIPT is low-risk and VSD is isolated, the likelihood of fetal chromosomal defects is not increased. However, when there are both intra- and extracardiac structural issues in addition to VSD, the possibility of pathogenic CNV is considerably greater and therefore, invasive prenatal diagnosis is recommended. It was additionally noted that isolated muscular septal defects usually do not require surgery, which can be used as a basis for prenatal counseling regarding fetal VSD.

Ventricular septal defect

non-invasive prenatal testing

copy number variation

invasive prenatal diagnosis

This study indicated that when NIPT is low-risk, an isolated VSD does not increase the probability of chromosomal abnormalities in the fetus; however, if the VSD is non-isolated and associated with either intra- or extracardiac structural issues or FGR, the risk of pathogenic CNV is significantly higher, thus recommending invasive prenatal diagnosis. Furthermore, it was observed that isolated muscular septal defects usually do not require surgical treatment, which provides a useful basis for prenatal counseling regarding fetal VSD.

Congenital heart disease (CHD) is a common birth defect that affects 3 to 11 out of every 1000 live births worldwide. Of the different types of CHD, Ventricular Septal Defect (VSD) is the most frequent, accounting for approximately 35% of all neonatal CHD cases. Unfortunately, those with VSD usually experience a lower survival rate than the rest of the population[1]. VSD can be seen as an individual anomaly, but it can also form part of other complex heart conditions, including Tetralogy of Fallot, Univentricular Atrioventricular Junction, Transposition of the Great Arteries, and Aortic constriction/disruption[2]. Recent advances in prenatal screening technology have led to the development of non-invasive prenatal testing (NIPT), which improved screening capability has been shown to significantly enhance the detection of trisomy 13, 18, and 21, as well as specific chromosomal microdeletion/microduplication syndromes[3]. This not only reduces the risk of fetal miscarriage, but also reduces patient anxiety, making it a valuable option for ensuring a healthy pregnancy and reducing the incidence of birth defects. It has been reported that 20–40% of VSDs are associated with chromosomal abnormalities. Isolated VSDs may not significantly increase the risk of fetal chromosomal abnormalities in cases of low-risk prenatal screening. In contrast, the rate of chromosomal abnormalities tends to be higher in non-isolated VSDs, it is suggested that invasive prenatal diagnosis may not be necessary for isolated VSD[2, 4]. NIPT is an effective way of diagnosing these abnormalities, but NIPT may not be able to detect all chromosomal abnormalities in fetuses with VSD. The correlation between different types of VSD and chromosomal abnormalities in the Chinese population is still unclear. This study seeks to explore the relationship between different subtypes of VSD and fetal chromosomal abnormalities in the context of low-risk NIPT, to reduce the need for invasive prenatal diagnosis and the potential for missed or false diagnosis.

1 Clinical data

This study was conducted at Tianjin Central Hospital of Obstetrics and Gynecology, and focused on pregnant women who underwent amniocentesis due to fetal VSD between May 2017 and May 2022. Those with either isolated or non-isolated VSDs diagnosed through echocardiography were included, while those with NIPT, high-risk NIPT, genetic disorders, and those lost to follow-up were excluded. To monitor the pregnancy outcomes, phone calls were made and newborns were followed up for at least six months after delivery. The data collected and analyzed included prenatal and postpartum diagnoses and prognoses, such as NIPT and CNVs results, those that required surgical intervention and those that healed naturally without surgery, either inside or outside the uterus. The process of data collection and analysis is illustrated in Fig. 1.

2 The ultrasonic diagnosis criteria and classification of fetal VSD

An transabdominal ultrasound was conducted using the GE Volson E10 color Doppler ultrasound diagnostic instrument, with the C1-5-D probe of 3.5-5.5MHz frequency, to diagnose fetal VSD. The continuous disruption of the ventricular septum in the parasternal four-chamber view, along with enhanced echo at the septal end, which was made visible with color Doppler imaging, were used to make the diagnosis. Our hospital's cardiac ultrasound experts and prenatal diagnosis specialists, who have more than five years of experience, confirmed the diagnosis. After a woman is diagnosed with VSD, genetic counseling is provided and amniocentesis is recommended for genetic testing.

