TAFAZZIN

Inheritance Pattern: XL

Disease ID:MONDO:0010543

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0010543

Submitter: ClinGen

*TAFAZZIN*, historically known as G4.5, was first reported in relation to X-linked Barth syndrome in 1996 (Bione et al., PMID: 8630491). This disorder was formally characterized by Barth et al. in 1983 as an X-linked mitochondrial disease with the characteristic phenotypes of dilated cardiomyopathy, skeletal myopathy, neutropenia, and and prepubertal growth delay (PMID:25299040). Barth syndrome can prenatally present as fetal DCM, hydrops, severe fetal decompensation necessitating emergency delivery and stillbirth, as seen in molecularly confirmed cases (PMID: 20812380). Additionally male miscarriages, stillbirth have been noted in multiple Barth syndrome families (PMIDs: 20812380, 27124939, 10484795, 28183324). Cardiomyopathy commonly presents before 5 years of age as DCM with or without endocardial fibroelastosis and/or left ventricular noncompaction, and in combination with other features of Barth syndrome. Hypertrophic cardiomyopathy has also been reported and probands are at an increased risk of heart failure, arrhythmias and sudden death (PMIDs: 16847078, 26337810, 9382097). Although multisystemic presentations predominate, isolated cardiac presentations have also been described (PMID: 9382097). Barth syndrome can be diagnosed in male probands either biochemically, with an increased monolysocardiolipin:cardiolipin ratio or molecularly, with the identification of a hemizygous pathogenic variant in TAFAZZIN. Elevated urinary and plasma 3-methylglutaconate and urinary 3-methylglutarate) can be observed. (GeneReviews: NBK247162). Affected females have been reported rarely. Over 100 variants, mostly premature termination or splice-altering with some missense, have been reported in humans to date. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene were curated from eleven probands in four publications (PMIDs: 8630491, 16906470, 10484795, 23031367) and segregated with disease in three of those families. This combination of significant segregation (Summed LOD score: 9.22) and high frequency of predicted/proven null variants reaches the maximum score for genetic evidence with more evidence available in the literature. The mechanism for disease is hemizygous loss-of-function, with loss of tafazzin enzymatic activity as a phospholipid acyltransferase affecting the maturation of the protein cardiolipin. Cardiolipin is an essential part of the mitochondrial membrane for mitochondrial morphology and function, as well as having other functions in cardiac function, apoptosis, autophagy, cell cycle regulation, and Fe-S cluster biosynthesis (PMID: 23200781). Dysregulation causes a cascade of effects including respiratory chain dysfunction, extensive mitochondrial aberrations, ultrastructural muscle damage, and destabilized super-complexes and metabolic complexes causing the observed phenotypes in Barth syndrome. This gene-disease association is supported by tafazzin and cardiolipin's biochemical functions and altered tafazzin enzymatic activity in patient fibroblasts. Several studies have been performed on "knockdown" mouse models expressing siRNAs to inhibit TAZ mRNA production when fed varying amounts of doxycycline. The results range in severity from premature lethality due to cardiomyopathy to relatively minor skeletal and cardiac abnormalities, recapitulating the phenotypes observed in human probands. Finally, a rescue performed on the same mice via AAV vectors with human TAZ cDNA restored cardiac and skeletal function of the mice to near WT levels while also improving the mitochondial abnormalities observed. In summary, *TAFAZZIN* is definitively associated with x-linked Barth syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the General IEM GCEP on December 8, 2022, and the summary was updated to include details on the cardiac presentation from the ClinGen Hereditary Cardiovascular Disease (HCVD) GCEP on Feb 22, 2026.

Inheritance Pattern: XL

Disease ID:MONDO:0010543

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0010543

Submitter: Labcorp Genetics (formerly Invitae)