Abstract 16329: Ten Novel Mutations of the TAZ Gene in Patients With Barth Syndrome
Introduction Barth Syndrome (BTHS) is an X-linked recessive multisystem disorder conventionally characterized by dilated cardiomyopathy (DCM) with endocardial fibroelastosis (EFE), skeletal myopathy, growth delay, neutropenia, organic aciduria and variable respiratory chain abnormalities. BTHS is a unique form of mitochondrial disease caused by mutations in the taffazin (TAZ) gene at Xq28 that result in cardiolipin deficiency and abnormal mitochondria. TAZ gene encodes a highly conserved acyltransferase and is ubiquitously expressed in all human tissues. To date, there is still no strong genotype-phenotype correlation, with patients presenting with a variable course of the disease.
Methods We conducted TAZ mutation analysis in a large cohort of 396 cases with suspected BTHS referred to our center for genetic testing. Peripheral blood-derived genomic DNA was used to amplify the 11 coding exons of the TAZ gene by polymerase chain reaction (PCR) using intron-based and exon-specific primers. The PCR products were purified and analyzed by bidirectional sequencing. Two computational programs, SIFT and PolyPhen-2, were used to predict the pathogenic probability of the identified missense variants.
Results A total of 26 mutations in the TAZ gene were identified in 35 patients with a definitive diagnosis of BTHS. This includes 4 nonsense and 6 frameshift mutations, 12 missense mutations and 4 splicing site mutations which distributed in exons 2 (n=4), 3 (n=1), 4 (n=4), 6 (n=3), 7 (n=1), 8 (n=5), 9 (n=2), 10 (n=1), and 11 (n=2) and introns 1, 3, 4 and 6 (n=1 each). Of these, 10 mutations including 2 missense mutations (H176P and R198L), 2 splicing site mutations (IVS3+5G>A and IVS4+1G>A), 1 nonsense mutation (G195X) and 5 frameshift mutations (c.294delT/insAGGGGTCCTAA, c.492insC, c.728_737delTCAGTGCCCT, c.823insTC and c.873delG) were not reported previously, to our knowledge. The two novel missense variants H176P and R198L were predicted to be pathogenic by SIFT and PolyPhen-2.
Conclusions Our study further expanded the spectrum of TAZ mutations in patients with BTHS and provided more information towards the understanding of genotype-phenotype correlation in BTHS.
- © 2011 by American Heart Association, Inc.