When silence is noise: infantile-onset Barth syndrome caused by a synonymous substitution affecting TAZ gene transcription

• Published in: Clinical genetics 2016-11, Vol.90 (5), p.461-465
• Main Authors: Ferri, L., Dionisi-Vici, C., Taurisano, R., Vaz, F. M., Guerrini, R., Morrone, A.
• Format: Article
• Language: English
• Subjects: Acidosis; Acidosis, Lactic - genetics; Acidosis, Lactic - physiopathology; Aciduria; Amino acid sequence; Amino acids; Barth syndrome; Barth Syndrome - blood; Barth Syndrome - genetics; Barth Syndrome - physiopathology; Cardiolipin; Cardiolipins - blood; Cardiomyopathy; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - physiopathology; Child; Dilated cardiomyopathy; exon skipping; Exons - genetics; Female; Fibroblasts; Gene dosage; Gene expression; Genetic disorders; Heterozygote; Humans; Hypoglycemia; Hypoglycemia - genetics; Hypoglycemia - physiopathology; Inborn errors of metabolism; Lactic acidosis; Lysophospholipids - blood; Male; Mutation; Myopathy; Neutropenia; silent mutation; Splicing; synonymous mutation; TAZ gene; Transcription; Transcription factors; Transcription Factors - genetics; Transcription, Genetic
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.12756

Barth syndrome (BTHS) is an X‐linked inborn error of metabolism which affects males. The main manifestations are cardiomyopathy, myopathy, hypotonia, growth delay, intermittent neutropenia and 3‐methylglutaconic aciduria. Diagnosis is confirmed by mutational analysis of the TAZ gene and biochemical dosage of the monolysocardiolipin/tetralinoleoyl cardiolipin (MLCL:L4‐CL) ratio. We report a 6‐year‐old boy who presented with severe hypoglycemia, lactic acidosis and severe dilated cardiomyopathy soon after birth. The MLCL:L4‐CL ratio confirmed BTHS (3.90 on patient's fibroblast, normal: 0–0.3). Subsequent sequencing of the TAZ gene revealed only the new synonymous variant NM_000116.3 (TAZ):c.348C>T p.(Gly116Gly), which did not appear to affect the protein sequence. In silico prediction analysis suggested the new c.348C>T nucleotide change could alter the TAZ mRNA splicing processing. We analyzed TAZ mRNAs in the patient's fibroblasts and found an abnormal skipping of 24 bases (NM_000116.3:c.346_371), with the consequent ablation of 8 amino acid residues in the tafazzin protein (NP_000107.1:p.Lys117_Gly124del). Molecular analysis of at risk female family members identified the patient's sister and mother as heterozygous carriers. Apparently harmless synonymous variants in the TAZ gene can damage gene expression. Such findings widen our knowledge of molecular heterogeneity in BTHS.