Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 15459006; ICD10CM: Q21.2, Q21.20; ICD9CM: 745.6, 745.60; ORPHA: 98722; DO: 0050651;
Cytogenetic location: 1p31-p21 Genomic coordinates (GRCh38): 1:60,800,001-106,700,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p31-p21 | {Atrioventricular septal defect, susceptibility to, 1} | 606215 | 2 |
The term 'atrioventricular septal defect' (AVSD) covers a spectrum of congenital heart malformations characterized by a common atrioventricular junction coexisting with deficient atrioventricular septation. In ostium primum atrial septal defect (ASD) there are separate atrioventricular valvar orifices despite a common junction, whereas in complete AVSD the valve itself is also shared (summary by Craig, 2006).
AVSD, also designated endocardial cushion defect or atrioventricular canal defect (AVCD), is known to occur in either a nonsyndromic (isolated) form or, more commonly, as part of a malformation syndrome. The 2 syndromes most frequently associated with AVSD are Down syndrome (190685), in which AVSD is the most frequent congenital heart defect, and Ivemark syndrome (208530) (summary by Carmi et al., 1992).
Genetic Heterogeneity of Isolated Atrioventricular Septal Defect
An AVSD susceptibility locus (AVSD1) maps to chromosome 1p31-p21; AVSD2 (606217) is caused by mutation in the CRELD1 gene (607170) on chromosome 3p25; AVSD4 (614430) is caused by mutation in the GATA4 gene (600576) on chromosome 8p23.1; and AVSD5 (614474) is caused by mutation in the GATA6 gene (601656) on chromosome 18q11.
A form of AVSD, designated AVSD3, was thought to be caused by mutation in the GJA1 gene (121014.0011), but this variant has been reclassified as a variant of unknown significance.
Somatic mutations in the HAND1 gene (602406) have been identified in tissue samples from patients with AVSDs.
The clinical presentation and course in AVSD relates to the specific morphology of the defect and the presence of associated defects. (1) In infants with complete AVSD and a sizable interventricular component, congestive cardiac failure is likely to develop within the first few months of life as pulmonary vascular resistance falls. If there is significant regurgitation of the common atrioventricular valve, associated coarctation of the aorta or ventricular imbalance, cardiac failure may occur much earlier and often within the first week of life. Without surgery, many of these patients will die in infancy and those who survive will develop pulmonary vascular disease and eventually die with Eisenmenger syndrome. (2) The infant with AVSD may present with a mild degree of central cyanosis. This finding relates to bidirectional shunting at both the atrial and ventricular level in the presence of elevated pulmonary vascular resistance at birth. The only positive precordial findings of a congenital heart defect at this time may be a right ventricular impulse and accentuated pulmonary component of the second heart sound. A precordial murmur may, at this stage, be much abbreviated or absent. (3) In patients with complete AVSD and a small interventricular component, or in patients with ostium primum ASD where atrioventricular valve regurgitation is minimal, cardiac failure is rare and clinical symptoms may be minimal or absent in infancy and childhood. Without surgery, however, there is considerable longer term morbidity and mortality with only 25% survival beyond 40 years of age (summary by Craig, 2006).
Amati et al. (1995) noted that in patients with AVSD with normal chromosomes there is a prevalence of partial forms and left side obstructions, right malalignment of the AVSD, including left ventricle hypoplasia.
Although nonsyndromic AVSD has been attributed to multifactorial inheritance, the occurrence of a few kindreds with multiple affected individuals has suggested that a major genetic locus can account for the disorder in some families (Amati et al., 1995).
Sanchez-Cascos (1978) did not differentiate sibs from offspring but found 14 of 161 relatives (8.7%) to be affected. Among 52 offspring of adults with AVSD, Emanuel et al. (1983) found 5 (9.6%) affected offspring. Two of the instances were cases of tetralogy of Fallot. Given the abnormal anterior displacement of the aorta in AVSD, it is possible that there is an etiologic relationship between the 2 defects in these families.
In a large family study, Digilio et al. (1993) found a consecutive series of 103 isolated AVSD probands to have 4/111 (3.6%) similarly affected sibs, 4/206 (1.9%) affected parents, and 5/644 (0.8%) affected uncles and aunts.
