Case Report: Deletion in the 5' untranslated region of TAFAZZIN in a boy with Barth syndrome.

BACKGROUND: Barth syndrome is an X-linked disorder characterised by cardiomyopathy, growth abnormalities, neutropenia, and 3-methylglutaconic aciduria. It is caused by pathogenic variants in TAFAZZIN, which encodes a mitochondrial protein essential for cardiolipin remodelling. In this study, we describe the case of a patient with Barth syndrome in whom initial research genetic testing missed a 5' untranslated region deletion in TAFAZZIN that was later identified through a phenotype-guided reanalysis of exome sequencing data.

CASE PRESENTATION: A male infant presented with dilated cardiomyopathy at 7 months of age and underwent cardiac transplantation at 19 months. Initial comprehensive cardiac genetic testing was indeterminate. Subsequent clinical investigations recorded a slight increase in the levels of 3-methylglutaconic acid and intermittent neutropenia, and a history of intermittent neutropenia was noted in his mother and maternal grandmother, prompting a consideration of Barth syndrome. A reanalysis of exome sequencing data identified a hemizygous 116 base pair deletion spanning the 5' untranslated region and start codon of TAFAZZIN. An RNA analysis from the proband's cardiac tissue amplified truncated TAFAZZIN transcripts, and Western blotting confirmed the complete loss of full-length protein, consistent with the loss of the start codon and failure of translation initiation from a downstream in-frame methionine.

CONCLUSION: We report a novel 116 bp TAFAZZIN deletion that prevents protein expression due to the loss of the canonical start codon. This case highlights the importance of including non-coding regions in genetic analysis and the diagnostic value of phenotype-guided reanalysis of genetic test data.