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Abstract

Background hypertrophic Cardiomayopathy is an inherited heart muscle disease with considerable heterogeneity at genetic and phenotypic levels and poor correlation between genotype and phenotype. Next generation sequencing could help in addressing this problem. Subjects and Methods The present study involved 144 unrelated consecutive index HCM patients enrolled in the BA HCM National Program in Egypt subjected to large scale high throughput targeted next generation of coding and exon flanking regions of over 100 genes involved in inherited cardiac conditions (ICC) including genes with a known role in HCM (Illumina HiSeq) Results Putative pathogenic variants were detected in 67 samples (67/144, 46%), mostly found in sarcomeric genes in the order of: MYBPC3 (38.8%), followed by MYH7 (33%), MYL3 (9%), TNNT2 (4.5%), TNNI3 (in 2 samples). TNNC1, MYLK2 and TPM1, ACTN2, TCAP, PLN, ACTN2, MYH6 showed a potentially pathogenic in 1 patient, each. Validation was performed by Sanger sequencing. Twenty six variants were novel (26/144, 18%) and were not found in any of the control series and by in silico analysis were scored as potentially pathogenic, hence were considered as variants of unknown significance and should be tested for coseggregation. An approximate of 10% (14/144) of the samples revealed likely pathogenic variants in genes not commonly known to be linked to HCM. Complex heterozygosity involving sarcomeric and non sarcomeric genes particularly ion channel genes was observed in almost a quarter of the samples in the present cohort (35/144, 24%), and homozygousity was found in nine patients(9/67, 9%). This could provide an explanation to the heterogeneity of the phenotype observed amongst different members within the same family and among unrelated patients having the same sarcomeric mutation. The studied cohort involved six HCM phenocopies 3 had mutations in PTPN11 and two cases had novel possibly pathogenic variants in RAF1. One Fabry case with a reported pathogenic mutation in GLA gene. Conclusion High throughput NGS has enabled detection of possibly/likely pathogenic variants in over 60% of samples studied. The detection of homozygous patients and complex heterozygosity in almost a quarter of the HCM patients provides a possible explanation to the phenotype heterogeneity observed in HCM.

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/content/papers/10.5339/qfarc.2014.HBPP0650
2014-11-18
2019-12-12
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