Nora (1971) found no affected individuals in 70 families, but found one family with 4 affected individuals in one sibship. In the past, families such as this, and the 4 sibs with ostium primum septal defect and normal parents reported by Yao et al. (1968), would have prompted the suggestion of a recessive form, but the offspring studies make it at least as likely that these are examples of nonpenetrance or gonadal mosaicism in 1 parent.
The report of an extensive dominant pedigree by O'Nuallain et al. (1977) and similar large dominant pedigrees with incomplete penetrance reported by Wilson et al. (1993), Cousineau et al. (1994), and Digilio et al. (1993) reinforce the case for a single dominant gene defect in the isolated form.
AVSD1
In a family with AVSD mapping chromosome 1p reported by Sheffield et al. (1997), inheritance followed an autosomal dominant pattern with incomplete penetrance.
Craig (2006) reviewed diagnostic features of AVSD ascertained by chest radiograph, electrocardiogram, echocardiogram, and MRI.
Prenatal Diagnosis
Prenatal diagnosis of AVSD can be made through the 4-chamber view of the heart on routine antenatal ultrasound. The key diagnostic feature is the presence of a common atrioventricular valve (Craig, 2006).
The mainstay of management in AVSD is surgical correction of the defect (Craig, 2006).
Population data on AVSD came from the Baltimore-Washington Infant Study (BWIS) which identified 336 children with AVSD among 4,385 infants with confirmed heart defects presenting under 1 year of age (7.7%) (Carmi et al., 1992). Of these 336 children, 76% were syndromic; of the syndromic cases, 78% were trisomy 21 (190685), or just under 60% of the total series. This represented 56% of the heart malformations associated with Down syndrome.
A locus for AVSD on chromosome 21 was suggested by the high incidence of AVSD in cases of Down syndrome (190685).
Digilio et al. (1993) reviewed the literature on 8p deletion suggesting an AVSD critical region around band 8p23.
Carmi et al. (1992) reported cases of AVSD with partial 10q monosomy, partial 13q monosomy, ring 22, 14q+, and 1p+3p- due to an unbalanced translocation.
Sheffield et al. (1997) used a combination of DNA pooling and shared segment analysis to perform a high density screen of the entire autosomal human genome in an extended kindred segregating isolated AVSD. In so doing they identified a genetic locus, which they symbolized AVCD, on chromosome 1p31-p21 shared by all affected individuals.
Exclusion Studies
Wilson et al. (1993) carried out multipoint analysis of linkage data from a large 3-generation family segregating AVSD. Ten polymorphic markers spanning the Down syndrome critical region excluded the causative gene from this region. A parallel study by Cousineau et al. (1994) of their 4-generation family with isolated AVSD also achieved significant negative lod scores for chromosome 21. Thus, the phenotype is likely to be genetically heterogeneous.
Because of a striking association between 8p deletion and atrioventricular canal defect, Amati et al. (1995) studied 2 pedigrees with autosomal dominant AVCD using a set of DNA markers from the 8pter-q12 region. These 2 families included affected individuals and subjects who had transmitted the defect but were not clinically affected. Significantly negative 2-point lod scores were observed for all markers at penetrance levels of 90% and 50%. Results corroborated heterogeneity of this heart defect and indicated that the genetic basis of familial AVCD is different from that associated with either Down syndrome (trisomy 21) or 8p deletion.
Associations Pending Confirmation
Smith et al. (2009) sequenced 32 candidate genes known to be important in development of the atrioventricular septum (AVS) in 190 patients with AVS defects, and identified 2 missense variants in the ACVR1 gene (102576) that were not found in 350 controls, only 1 of which showed a functional difference compared to wildtype. The 1 variant, a heterozygous L343P substitution, was identified in a male proband of European ancestry who had a primum-type ASD with a cleft anterior mitral valve leaflet, resulting in a small left-to-right shunt and mild mitral regurgitation. The proband's father, who also carried the L343P variant, had a cardiac murmur noted at 14 years of age, and echocardiography revealed calcification of the annulus of the posterior mitral valve leaflet and prolapse of both leaflets. Functional analysis revealed that the L343P variant reduces ALK2 (ACVR1) signaling in vitro and disrupts the kinase activity of the receptor, and in vivo analysis of zebrafish embryos injected with ACVR1 L343P RNA revealed improper atrioventricular canal formation. Noting that the father's phenotype could not be unambiguously classified as a congenital heart defect and was clinically nonpenetrant, Smith et al. (2009) concluded that L343P represented a dominant-negative allele and suggested that mutation in ACVR1 may be causative for AVS defects.
