The Good SHP2 Association

Abstract

In this issue of the Journal, Goodship and colleagues report results from an association study for common genetic variants underlying tetralogy of Fallot (TOF).1 By studying a limited number of single-nucleotide polymorphisms (SNPs) tagging haplotypes at 22 candidate genes, they associated a single SNP at a chromosome 12 locus harboring PTPN11 , which encodes the protein tyrosine phosphatase SHP2, and other genes with TOF. This SNP was calculated to have a per-allele risk of 1.34 and a population-attributable risk of roughly 5%. If this study, undertaken with British white subjects, can be replicated in additional populations, it will represent a significant advance in our understanding of the genetics of congenital heart defects (CHD). Article see p 287 The genetic architecture of CHD has been the source of considerable debate and uncertainty. It has been known for some time that chromosomal defects and single-gene mutations can cause CHD, often in the context of a multisystem disease. For TOF, examples include trisomy 21 and TBX5 point mutations underlying Down and Holt-Oram syndromes, respectively.2 The discovery of 22q11 microdeletions, usually arising de novo, added significantly to our understanding of the genetic underpinnings of conotruncal forms of CHD, as these account for substantial percentages of some cardiac lesions (eg, 34% of truncus arteriosus and 16% of TOF).3 Nonetheless, these known genetic causes of CHD are estimated to account for less than 20% of cases overall. Epidemiological studies of CHD have strongly pointed to genetic factors as the predominant cause, although environmental exposures are also relevant. Parental consanguinity significantly increases the risk of CHD in offspring, probably as the result of the shared genetic background of unaffected parents.4 In countries where consanguineous marriages are customary, the rates of consanguinity are 2- to 3-fold higher among couples with offspring with CHD than …