The classification of VSD into isolated and non-isolated types was based on the presence of other cardiac and extracardiac abnormalities on ultrasound examination. Isolated VSD was further divided into muscle defect and non-muscle defect groups, with the latter including perimembranous and mixed-type defects. Non-isolated VSD included intracardiac and extracardiac structural abnormalities, such as atrioventricular septal defect, coarctation of the aorta, and Fallot's tetralogy. Additionally, extracardiac abnormalities could include Fetal Growth Restriction (FGR), enlarged lateral ventricles, enlarged double renal pelvis, digestive tract obstruction, hypospadias, and short long bones.

3 Chromosomal examination

NIPT screening was performed using the shallow-depth whole genome sequencing‐based noninvasive prenatal subchromosomal copy number variation detection (NIPSCCD) method as previously reported[5]. Samples were sequenced on the Nextseq550AR platform. Subchromosomal segments with absolute values of the final Z‐scores above 1.28 were considered indicative of CNVs, while Z‐scores of a whole chromosome above 3 were considered as trisomy 21/18/13, and these were considered NIPT high-risk.

Chromosome G banding karyotype analysis and CNV-seq based on high-throughput sequencing were performed at 18–24 weeks gestation, with Fluorescence in situ hybridization (FISH) and CNV-seq also conducted after 24 weeks. The ACMG2019 guidelines were used to classify the results of CNV-seq, which included Pathogenic (P), Likely Pathogenic (LP), Uncertain Significance (VUS), Likely Benign (LB), and Benign (B). After a thorough evaluation of CNV-seq and G banding karyotype analysis/FISH, the cases in this study were categorized as non-probable pathogenic (LP) CNV patients, which were divided into pathogenic CNV (P) and nonpathogenic CNV, including CNV of unknown clinical significance and benign CNV. This allowed women and their families to make an informed decision on whether to continue or terminate the pregnancy, based on the presence of pathogenic CNV, gestational age, and the severity of fetal structural abnormalities.

4 Statistical analysis

SPSS 24.0 was utilized in data processing. Continuous variables that do not conform to the normal distribution use median (IQR). To compare the incidence of pathogenic CNV in various kinds of VSD and the rate of surgical intervention between the groups, χ2 test (with continuous correction or Fisher's test) was employed. A P-value of less than 0.05 showed that the difference was statistically significant.

1 Analysis of the composition ratio of each type of VSD and the incidence of pathogenic CNV

The basic information of the 74 VSD patients was shown in Table 1. Table 2 showed that out of the 74 fetuses with VSD, 45 (60.8%) had isolated VSD (IVSD) and 29 (39.2%) had non-isolated VSD (NIVSD). Of the isolated cases, 9 (12.2%) had muscular septal defect (MSD) and 36 (48.6%) had non-MSD. As for the non-isolated cases, 10 (13.5%) had VSD combined with intracardiac structural anomalies and 19 (25.7%) had VSD combined with extracardiac structural anomalies. Regarding the incidence of pathogenic CNV in different types of VSD, none of the 9 patients with isolated MSD and 36 patients with non-MSD had pathogenic CNV (0/9, 0%; 0/36, 0%). However, two out of 10 patients with VSD combined with intracardiac structural abnormalities (ISA) had pathogenic CNV (2/10, 20%) and five out of 19 patients with VSD combined with extracardiac structural abnormalities (ESA) had pathogenic CNV (5/19, 26.3%). Additionally, non-pathogenic CNV included clinically significant unknown and normal CNV (Table 2).

