Prenatal case report of Barth syndrome caused by novel TAFAZZIN mutation: Clinical characteristics of fetal dilated cardiomyopathy with ascites

Abstract

Barth syndrome (BTHS) is a rare X-linked recessive genetic disease, which appears in infancy with myocardial and skeletal muscle diseases, neutropenia, growth retardation, and other clinical features. TAFAZZIN is the pathogenic gene of BTHS, which encodes the tafazzin protein of the inner membrane of the mitochondria, a phosphatidyltransferase involved in cardiolipin remodeling and functional maturation. At present, BTHS has been widely reported, but prenatal cases are rare. We report a 24⁺⁴-week fetus with clinical manifestations including left ventricular insufficiency and ascites. After induced labor, whole exome sequencing detection of fetal skin tissue showed that TAFAZZIN had the mutation c.311A > C/p.His104Pro and that his mother was the carrier. This His104Pro mutation has hitherto not been reported, and it is rated as likely to be pathogenic according to the American College of Medical Genetics and Genetics guidelines. Molecular dynamics and protein expression experiments on the His104Pro mutation showed that the stability of the local protein structure and protein expression were reduced. In conclusion, the case presented in this study enriches our knowledge of the TAFAZZIN mutation spectrum and suggests that His104Pro may lead to cardiac structural abnormalities in the early embryo. The possibility of BTHS should be considered when an abnormal cardiac structure or ascites appear in a prenatal ultrasound.

Keywords: LVNC; WES; congenital heart disease; prenatal diagnosis; tafazzin.

Figure 1

Clinical characteristics of the fetus in this study. (A) Ultrasound showed that the fetal cardiothoracic area ratio was increased, approximately 0.45, and the left atrium and left ventricle sizes were increased substantially. (B) Ultrasound showed hypertrophy of fetal myocardium and free fluid in the pericardial cavity (white arrow). (C) Ultrasound showed a large amount of free fluid in the fetal abdominal cavity and thickened abdominal skin tissue (white arrow). (D) After induced labor, autopsy revealed the heart was considerably enlarged. (E) Pathological sections showed thickening and fibrosis of the endocardial tissue (red arrows). (F) The muscular trabeculae were thick, the sinus recess of the myocardium persisted, the deep depression was staggered, the formation of dense myocardium in the corresponding area was reduced and thin, and the ventricular wall muscle layer remained loose (red circle).

Figure 2

Information on the mutation found in this case. (A) The results of gene detection showed that TAFAZZIN had a missense mutation, c.311A > C/p.His104Pro. The father carried the wild-type form, while the mother carried the mutation. Sanger sequencing confirmed the existence of the mutation. (B) His104 is conserved between species (red box). (C) The crystal structure model analysis results show that the main chain N–H bond of His104 forms a hydrogen bond with Lys101, and the side chain forms a hydrogen bond with Glu73. When the mutation of His104Pro occurs, the hydrogen bond between Lys101 and Glu73 is broken because Pro104 has a five-membered ring structure with greater rigid strength than the straight-chain structure. Simultaneously, owing to the steric hindrance of Pro104, the secondary structure (part of the α-helix) may become a loop domain (red box). Therefore, the His104Pro mutation may reduce the stability of the local protein structure and affect its biological function.

Figure 3

Western blotting results show that the protein expression in TAFAZZIN-MUT (the His104Pro mutant) is significantly lower than that in TAFAZZIN-WT (the wild type), indicating that His104Pro may reduce human TAFAZZIN protein expression and affect relevant biological functions. *, p < 0.05; NC, negative control.