Ackerman et al. (2012) used a candidate gene approach among individuals with Down syndrome and complete atrioventricular septal defect (AVSD) (141 cases) and Down syndrome with no congenital heart defect (141 controls) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. Ackerman et al. (2012) found a significant excess (p less than 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, they found potentially damaging variants in nearly 20% of cases but in fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in 6 genes: COL6A1 (120220), COL6A2 (120240), CRELD1 (607170) (already identified as a cause of AVSD; see 606217), FBLN2 (135821), FRZB (605083), and GATA5 (611496). Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGFA (192240) pathway, suggesting to Ackerman et al. (2012) that rare variants in this pathway might contribute to the genetic underpinnings of AVSD in humans.
D'Alessandro et al. (2016) performed whole-exome sequencing in 81 unrelated probands with AVSD to identify potential causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR) 1.52; 95% confidence interval (CI), 1.35-1.71; p = 4.8 x 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR 2.25; 95% CI, 1.84-2.76; p = 2.2 x 10(-16)). Six genes (NIPBL, 608667; CHD7, 608892; CEP152, 613529; BMPR1A, 601299; ZFPM2, 603693; and MDM4, 602704) were enriched for rare variants in AVSD compared with controls, including 3 syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. D'Alessandro et al. (2016) concluded that mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. Of the 34 probands with variants in the 6 prioritized genes, 8 probands had a rare or rare damaging nonsynonymous variant in more than 1 gene, of which 6 had a second mutation in ZFPM2. In addition, 1 patient had variants in CHD7, NIPBL, and CEP152 and another had variants in CEP152 and NIPBL. Interestingly, 2 patients showed the same NIPBL variant (N393K), which occurred in only 1 individual in the Exome Variant Server (EVS).
A complex allele (121014.0011) reported by Dasgupta et al. (2001) has been reclassified as a variant of unknown significance. In a pediatric heart transplant patient with an atrioventricular canal defect, Dasgupta et al. (2001) identified 4 substitutions in the GJA1 gene: 2 missense mutations and 2 silent polymorphisms (see 121014.0011).
Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L. An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects. Am. J. Hum. Genet. 91: 646-659, 2012. [PubMed: 23040494] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.017]
Amati, F., Mari, A., Mingarelli, R., Gennarelli, M., Digilio, M. C., Giannotti, A., Marino, B., Novelli, G., Dallapiccola, B. Two pedigrees of autosomal dominant atrioventricular canal defect (AVCD): exclusion from the critical region on 8p. Am. J. Med. Genet. 57: 483-488, 1995. [PubMed: 7677156] [Full Text: https://doi.org/10.1002/ajmg.1320570325]
Carmi, R., Boughman, J. A., Ferencz, C. Endocardial cushion defect: further studies of 'isolated' versus 'syndromic' occurrence. Am. J. Med. Genet. 43: 569-575, 1992. [PubMed: 1534968] [Full Text: https://doi.org/10.1002/ajmg.1320430313]
Cousineau, A. J., Lauer, R. M., Pierpont, M. E., Burns, T. L., Ardinger, R. H., Patil, S. R., Sheffield, V. C. Linkage analysis of autosomal dominant atrioventricular canal defects: exclusion of chromosome 21. Hum. Genet. 93: 103-108, 1994. [PubMed: 8112730] [Full Text: https://doi.org/10.1007/BF00210591]