Table 1

Basic information of VSD patients
	isolated VSDs(n = 45)		non-isolated VSDs(n = 29)
	Muscle VSD n = 9	Non-muscle defect n = 36	ISA n = 10	ESA n = 19
Maternal age (year)	30.5(26.75–34.75)	31(27.75-33)	28(27.5–34.5)	30(28-30.5)
GA at amniocentesis (wk + d)	29^+ 3(25^+ 1-32^+ 5)	27^+ 1(25^+ 1-29^+ 0)	26^+ 1(24^+ 5-28^+ 1)	27^+ 6(24^+ 6-31^+ 5)
VSD size at diagnosed(mm)	2(1.05–2.9)	3(2-4.025)	3(2.4-7)	2.5(2-3.9)
GA: Gestational age

Table 2

Incidence of pathogenic CNV of different types of VSD
Groups	Total number (n = 74)	Pathogenic CNV [n (%)]	Nonpathogenic CNV
Groups	Total number (n = 74)	Pathogenic CNV [n (%)]	unknown Clinical significance (n = 7)	Not found (n = 60)	Total [n (%)]
Isolated MSD	9	0(0)	2	7	9(100)
Isolated MSD	36	0(0)	3	33	36(100)
NIVSD combined with ISA	10	2(20)	0	8	8(80)
NIVSD combined with ESA	19	5(26.3)	2	12	14(73.7)

2. Comparison of pathogenic CNV rates among groups

A comparison of the occurrence of pathogenic CNV in isolated and non-isolated VSD showed a significant difference, with none of the isolated VSD cases exhibiting the condition whilst 24.1% (7/29) of the non-isolated VSD cases did, as indicated by a chi-squared test (χ2 = 9.344, P < 0.05). An analysis of the non-isolated VSD subgroups revealed that CNV was present in 20% (2/10) of cases with ISA and 26.3% (5/19) of cases with ESA, although no significant difference was detected between the two groups (Table 3). In contrast, none of the isolated VSD subgroups had pathogenic CNV.

Table 3

Comparison of the incidence of pathogenic CNV in different groups
Groups	Total number (n=)	Pathogenic CNV [n(%)]	Nonpathogenic CNV [n(%)]	χ2	P
IVSD	45	0(0)	45(100)
NIVSD	29	7(24.1)	22(75.9)	9.344	0.002 ^a
ISA	10	2(20.0)	8(80.0)
ESA	19	5(26.3)	14(73.7)		0.541^b
^a Continuity chi-square test
^b Fish exact probability method

3. Clinical characteristics and pregnancy outcome of pathogenic CNV and CNV of unknown clinical significance

Out of the 74 cases, 7 were identified as pathogenic CNV (1–7), including a VSD combined with left subclavian artery vagal and aortic stenosis (No. 1), VSD with membranous aneurysm and left heart enlargement (No. 2), and three cases of VSD with fetal growth restriction (FGR) with or without amniotic fluid and heart enlargement (Nos. 3). All seven cases were selected for termination of pregnancy. The CNV results and VSD phenotypes were indicated in Table 4. An additional seven cases had CNV of unknown clinical significance (Nos. 8–14). These included one VSD with hypospadias (No. 13), one tetralogy of Fallot (No. 14), three isolated non-muscular defects (Nos. 8–10), and two isolated muscular septal defects (Nos. 11–12). Except for No. 13, all these cases opted for TOP. The remaining pregnant women chose to continue their pregnancies, with no other complications and good outcomes. The CNV results and VSD phenotypes were detailed in Table 5.

Table 4

Clinical data and pregnancy outcome of 7 fetuses with pathogenic CNV
Groups	Number	Clinical phenotypes	Results of CNV	Pregnancy outcome
VSD combined with ISA	1	Aberrant left subclavian artery, aortic stenosis	1.25Mb missing at 9q34.3	TOP
VSD combined with ISA	2	Ventricular defect with membranous tumor, left heart enlargement	8.0Mb missing at 18p11.32p11.23	TOP
VSD combined with ESA	3	FGR、excessive amniotic fluid	2 repeats of 9.6 Mb fragment at 15q11.2q13.3	TOP
	4	FGR、cardiomegaly	12.7 Mb fragment missing at 14q32.12q32.33 segment	TOP
	5	Widening of the lateral ventricles	5.35 Mb missing at 15q26.2- 15q26.3, along with a 14.2 Mb repeat at 8q24.22-8q24.3	TOP
	6	FGR	47XN + 9[64%]/46XN[36%]	TOP
	7	Bilateral renal pelvic dilatation	8.95 Mb chimeric repeat at 22q11.1q11.23 with a chimeric ratio of 67%	TOP

