Atrial Septal Defect 3

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

MYH6, NKX2-5, GATA4, GATA6, ACTC1, TLL1, CITED2, TBX20, PQBP1, PTPN11, TAB2, TBX5, RPL11, NF1, GDF1, F5, F2, ARSD, MTHFR, P2RY12, CHDH, CLNK, STX18, G6PC3, NNT, LBX2, NPPB, VWF, RENBP, APOC3

MYH6, NKX2-5, GATA4, GATA6, ACTC1, TLL1, CITED2, TBX20, PQBP1, PTPN11, TAB2, TBX5, RPL11, NF1, GDF1, F5, F2, ARSD, MTHFR, P2RY12, CHDH, CLNK, STX18, G6PC3, NNT, LBX2, NPPB, VWF, RENBP, APOC3, MSX2, MSX1, F3, COX8A, CHM, ATP1A2, C20orf181

Drugs

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A number sign (#) is used with this entry because this form of atrial septal defect (ASD3) is caused by heterozygous mutation in the myosin heavy chain-6 gene (MYH6; 160710) on chromosome 14q11.

For a general phenotypic description and a discussion of genetic heterogeneity of atrial septal defect, see ASD1 (108800).

Clinical Features

Ching et al. (2005) described a 4-generation family with ASD and no other cardiac abnormalities, or other malformations of any type. All affected individuals had an ASD of the secundum type, defined as an unrestrictive ASD with increased right ventricular preload and increased pulmonary blood flow of more than 1.5 times systemic flow according to the Doppler continuity equation. Several individuals had surgical closure of ASD in childhood. No ASD detected in childhood closed spontaneously.

Mapping

By genomewide linkage screen in a large family with dominantly inherited atrial septal defect and no other cardiac abnormalities, Ching et al. (2005) established linkage to markers on 14q12 with a maximum lod score of 2.5. Fine mapping of the critical region using 7 additional microsatellite markers narrowed the disease locus to an interval between D14S283 and D14S972, with a peak lod score of 4.22 at theta = 0.0 for D14S990, assuming a penetrance of 80%.

Molecular Genetics

Within the atrial septal defect critical region on chromosome 14q12, Ching et al. (2005) identified MYH6, which is expressed mainly in atrial tissue, as the best candidate gene. They screened the 39 exons of MYH6 in all members of the family using denaturing high-performance liquid chromatography. Sequencing identified an ile820-to-asn mutation (I820N; 160710.0003) in all affected family members, all obligate carriers, and in 1 other individual, but not in unaffected family members or in 200 chromosomes screened from healthy unrelated individuals. Ching et al. (2005) pointed out that cardiac transcription factor TBX5 (601620) strongly regulates expression of MYH6, but mutant forms of TBX5, which cause Holt-Oram syndrome (HOS; 142900), do not regulate MYH6. Morpholino knockdown of expression of the chick MYH6 homolog eliminated the formation of the atrial septum without overtly affecting atrial chamber formation. These data provided evidence for a link between a transcription factor, a structural protein, and congenital heart disease.