Craig, B. Atrioventricular septal defect: from fetus to adult. Heart 92: 1879-1885, 2006. [PubMed: 17105897] [Full Text: https://doi.org/10.1136/hrt.2006.093344]
D'Alessandro, L. C. A., Al Turki, S., Manickaraj, A. K., Manase, D., Mulder, B. J. M., Bergin, L., Rosenberg, H. C., Mondal, T., Gordon, E., Lougheed, J., Smythe, J., Devriendt, K., UK10K Consortium, Bhattacharya, S., Watkins, H., Bentham, J., Bowdin, S., Hurles, M. E., Mital, S. Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect. Genet. Med. 18: 189-198, 2016. [PubMed: 25996639] [Full Text: https://doi.org/10.1038/gim.2015.60]
Dasgupta, C., Martinez, A.-M., Zuppan, C. W., Shah, M. M., Bailey, L. L., Fletcher, W. H. Identification of connexin43 (alpha-1) gap junction gene mutations in patients with hypoplastic left heart syndrome by denaturing gradient gel electrophoresis (DGGE). Mutat. Res. 479: 173-186, 2001. [PubMed: 11470490] [Full Text: https://doi.org/10.1016/s0027-5107(01)00160-9]
Digilio, M. C., Giannotti, A., Marino, B., Dallapiccola, B. Atrioventricular canal and 8p syndrome. (Letter) Am. J. Med. Genet. 47: 437-438, 1993. [PubMed: 8135296] [Full Text: https://doi.org/10.1002/ajmg.1320470331]
Digilio, M. C., Marino, B., Cicini, M. P., Giannotti, A., Formigari, R., Dallapiccola, B. Risk of congenital heart defects in relatives of patients with atrioventricular canal. Am. J. Dis. Child. 147: 1295-1297, 1993. [PubMed: 8249947] [Full Text: https://doi.org/10.1001/archpedi.1993.02160360037013]
Emanuel, R., Somerville, J., Inns, A., Withers, R. Evidence of congenital heart disease in the offspring of parents with atrioventricular defects. Brit. Heart J. 49: 144-147, 1983. [PubMed: 6824534] [Full Text: https://doi.org/10.1136/hrt.49.2.144]
Nora, J. J. Etiologic factors in congenital heart diseases. Pediat. Clin. N. Am. 18: 1059-1074, 1971. [PubMed: 5138391] [Full Text: https://doi.org/10.1016/s0031-3955(16)32629-3]
O'Nuallain, S., Hall, J. G., Stamm, S. J. Autosomal dominant inheritance of endocardial cushion defect. Birth Defects Orig. Art. Ser. XIII(5A): 143-147, 1977.
Sanchez-Cascos, A. The recurrence risk in congenital heart disease. Europ. J. Cardiol. 7: 197-210, 1978. [PubMed: 668753]
Sheffield, V. C., Pierpont, M. E., Nishimura, D., Beck, J. S., Burns, T. L., Berg, M. A., Stone, E. M., Patil, S. R., Lauer, R. M. Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis. Hum. Molec. Genet. 6: 117-121, 1997. [PubMed: 9002679] [Full Text: https://doi.org/10.1093/hmg/6.1.117]
Smith, K. A., Joziasse, I. C., Chocron, S., van Dinther, M., Guryev, V., Verhoeven, M. C., Rehmann, H., van der Smagt, J. J., Doevendans, P. A., Cuppen, E., Mulder, B. J., ten Dijke, P., Bakkers, J. Dominant-negative ALK2 allele associates with congenital heart defects. Circulation 119: 3062-3069, 2009. [PubMed: 19506109] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.108.843714]
Wilson, L., Curtis, A., Korenberg, J.R., Schipper, R.D., Allan, L., Chenevix-Trench, G., Stephenson, A., Goodship, J., Burn, J. A large, dominant pedigree of atrioventricular septal defect (AVSD): exclusion from the Down syndrome critical region on chromosome 21. Am. J. Hum. Genet. 53: 1262-1268, 1993. [PubMed: 8250042]
Yao, J., Thompson, M. W., Trusler, G. A., Trimble, A. S. Familial atrial septal defect of the primum type: a report of four cases in one sibship. Canad. Med. Assoc. J. 98: 218-219, 1968. [PubMed: 20329145]