Balkan Journal of Medical Genetics

A NOVEL INTRONIC SPLICE SITE TAFAZZIN GENE MUTATION DETECTED PRENATALLY IN A FAMILY WITH BARTH SYNDROME
Bakšienė M, Benušienė E, Morkūnienė A, Ambrozaitytė L, Utkus A, Kučinskas V
*Corresponding Author: Marija Bakšienė, M.D., Department of Human and Medical Genetics, Vilnius University, Santarişkių Str. 2, LT-08861 Vilnius, Lithuania. Tel: +3702365116. E-mail: m.baksiene@gmail. com
page: 95

DISCUSSION

To date, more than 220 different TAZ gene mutations in all exons have been identified [Human Tafazzin (TAZ) Gene Mutation and Variation Database (last updated March 28, 2015; http://www.barthsyndrome.org/home)], 94 of which were found in patients with diagnosed BTHS (Human Gene Mutation Database Professional 2015.4; http:// www.hgmd.cf.ac.uk/ac/index.php). Only 13.0% of boys with BTHS carry de novo mutations [15]. Phenotypegenotype correlations have not yet been identified [16,17]. It has been observed that mutations in the TAZ gene also result in non syndromic left ventricular non compaction, endocardial fibroelastosis, X-linked infantile cardiomyopathy and dilated cardiomyopathy. Thus, mutations in the TAZ gene can result in a broad spectrum of clinical phenotypes including, but not limited to classical BTHS. The c.285-1G>C mutation has not been previously reported in the Human Tafazzin (TAZ) Gene Mutation and Variation Database (last updated March 28, 2015; http:// www.barth syndrome.org/home). The mutation is predicted to alter the wild type constitutive acceptor splice site. Most probably the presence of mutation affects splicing in tafazzin [18]. Family studies showed that the proband, her mother and maternal grandmother carried the same mutation. Our proband’s fetus as well as her brother was affected with BTHS, suggesting that this newly discovered splice site mutation is an anomaly strongly affecting the normal function of the tafazzin protein, and thus, is likely to be pathogenic (Figure 3). An intronic TAZ gene mutation (aberrant splicing and elongation of exon 3 because of the insertion of 106 bases between exons 3 and 4) has been reported in a Japanese patient with BTHS, who had very similar symptoms and course of the disease as the third brother of our patient [19]. Our proband decided to terminate the pregnancy. Fetal autopsy was inconclusive. Evidence is accumulating that the disorder is substantially underdiagnosed. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder that may be first seen by many different specialists. Phenotypic variability raises a major challenge, as some children with BTHS have never showed neutropenia, others lack increased 3-methylglutaconic acid and a minority has occult or absent cardiomyopathy [20]. Furthermore, BTHS was described in 2010 as an unrecognized cause of fetal death. It is recommended that investigation for BTHS should now be seriously considered in male neonates, babies and young boys presenting with idiopathic dilated cardiomyopathy or left ventricular non compaction, and in males with unexplained ventricular arrhythmia or sudden death [20]. Female carriers are usually healthy and have no cardiovascular pathology. It is however theoretically possible for a female to develop symptoms of the disease because of impaired X chromosome inactivation. The only female ever described with the disease had abnormalities of both X chromosomes [21]. In this case, the proband, her mother and maternal grandmother had normal electrocardiograms and no history of cardiac disease.

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