AbstractBarth syndrome (BTHS) is an X‐linked disorder characterized by cardiomyopathy, skeletal myopathy, and 3‐methylglutaconic aciduria. The causative pathogenic variants for BTHS are inTAZ, which encodes a putative acyltransferase named tafazzin and is involved in the remodeling of cardiolipin in the inner mitochondrial membranes. Pathogenic variants inTAZresult in mitochondrial structural and functional abnormalities. We report a case of infantile BTHS with severe heart failure, left ventricular noncompaction, and lactic acidosis, having a missense c.640C>T (p.His214Tyr) variant inTAZ, which is considered a pathogenic variant based on the previously reported amino acid substitution at the same site (c.641A>G, p.His214Arg). However, in this previously reported case, heart function was compensated and not entirely similar to the present case. Silico prediction analysis suggested that c.640C>T could alter theTAZmessenger RNA (mRNA) splicing process.TAZmRNAs in isolated peripheral mononuclear cells from the patient and in vitro splicing analysis using minigenes ofTAZfound an 8 bp deletion at the 3′ end of exon 8, which resulted in the formation of a termination codon in the coding region of exon 9 (H214Nfs*3). These findings suggest that splicing abnormalities should always be considered in BTHS.