Table 5

Clinical data and pregnancy outcome of 7 fetuses with CNV of unknown clinical significance
Groups	Number	Clinical phenotypes	Results of CNV	Pregnancy outcome
IVSD	8	Non-muscular VSD	1.3Mb repeat at 8q21.13 segment	Full-term labor
	9	Non-muscular VSD	1.25Mb repeat at 2q14.3 region	Full-term labor
	10	Non-muscular VSD	700Kb missing at 3p24.3-3p24.3	Full-term labor
	11	Muscular VSD	306.4Kb missing at 4q22.1 region	Full-term labor
	12	Muscular VSD	1.45 Mb repeats at 2p12 region	Full-term labor
NIVSD	13	VSD with hypospadias	450kb repeat at Xp11.22 region	TOP
	14	Tetralogy of Fallot	541.1Kb fragment repeat at 17p13.3 region	Full-term labor

4. Comparison the rate of surgical interventions for in neonates with various forms of VSD

Out of the 67 cases of non-pathogenic CNV, 7 opted to induce labor for personal reasons, 1 passed away due to metabolic disease after delivery, and the remaining 59 neonates were born without complications and survived. The details of these cases were presented in Table 5. Excluding induction of labor and death, the rate of surgical intervention for newborns or infants with isolated MSD was 0% (0/9), while the rate of surgery for newborns or infants with isolated non-MSD was 20% (7/35). The surgery rate for newborns or infants with VSD combined with ISA was significantly higher than that of newborns or infants with VSD combined with ESA (83.3% vs 11.1%, P < 0.05). However, there was no significant difference in the surgery rate between the isolated MSD group and the isolated MSD group (Table 6).

Table 6

Surgical interventions in 59 neonates with normal and surviving CNVs
Groups	Neonatal outcome		Non-surgical interventions			Surgical interventions [n (%)]	χ2	P
Groups	Normal (n)	Termination of pregnancy (n)	Natural closure [n (%)]	Observation [n (%)]	Total [n (%)]	Surgical interventions [n (%)]	χ2	P
MSD (n = 9)	9	0	5(55.6)	4(44.4)	9(100)	0(0)
Non-MSD (n = 36)	35	1#	2(5.6)	26(72.2)	28(80)	7(20)	0.907	0.341^a
NIVSD combined with ISA (n = 8)	6	2	0(0)	1(16.7)	1(16.7)	5(83.3)		0.002^b
NIVSD combined with ESA n = 14	9	5	3(33.3)	5(55.6)	8(88.9)	1(11.1)		0.5^c

#: death after birth due to metabolic disease

^a Isolated MSD vs isolated Non-MSD, continuity chi-square test

^b Isolated MSD vs non-isolated VSD combined with ISA, Fish's exact probability method

^c Isolated MSD vs non-isolated VSD combined with ESA, Fish exact probability method

Recent research has revealed a strong connection between VSD and chromosomal abnormalities, particularly trisomies of 21, 18, and 13, as well as sex chromosome abnormalities[6]. However, the prenatal chromosomal serological screening or NIPT results of these pregnant women were not mentioned. In this research, all seven cases of pathogenic CNV had chromosomal deletions or duplications with fragment sizes ranging from 1.25 Mb to 14.2 Mb, but NIPT screening failed to identify them. This could be due to the limitations of NIPT, such as its targeted random quantitative sequencing of cffDNA in maternal plasma, which may not cover all chromosome fragments. The sensitivity of NIPT in detecting CNVs less than 3 Mb in size was only 78.57%[7]. Additionally, the location of the chromosome deletions or repetitive fragments may also affect the results of the detection. Other factors that could influence the results include false positive rate, fetal free DNA concentration, and sequencing depth[8]. Despite the fact that some pregnant women with invasive prenatal testing of fetal VSD may be screening high-risk population, many studies have not taken into account the prenatal chromosome serological screening or NIPT results of these women. Therefore, it can be assumed that the rate of fetal ventricular septal defect with chromosomal abnormalities is high. It is uncertain whether prenatal testing of these pregnant women is a result of the combined screening of fetal VSD with a high risk or just because of fetal VSD. This study examined the relationship between different types of VSD fetuses, chromosomes, and prognosis in low-risk NIPT conditions.

