New clinical and molecular insights on Barth syndrome

Abstract

BackgroundBarth syndrome (BS) is an X-linked infantile-onset cardioskeletal disease characterized by cardiomyopathy, hypotonia, growth delay, neutropenia and 3-methylglutaconic aciduria. It is caused by mutations in the TAZ gene encoding tafazzin, a protein involved in the metabolism of cardiolipin, a mitochondrial-specific phospholipid involved in mitochondrial energy production.MethodsClinical, biochemical and molecular characterization of a group of six male patients suspected of having BS. Three patients presented early with severe metabolic decompensation including respiratory distress, oxygen desaturation and cardiomyopathy and died within the first year of life. The remaining three patients had cardiomyopathy, hypotonia and growth delay and are still alive. Cardiomyopathy was detected during pregnancy through a routine check-up in one patient. All patients exhibited 3-methylglutaconic aciduria and neutropenia, when tested and five of them also had lactic acidosis.ResultsWe confirmed the diagnosis of BS with sequence analysis of the TAZ gene, and found five new mutations, c.641A>G p.His214Arg, c.284dupG (p.Thr96Aspfs*37), c.678_691del14 (p.Tyr227Trpfs*79), g.8009_16445del8437 and g.[9777_9814del38; 9911-?_14402del] and the known nonsense mutation c.367C>T (p.Arg123Term). The two gross rearrangements ablated TAZ exons 6 to 11 and probably originated by non-allelic homologous recombination and by Serial Replication Slippage (SRS), respectively. The identification of the breakpoints boundaries of the gross deletions allowed the direct detection of heterozygosity in carrier females.ConclusionsLactic acidosis associated with 3-methylglutaconic aciduria is highly suggestive of BS, whilst the severity of the metabolic decompensation at disease onset should be considered for prognostic purposes. Mutation analysis of the TAZ gene is necessary for confirming the clinical and biochemical diagnosis in probands in order to identify heterozygous carriers and supporting prenatal diagnosis and genetic counseling.

Intra-individual plasticity of the TAZ gene leading to different heritable mutations in siblings with Barth syndrome

“…The primer pair used was DNASE1L-ex10fw (5′-TGACCCTTCTAGCGTCCC-3′) and Taz6-7rv (5′-AGGCCTAGTC TCAGCACCTG-3′). 4 The reverse primer Taz6-7rv anneals within intron 7 of TAZ, which was confirmed to be present in proband IV-L by routine amplification of the TAZ coding region and intron-exon boundaries. Primer DNASE1L-ex10fw anneals 9.95 kb upstream of the start codon (ATG) of the TAZ gene within exon 10 of the DNASE1L gene, which is located in the opposite orientation to, but partially overlaps with, the TAZ gene.…”

“…Isolation of genomic DNA and molecular analysis of the TAZ gene sequence were performed as previously described, 4 after informed consent had been obtained from all subjects to be analysed, in accordance with local ethical committee recommendations. Multiplex PCR analyses were performed by using our previously reported primer pairs (Table 1 in Ferri et al 4 ).…”

“…The efficacy of the method was, however, confirmed by the successful detection of heterozygosity of a TAZ exons 6-11 deletion in two DNAs from females harbouring the previously described NG_009634.1:g.[9777_9814del; 9911-?_14402del] TAZ complex rearrangement. 4 …”

“…1-3 3-Methylglutaconic aciduria and lactic acidosis can represent early biochemical markers. 1, [4][5][6] The estimated prevalence of BTHS is around 1/300 000-400 000 live births (BSF, http://www.barthsyndrome.org/home), but evidence is growing that the disease may be underdiagnosed. 2 BTHS is caused by mutations in the TAZ gene at Xq28, 7 which encodes tafazzin, an acyltransferase which promotes molecular symmetry among cardiolipin (CL) species with different fatty acyl moieties.…”

“…We have recently shown that the TAZ gene sequence is enriched in interspersed repeats, sequence elements that can promote the formation of gross genetic rearrangements during meiosis or DNA replication. 4,17 Here we describe the intriguing case of a BTHS family in which an asymptomatic mother gave birth to two male sons who harboured non-identical gross TAZ gene rearrangements. If found not to be uncommon, such 'double hit' situations could complicate the molecular prenatal diagnosis of BTHS.…”