CORRESPONDENCE: LETTERS TO THE EDITOR
Standard Mutation Nomenclature in Hypertrophic Cardiomyopathy: An Urgent Need
Manuel Hermida-Prieto, PhD*,
Rafael Laredo, PhD,
Lorenzo Monserrat, MD and
Alfonso Castro-Beiras, MD
* Instituto Universitario Ciencia de la Salud, Hospital Mar timo de Oza, As Xubias, 15006 A Coruña, Spain (Email: mhermidap{at}canalejo.org).
The report by Van Driest et al. (1) is the biggest population study published searching for mutations associated with hypertrophic cardiomyopathy (389 patients). This type of study is essential to uncover the genetic basis and molecular spectrum of such a complex disease.
However, we would like to call attention to two aspects that are usually forgotten in such studies and that might create confusion. First, Van Driest et al. (1) report 46 mutations in the MyBPC3 gene, including 33 claimed as "novel." But at least one of them, the K811del mutation, has been previously reported by Jaaskelainen et al. (2); thus, it is not correct to call it "novel." Moreover, the mutation W890X was reported in 2004 (3).
Second, it is mandatory to use an unequivocal and unified nomenclature system to identify the mutations. Nowadays there is a standard nomenclature system (4,5) that includes the mention of the reference sequence employed to numerate the residues, the position of the mutated nucleotide, and the affected amino acid within the protein.
None of the mutations reported by Van Driest et al. (1) follow the admitted nomenclature system, and because of this, in some cases it is not possible to identify the exact place where the mutation occurs. For example (Table 1, p. 1906 in their study), the SNPs 2, 23, 30, 34, and 35 cannot be positioned in the reference sequence (it seems to be the GI:2920822, even though it is not mentioned in the report) because the investigators only give the amino acid number, and never the nucleotide. The description of the nucleotide change in essential because the genetic code is degenerated.
Also, with the use of an equivocal nomenclature system, the same mutation may be reported in two or more different ways. We believe that Van Driest et al. consider as novel—because of a nomenclature error—mutations that have been previously described. For example, they refer the SNP 43 as "ins aa G1041fs"; in this case, it is impossible to determine where the muta-tion occurs, because the number of the nucleotide where aa is inserted is not given, but we believe it could correspond to g.20025_20026insAA T1042fs described by Niimura et al. (6). The same occurs with the SNPs 8 described by Erdmann et al. (7).
Finally, we have detected similar pitfalls in other published studies on cardiomyopathies. Because of this, we would like to see an increase in the quality of the genetic information published on cardiomyopathies by employing the standard mutations’ nomenclature.
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1. Van Driest SL, Vasile VC, Ommen SR, et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy J Am Coll Cardiol 2004;44:1903-1910.[Abstract/Free Full Text]
2. Jaaskelainen P, Kuusisto J, Miettinen R, et al. Mutations in the cardiac myosin-binding protein C gene are the predominant cause of familial hypertrophic cardiomyopathy in eastern Finland J Mol Med 2002;80:412-422.[CrossRef][Web of Science][Medline]
3. Genomics of cardiovascular development, adaptation, and remodeling. NHLBI Program for Genomic Applications, Harvard Medical School. Available at: http://www.cardiogenomics.org. Accessed February 2004..
4. den Dunnen JT, Antonarakis SE. Nomenclature for the description of human sequence variations Hum Genet 2001;109:121-124.[CrossRef][Web of Science][Medline]
5. den Dunnen JT, Paalman MH. Standardizing mutation nomenclaturewhy bother?. Hum Mutat 2003;22:181-182.[CrossRef][Medline]
6. Niimura H, Bachinski LL, Sangwatanaroj S, et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy N Engl J Med 1998;338:1248-1257.[Abstract/Free Full Text]
7. Erdmann J, Raible J, Maki-Abadi J, et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy J Am Coll Cardiol 2001;38:322-330.[Abstract/Free Full Text]
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