Studies have revealed that out of 568 fetuses with isolated VSD, 8 had a pathogenic CNV. This rate was similar to the rate of the general pregnant population of 1.6–1.7%[9]. Investigations conducted on pregnancies with low comprehensive risk assessment and isolated VSD before childbirth indicated that the incidence of chromosomal abnormalities was 0.7% lower than the rate in the general pregnant population [10]. Additionally, isolated muscular septal defect may be a benign variation[6]. Our research found that in the context of low-risk NIPT, 45 fetuses with isolated ventricular septal defect had no pathogenic CNVs, indicating that the defect may be a benign variation. In contrast, non-isolated VSD had a chromosomal abnormality rate of 14.6%[9]. The incidence of non-isolated VSD-associated CNV was significantly higher than that of isolated VSD, with a ratio of 24.1–0%, particularly when combined with extra-cardiac structural abnormalities. The prevalence of pathogenic CNV in this group was 26.3%, which was slightly lower than the 40% chromosomal abnormalities of VSD with extracardiac abnormalities reported by Alan et al.[11]. The case data omits high-risk VSD of NIPT, implying that for fetuses with isolated VSD, invasive prenatal diagnosis was not necessary when NIPT was low risk. Conversely, for those with non-isolated VSD, even if NIPT was low risk, it is strongly advised to perform invasive prenatal diagnosis, particularly if combined with ESA, to avoid any missed diagnosis and potential detrimental pregnancy outcomes.

Analysis of pathogenic CNV malformations revealed that five out of seven cases were VSD with extra-cardiac structural issues, and three of them had FGR. It is uncertain whether the association between VSD and FGR is caused by hemodynamic alterations or changes in the placenta-heart axis during the early stages of embryonic development[12]. Further research is needed to determine if VSD is more likely to combine with FGR[13]. Consequently, it is recommended that pregnant women with non-isolated VSD, particularly when associated with FGR, should undergo an invasive prenatal diagnosis and CNV examination.

Reports suggest that the rate of spontaneous closure for isolated ventricular septal muscle defects and isolated perimembranous VSD in fetuses was 31/64 and 3/11, respectively. At 2 years old, the rate was 92.2% and 45.5%, respectively[14]. Generally, isolated ventricular septal muscle defects close in utero or during the initial two years of life, while isolated perimembranous VSD may require intervention postnatally[4]. This study tracked all cases for at least 6 months following birth and the results revealed that the closure rate for isolated muscle defects was 55.6%, compared to 5.6% for non-muscle defects. This is consistent with our study's findings, which indicate that isolated ventricular septal muscle defects have the best chance of closing naturally and may not need surgical treatment, whereas isolated non-muscle defects should be evaluated carefully. It has been reported that a defect of ≥ 4 mm is an independent predictor of non-spontaneous closure of perimembranous VSD[15]. In this study, the average size of isolated muscle defects was 2.18 mm, with a maximum of 3.5 mm, and no surgical intervention was performed. On the other hand, the average size of non-muscular defects was 3.07 mm, with 8 cases having a size of more than 4 mm and a 20% surgical intervention rate. This could explain why the natural healing rate of non-muscular defects was lower than that of muscular defects, although no significant data was found (data not shown). Those with non-isolated VSD had a higher rate of pathogenic CNVs, and most people opt for induced labor. After eliminating chromosomal issues, the surgical intervention rate for VSD combined with ISA was 83.3%, while for VSD combined with ESA, the rate was 11.1%. Research suggests that the prognosis of VSD patients with chromosomal abnormalities combined with ESA may be better than those with isolated non-muscular defects and VSD combined with ISA. Despite the small sample size, further studies are needed to confirm this. A study revealed that 45.4% of VSD closed in the womb, 30.9% closed in the first year of life, and those with a defect larger than 3mm did not close spontaneously[16]. The average size of VSD in the operative and the non-operative groups was 3.89mm and 2.87mm, respectively (data not shown). Although no significant difference was observed, the size of the defect should still be taken into account for better patient care.

