BTHS; Barth syndrome; CMD3A; EFE; EFE2; G4.5; LVNCX; Taz1
The TAZ gene is associated with X-linked Barth Syndrome (BTHS), also known as 3-methylglutaconic aciduria type II (MedGen UID: 107893), and dilated cardiomyopathy (DCM) (MedGen UID: 2880).
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TAZ is the only gene associated with Barth syndrome.
The TAZ gene encodes the tafazzin protein which promotes cardiolipin acyl chain remodeling.
The TAZ gene is associated with X-linked Barth syndrome (BTHS), also known as 3-methylglutaconic aciduria type II (MedGen UID: 107893), and dilated cardiomyopathy (DCM; MedGen UID: 2880).
Barth syndrome is a multi-system disorder characterized by cardiomyopathy, neutropenia, skeletal myopathy, growth and/or developmental delay, increased 3-methylglutaconic acid, and distinct facial features in affected males (PMID: 1719174, 6142097, 19648820). Overall, phenotypic expression is widely variable among patients and in the same patients over time (PMID: 23045169). Carrier females are reported to be unaffected and without detectable biochemical abnormalities (PMID: 15098233). In families with pathogenic variants in TAZ, multiple miscarriages, fetal loss, or stillbirth of males has been reported (PMID: 20812380).
Cardiomyopathy is the most common feature and cause of death, frequently observed by one year of age and presenting as DCM or left ventricular non-compaction (LVNC; PMID: 15098233). DCM is defined by left ventricular dilation and systolic dysfunction, which may lead to heart failure, arrhythmias or conduction system disease, and thromboembolic disease (PMID: 15808750). LVNC occurs when the ventricular wall does not finish developing and retains a spongy or “trabeculated” appearance, causing a risk of heart failure, arrhythmia, and an increased risk for blood clots or stroke (PMID: 24282766). Variations in TAZ have also been reported in non-syndromic DCM and LVNC (PMID: 9382096, 12468278).
Skeletal myopathy typically presents as proximal and non-progressive muscle weakness affecting gross motor ability and can also affect grip (PMID: 23398819).
Characteristic biochemical findings in males include elevations of 3-methylglutaconic acid, 3-methylglutaric acid, and 2-ethylhydracrylic acid in urine or plasma, as well as an altered monolysocardiolipin to cardiolipin (CL) ratio in fibroblasts (PMID: 1719174, 16873891).
The TAZ gene encodes the tafazzin protein, which promotes CL acyl chain remodeling by adding a linoleic acid to the molecule (PMID: 16873891). CL is found in the inner membrane of mitochondria, is required for maintaining the structure of respiratory chain complexes, and plays a role in oxidative phosphorylation (PMID: 16873891). Loss of function variants reduce the formation of the CL isoform predominantly found in cardiac and skeletal muscle, impairing their function (PMID: 23398819).
TAZ exhibits X-linked inheritance, and affected individuals are male. In an affected individual, a pathogenic variant is expected to be inherited from the mother or to occur de novo. Maternal genetic testing can help determine if a variant is inherited or de novo and inform recurrence risk for the siblings of an affected individual. Maternal germline mosaicism has been reported (PMID: 20303308, 23656970). Any female children of an affected male would inherit the pathogenic variant as unaffected carriers and male children would not inherit this variant.
Recommended management for cardiomyopathy (DCM and LVNC) includes a combination of medication, device therapy, and heart transplantation. Pre-symptomatic treatment may forestall symptoms and improve survival and quality of life. Surveillance of affected individuals includes periodic physical exams, echocardiograms, and ECG/EKG. It is recommended that management decisions be made based on clinical presentation, symptoms, and family history (PMID: 19254666).
Other management and surveillance recommendations include the following:
Review date: December 2017
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|