A new mutational mechanism for hypertrophic cardiomyopathy |
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Authors: | Laura Pezzoli Maria Elena Sana Paolo Ferrazzi Maria Iascone |
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Affiliation: | USSD Laboratorio Genetica Medica, Ospedali Riuniti, Bergamo, Italy. |
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Abstract: | We describe a male patient affected by hypertrophic cardiomyopathy (HCM) with no point mutations in the eight sarcomeric genes most commonly involved in the disease. By multiple ligation-dependent probe amplification (MLPA) we have identified a multi-exons C-terminus deletion in the cardiac myosin binding protein C (MYBPC3) gene. The rearrangement has been confirmed by long PCR and breakpoints have been defined by sequencing. The 3.5kb terminal deletion is mediated by Alu-repeat elements and is predicted to result in haploinsufficiency of MYBPC3. To exclude the presence of other rare pathogenic variants in additional HCM genes, we performed targeted next-generation sequencing (NGS) of 88 cardiomyopathy-associated genes but we did not identify any further mutation. Interestingly, the MYBPC3 multi-exons deletion was detectable by NGS. This finding broadens the range of mutational spectrum observed in HCM, contributing to understanding the genetic basis of the most common inherited cardiovascular disease. Moreover, our data suggest that NGS may represent a new tool to achieve a deeper insight into molecular basis of complex diseases, allowing to detect in a single experiment both point mutations and gene rearrangements. |
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Keywords: | 1KGP, 1000 Genomes Project ACTC1, cardiac actin Bp, basepair(s) BWA, Burrows–Wheeler aligner ESP, exome sequencing project Fs, frameshift GAMES, genomic analysis of mutations. extracted by sequencing Gln, glutamine GRCh37/hg19, genome reference consortium human genome build 37/human genome UCSC version 19 HCM, hypertrophic cardiomyopathy HGMD, human gene mutation database HSF, human splicing finder IGV, integrative genomics viewer INDEL, insertion–deletion kb, kilobase MADD, MAP kinase-activating death domain MAF, minor allele frequence MLPA, multiplex ligation-dependent probe amplification MYBPC3, cardiac myosin-binding protein C MYH7, cardiac β-myosin heavy chain MYL2, myosin light chain regulatory MYL3, myosin light chain essential NGS, next-generation sequencing OMIM, online Mendelian inheritance in man PCR, polymerase chain reaction PolyPhen-2, polymorphism phenotyping v2 Pro, proline RefSeq, reference sequence ROI, region of interest SIFT, sorts intolerant from tolerant TNNI3, cardiac troponin I TNNT2, cardiac troponin T TPM1, alpha tropomyosin UCSC, University of California Santa Cruz UTR, untranslated region |
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