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SNOMEDCT: 253366007, 405752007, 70142008; ICD10CM: Q21.1, Q21.10; ORPHA: 1478; DO: 0110106;
Cytogenetic location: 5p Genomic coordinates (GRCh38): 5:1-48,800,001
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p | Atrial septal defect 1 | 108800 | Autosomal dominant | 2 |
Secundum atrial septal defect (ASD) is a common congenital heart malformation that occurs as an isolated anomaly in 10% of individuals with congenital heart disease. Uncorrected ASD can cause pulmonary overcirculation, right heart volume overload, and premature death (summary by Benson et al., 1998).
Genetic Heterogeneity of Atrial Septal Defect
The ASD1 locus has been mapped to chromosome 5p. Other forms of atrial septal defect that are associated with other congenital heart disease but no conduction defects or noncardiac abnormalities include ASD2 (607941), caused by mutation in the GATA4 gene (600576), and ASD4 (611363), caused by mutation in the TBX20 gene (606061). ASD3 (614089) and ASD5 (612794), in which atrial septal defect is not associated with other cardiac abnormalities, are caused by mutation in the MYH6 (160710) and ACTC1 (102540) genes, respectively. ASD6 (613087), in which atrial septal defect may be associated with aneurysm of the interatrial septum and cardiac arrhythmias, is caused by mutation in the TLL1 gene (606742). ASD7 (108900), in which ASD is often associated with atrioventricular conduction defects, is caused by mutation in the NKX2-5 gene (600584). ASD8 (614433), in which ASD may be associated with other cardiac anomalies, is caused by mutation in the CITED2 gene (602937). ASD9 (614475) is caused by mutation in the GATA6 gene (601656).
Somatic mutations in the HAND1 gene (602406) have been identified in tissue samples from patients with ASDs.
This congenital heart defect is almost always sporadic, but occasional families in which multiple persons have isolated ASD suggest that a single 'major' gene may sometimes be responsible. The family reported by Zuckerman et al. (1962) suggests dominant inheritance. Zetterqvist (1960) reported a family with 8 proved cases and 5 probable cases of ASD of secundum type in 3 generations. Johansson and Sievers (1967) found 6 proved and 1 probable case of ASD in 3 generations. Furthermore, they were able to show that Zetterqvist's and their cases traced their ancestry to a common couple who lived in the 18th century. Zetterqvist et al. (1971) gave a full report on the family which they felt provided strong evidence for the existence of a single major gene as a determining factor.
Sanchez-Cascos (1972) examined 109 cases of ASD, 84 of the ostium secundum type and 25 of the ostium primum type; of these, 92 presented ASD as an isolated defect and 17 were associated with other malformations. He concluded, from the incidence of familial aggregation among first-degree relatives of affected cases, from the fact that the sex ratio deviated from 1 for his cases (0.64 males per 1 female), and from other findings, that multifactorial inheritance is consistent with the demonstrated pattern of transmission. He also reported significant dermatoglyphic findings in these ASD cases--a high proportion of whorls and a parallel diminution in the number of ulnar loops.
Lynch et al. (1978) restudied a large kindred reported by Zuckerman et al. (1962) and concluded that 2 autosomal dominant forms of ASD occur: one with (108900) and one without prolongation of the PR interval. Li Volti et al. (1991) observed 3 Sicilian families in which 17 persons (10 females and 7 males) had atrial septal defect of the ostium secundum type without conduction defects. There were several instances of male-to-male transmission.
Mohl and Mayr (1977) studied 3 multigeneration families with secundum type ASD and found no recombination with HLA (which is at chromosome 6p21.3). The data yielded a lod score of +3.612 at a recombination fraction of 0.000, but the confidence limits were wide. Insufficient information was given to know whether this was the Holt-Oram syndrome (142900) or ASD with conduction defect (108900) rather than secundum type atrial septal defect. See another report on the ostium secundum type of ASD by the same group (Mohl et al., 1979).
Benson et al. (1998) reported an evaluation of 3 families in which individuals in multiple generations had ASD. The most common anomaly was ASD, but other heart defects occurred alone or in association with ASD in individuals from each kindred. In 1 kindred genomewide linkage studies localized a familial ASD gene to chromosome 5p (multipoint lod score = 3.6, theta = 0.0 at D5S406). Of 20 family members with the disease haplotype, 9 had ASD, 8 were clinically unaffected, and 3 had other cardiac defects (aortic stenosis, atrial septal aneurysm, and persistent left superior vena cava). Familial ASD did not map to chromosome 5p in the other 2 families. Thus, they emphasized reduced penetrance, variable expressivity, and genetic heterogeneity of familial atrial septal defects.
Benson, D. W., Sharkey, A., Fatkin, D., Lang, P., Basson, C. T., McDonough, B., Strauss, A. W., Seidman, J. G., Seidman, C. E. Reduced penetrance, variable expressivity, and genetic heterogeneity of familial atrial septal defects. Circulation 97: 2043-2048, 1998. [PubMed: 9610535] [Full Text: https://doi.org/10.1161/01.cir.97.20.2043]
Johansson, B. W., Sievers, J. Inheritance of atrial septal defect. (Letter) Lancet 289: 1224-1225, 1967. Note: Originally Volume I. [PubMed: 4165146] [Full Text: https://doi.org/10.1016/s0140-6736(67)92869-3]
Li Volti, S., Distefano, G., Garozzo, R., Romeo, M. G., Sciacca, P., Mollica, F. Autosomal dominant atrial septal defect of ostium secundum type: report of three families. Ann. Genet. 34: 14-18, 1991. [PubMed: 1952784]
Lynch, H. T., Bachenberg, K., Harris, R. E., Becker, W. Hereditary atrial septal defect: update of a large kindred. Am. J. Dis. Child. 132: 600-604, 1978. [PubMed: 148839] [Full Text: https://doi.org/10.1001/archpedi.1978.02120310064013]
Mohl, W., Mayr, W. R. Atrial septal defect of the secundum type and HLA. Tissue Antigens 10: 121-122, 1977. [PubMed: 70860] [Full Text: https://doi.org/10.1111/j.1399-0039.1977.tb01128.x]
Mohl, W., Mayr, W. R., Hauser, G., Reuer, E., Wimmer, M., Herbich, J. Gemeinsame Mechanismen der Missbildungsentstehung beim erblichen und sporadischen Vorhofseptumdefekt Typ II. Wien. Klin. Wochenschr. 91: 307-314, 1979. [PubMed: 452615]
Sanchez-Cascos, A. Genetics of atrial septal defect. Arch. Dis. Child. 47: 581-588, 1972. [PubMed: 4261647] [Full Text: https://doi.org/10.1136/adc.47.254.581]
Zetterqvist, P. Multiple occurrence of atrial septal defect in a family. Acta Paediat. 49: 741-747, 1960. [PubMed: 13788275] [Full Text: https://doi.org/10.1111/j.1651-2227.1960.tb16081.x]
Zetterqvist, P., Turesson, I., Johansson, B. W., Laurell, S., Ohlsson, N. M. Dominant mode of inheritance in atrial septal defect. Clin. Genet. 2: 78-86, 1971. [PubMed: 5116593] [Full Text: https://doi.org/10.1111/j.1399-0004.1971.tb00259.x]
Zuckerman, H. S., Zuckerman, G. H., Mammen, R. E., Wassermil, M. Atrial septal defect: familial occurrence in four generations of one family. Am. J. Cardiol. 9: 515-520, 1962.