This study has some limitations, mainly due to its small sample size and being conducted at a single center. Furthermore, the follow-up data of newborns was collected through telephone follow-up, which could be inaccurate, and the decision to perform a surgical intervention is based on certain human factors. In conclusion, this article explored the connection between various kinds of VSD and chromosomal abnormalities in the context of low-risk NIPT and surgical treatment of newborns and infants. The results indicated that if NIPT screening is low risk, isolated VSD does not increase the likelihood of chromosomal irregularities, thus eliminating the need for invasive prenatal diagnosis. Nevertheless, for non-isolated VSD cases, it is recommended to have an invasive prenatal diagnosis, especially if combined with ESA, to avoid missed diagnosis and unsatisfactory pregnancy outcomes. It is important to be aware that when a VSD is accompanied by FGR, an invasive prenatal diagnosis is suggested. Isolated VSDs, however, generally heal without needing surgery. A thorough examination should be conducted for isolated VSDs with ESA. Surgery is usually necessary for VSDs combined with ISA. Going forward, more attention should be given to the size and type of VSD when conducting research and offering clinical advice, in order to better decide if spontaneous closure or surgery is needed. This study provides a theoretical foundation for the connection between various types of VSDs and chromosomes under the condition of low-risk NIPT, thus supporting prenatal consultation for VSD patients.

Ethics approval and consent to participate

The studies involving human participants were reviewed and approved by Human Research Ethics Committee of Tianjin Central Hospital of Obstetrics and Gynecology. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All participants signed a written informed consent form prior to their participation in this study.

Consent for publication

Not Applicable

Availability of data and materials

The datasets generated and/or analysed during the current study are available in the [Science Data Bank] repository, [https://www.scidb.cn/en], the data named “Correlation between types of Ventricular Septal Defect and chromosomal abnormalities in Low-Risk Non-Invasive Prenatal Testing”.

Competing interests

All authors declare that they have no conflict of interest.

Fundings

National Key Specialties and Diseases Cohort Project (GJZDZKZBDL2022-04); National Natural Science Foundation of China (82001579); Natural Science Foundation of Tianjin (22JCYBJC01110).

Authors' contributions

Xiaomin Zhao: the acquisition, analysis, or interpretation of data for the work; Yongmei Shen: Drafting the work or revising it critically for important intellectual content; Dexuan Kong and Liying Yao: Ultrasonography; Shanshan Li and Wen Li: Writing-review and editing; Ying Chang: Substantial contributions to the conception or design of the work and final approval of the version to be published.

Acknowledgements

We gratefully acknowledge the Prenatal Diagnosis Center and Ultrasound Center of Tianjin Central Hospital of Obstetrics and Gynecology in supporting this collaborative research.

Conflict of interest statement

All authors declare that they have no conflict of interest.

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Correlation between types of Ventricular Septal Defect and chromosomal abnormalities in Low-Risk Non-Invasive Prenatal Testing

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusions

Figures

What does this study add to the clinical work

Introduction

Materials and Methods

1 Clinical data

2 The ultrasonic diagnosis criteria and classification of fetal VSD

3 Chromosomal examination

4 Statistical analysis

Results

2. Comparison of pathogenic CNV rates among groups

3. Clinical characteristics and pregnancy outcome of pathogenic CNV and CNV of unknown clinical significance

4. Comparison the rate of surgical interventions for in neonates with various forms of VSD

Discussion

Declarations

References

Status:

Version 1