Transposition Of The Great Arteries, Dextro-Looped 1

A number sign (#) is used with this entry because of evidence that dextro-looped transposition of the great arteries (D-TGA) is caused by heterozygous missense mutation in the mediator complex subunit 13-like gene (MED13L; 608771) on chromosome 12q24.

Heterozygous mutation in the MED13L gene can also cause mental retardation and distinctive facial features with or without cardiac defects (MRFACD; 616789).

Description

The more common form of transposition of the great arteries, dextro-looped TGA, consists of complete inversion of the great vessels, so that the aorta incorrectly arises from the right ventricle and the pulmonary artery incorrectly arises from the left ventricle. (In the less common type of TGA, levo-looped TGA, the ventricles are inverted instead) (Goldmuntz et al., 2002). This creates completely separate pulmonary and systemic circulatory systems, an arrangement that is incompatible with life. Patients with TGA often have atrial and/or ventricular septal defects or other types of shunting that allow some mixing between the circulations in order to support life minimally, but surgical intervention is always required.

Nomenclature

The symbol 'DTGA2' was originally used to designate isolated cardiac malformations associated with mutations in the CFC1 gene (605194) on chromosome 2; DGTA2 has since been reclassified as a variant of a heterotaxy syndrome (HTX2; 605376). The symbol 'DTGA3' was formerly used for transposition of the great arteries caused by mutation in the GDF1 gene (602880); the symbol for the multiple types of congenital heart defects caused by mutation in GDF1, including TGA, is CHTD6 (613854).

Inheritance

Becker et al. (1996) reported the frequency of cardiovascular malformations in first-degree relatives of probands with transposition of the great arteries. Patients were subdivided into levo-TGA (19), dextro-TGA (168), complex TGA (65), and asplenia with TGA (19). In the levo-TGA group, 1 of 50 sibs had a cardiovascular malformation while all parents were normal. In the dextro-TGA group, 1 of 369 sibs had cardiovascular malformation, and 1 father had levo-TGA. Four of 143 sibs in the complex-TGA group and 2 of the parents had cardiovascular malformation, and in the asplenia with TGA group, 1 of 50 sibs and no parents had a heart defect. Overall recurrence risk in sibs was 5 in 612 (0.82%).

Molecular Genetics

In a screening of 97 patients with isolated D-TGA for mutations in the THRAP2 gene, Muncke et al. (2003) identified 6 intronic polymorphisms, 6 silent mutations, and 4 missense mutations. Three of the heterozygous missense mutations (E251G, 608771.0001; R1872H, 608771.0002; and D2023G, 608771.0003) appeared to be disease causing, although there was evidence for incomplete penetrance in 1 family. Functional studies of the variants were not performed.