This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ho, C. Y. Articles by MacRae, C. A. Search for Related Content PubMed Articles by Ho, C. Y. Articles by MacRae, C. A. Related Collections Genomics Related Article

Editorials

Defining the Pathogenicity of DNA Sequence Variation

Carolyn Y. Ho, MD and Calum A. MacRae, MD, PhD

From the Cardiovascular Division (C.Y.H.), Brigham and Women’s Hospital, Boston, Mass; and the Cardiovascular Research Center and Cardiology Division (C.A.M.), Massachusetts General Hospital, Boston, Mass.

Correspondence to Calum A. MacRae, MD, PhD, Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. E-mail macrae@cvrc.mgh.harvard.edu

Key Words: genetics • pathogenicity • genetic testing

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
Understanding the relationship between genotype and phenotype remains one of the most challenging hurdles in human genetics, especially as efforts are made to translate genetic data into clinical prediction of disease or therapeutic outcomes.¹

	Mendelian Disorders

 
For many cardiac or vascular conditions in which the initial presentation may be fatal, a strong genotype–phenotype correlation is of fundamental importance if genetic diagnosis or prognostication is ever to be useful. Even in classic monogenic disorders, in which large effect sizes are observed, genetic prediction is often confounded by reduced penetrance, wide variation in the final phenotypes (pleiotropy), or sporadic phenocopies.² Although such trait "complexity" has been viewed largely in terms of environmental or genetic modifiers, such factors have proven difficult to identify. It is also possible that strong selection pressures against many cardiovascular traits may result in purely stochastic events playing a larger role in shaping phenotype.³ Rigorous genetic studies have identified many cardiovascular disease genes, leading to broader investigation in smaller families and individual probands. Although identifying variants in these same genes in unrelated individuals provides important confirmation and strengthens the initial data, the clinical significance of the numerous additional variants uncovered in subsequent resequencing efforts may be ambiguous.⁴ The level of support for these variants as disease causing is often much less robust than for the original discovery. As a result, rare (or not so rare) benign polymorphisms populate many mutation databases, often indistinguishable from pathogenic mutations.

Article see p 182

The interpretation of sequence data in the absence of relevant genetic . . . [Full Text of this Article]

Related Article

Multiple Mutations in Genetic Cardiovascular Disease: A Marker of Disease Severity?

Matthew Kelly and Christopher Semsarian
Circ Cardiovasc Genet 2009 2: 182-190. [Extract] [Full Text] [PDF]