Barth syndrome (BTHS) is an X-linked disorder characterised by cardiac and skeletal myopathy, growth delay, neutropenia and 3-methylglutaconic aciduria (3-MGCA). Patients have TAZ gene mutations which affect metabolism of cardiolipin, resulting in low tetralinoleoyl cardiolipin (CL4), an increase in its precursor, monolysocardiolipin (MLCL), and an increased MLCL/CL4 ratio. During development of a diagnostic service for BTHS, leukocyte CL4 was measured in 156 controls and 34 patients with genetically confirmed BTHS. A sub-group of seven subjects from three unrelated families was identified with leukocyte CL4 concentrations within the control range. This had led to initial false negative disease detection in two of these patients. MLCL/CL4 in this subgroup was lower than in other BTHS patients but higher than controls, with no overlap between the groups. TAZ gene mutations in these families are all predicted to be pathological. This report describes the clinical histories of these seven individuals with an atypical phenotype: some features were typical of BTHS (five have had cardiomyopathy, one family has a history of male infant deaths, three have growth delay and five have 3-MGCA) but none has persistent neutropenia, five have excellent exercise tolerance and two adults are asymptomatic. This report also emphasises the importance of measurement of MLCL/CL4 ratio rather than CL4 alone in the biochemical diagnosis of the BTHS.

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Paediatric cardiomyopathy (PC) has multiple genetic causes and can present in infancy with cardiac failure and sudden death. Within the Bristol Genetics Laboratory analysis of Barth Syndrome (TAZ gene) is triggered by an abnormal cardiolipin ratio, but only 7% of referred cases are mutation positive. Next generation sequencing technology enables large sets of related genes to be analysed simultaneously. As considerable clinical and genetic heterogeneity exists within and between PC families, a one off cost-effective gene panel test helps diagnosis and elucidates complex clinical presentations. An Agilent SureSelect custom enrichment kit was designed to include 71 paediatric cardiomyopathy genes, with data analysis through an in-house bioinformatics pipeline (Broad Institute) and Geneticist Assistant (SoftGenetics). This assay has been validated and introduced into service as a United Kingdom Genetic Testing network (UKGTN) approved test.Validation involved two runs using 17 patients, including 14 with known pathogenic variants with100% concordance. The assay coverage at 30x was close to the predicted 99.7% at design with one exonic gap (CTF1, exon 3). Since introduction into service 37 patients have been tested, including infantile/paediatric cases; patients negative for other genes and patients who have phenotypic incompatibility with their reported pathogenic variant where digenic inheritance is suspected. 32/37 (86%) patients have at least one potentially pathogenic variant.In onefamily with HCM, aMYBPC3 variant c.1505G >A, p.(Arg502Gln) and a previously reportedNEBL pathogenic variant c.180G >C, p.(Lys60Asn) (nebulette protein) were detected in a severely affected male demonstrating that multiple variants can explain phenotypic severity. The utility of testing rare genes is exemplified by: 1) A teenager with LV dilation and FH of sudden death who was heterozygous for a RMB20 (RNA binding protein) variant c.1907G >A, p.(Arg636His), previously reported with severe familial DCM; 2) a patient with congenital heart block, LV dilation and FH was heterozygous for a novel likely pathogenic MYH6 (alpha heavy chain subunit) variant c.3578C >T, p.(Ala1193Val). Furthermore, a novel heterozygous TTN A-band frameshift variant was identified in an infantile DCM patient; recent data suggests TTN frameshift variants have not been reported in infantile cardiomyopathy.Details of the validation of this technology, an audit of this patient cohort illustrated by interesting cases will be presented.