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Cardiac disease is genetically heterogeneous with genes associated with multiple cardiac diseases, multiple causal genes per disease, and often multiple variants in one or more genes contributing to disease presentation. Gene panel testing, either through a specific targeted design, or by virtual analysis from the exome/clinical exome is an ideal approach for genetic diagnosis and provides information regarding complexity of these diseases. Bristol Genetics Laboratory provides a targeted gene panel for paediatric cardiomyopathy (PC) (71 genes, Agilent SureSelect) and a variety of virtual gene panels from Agilent Focussed Exome; Congenital Heart Defect (CHD) (38 genes), Aortopathy (28 genes), Arrhythmia (54 genes), Cardiomyopathy (119 genes), Connective Tissue (42 genes) Molecular Autopsy (208 genes) and bicuspid aortic valve (8 genes). Whole clinical exome analysis (6110 genes) with phenotypic prioritisation of variants based on HPO terminology using Exomiser can also be performed for patients with complex phenotypes whose phenotype does not clearly fit into a pre-defined gene panel or for patients who tested negative for a specific panel. 133 patients have been tested, including newly diagnosed cardiac cases, patients negative for other cardiac gene testing, and patients who have phenotype/genotype incompatibility where contribution of more than one gene is suspected. 41/133 (30%) patients have at least one potentially pathogenic variant. 22 patients have multiple plausible variants. We present data from the cardiac cohort tested to date and cases illustrating the utility and complexity of gene panel testing for cardiac disease including; 1) A paediatric patient with Left Ventricular Non-Compaction (LVNC), dilated aortic root and sinus brachycardia heterozygous (on the PC 71 gene panel) for a novel TMEM43 variant c.994A>G, p.(Thr332Ala) of unknown clinical significance. Further testing using a bespoke 138 gene cardiac panel from the Focused Exome detected a novel splice variant in the HCN4 gene associated with LVNC and primary sinus brachycardia (Milano et al , 2014). This patient’s mother who has aortic dilation and regurgitation was heterozygous for the TMEM43 variant and the half-brother who also has dilated aortic root and LVNC did not carry either variant. 2) A large Dilated Cardiomyopathy (DCM) family with variable severity between family members, one affected cousin was heterozygous for a variant of uncertain significance in MYBPC3 c.3384G>C, p.(Glu1128Asp) and another affected cousin heterozygous for a truncating TTN variant, c.89244del, p.(Phe29748Leufs*7). Further family studies are ongoing. Detailed phenotypic assessment (using a clinical proforma) has been shown to increase diagnostic yield in patients with complex cardiac disease. Reference Milano et al. J Am Coll Cardiol 2014;64(8):745–56

Erratum to: J Inherit Metab Dis (2015) 38:279–286 DOI 10.1007/s10545-014-9747-y The original version of this article unfortunately contained a mistake. The reference by Whited is incomplete. The corrected reference is: Whited K, Baile MG, Currier P, Claypool SM (2013) Seven functional classes of Barth syndrome mutation. Human Molecular Genetics 22:483–492.

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, a MYBPC3 variant c.1505G >A, p.(Arg502Gln) and a previously reported NEBL 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.