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A Common Variant in the PTPN11 Gene Contributes to the Risk of Tetralogy of Fallot

Lookup NU author(s): Professor Judith Goodship, Dr Darroch Hall, Dr Ana TopfORCiD, Valentina Mamasoula, Dr Helen GriffinORCiD, Dr Thahira Rahman, Dr Elise Glen, Angeline Tan, Addison Palomino Doza, Professor Caroline Relton, Professor Heather Cordell, Professor Bernard Keavney


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Background-Tetralogy of Fallot (TOF) is the commonest cyanotic form of congenital heart disease. In 80% of cases, TOF behaves as a complex genetic condition exhibiting significant heritability. As yet, no common genetic variants influencing TOF risk have been robustly identified. Methods and Results-Two hundred and seven haplotype-tagging single nucleotide polymorphisms in 22 candidate genes were genotyped in a test cohort comprising 362 nonsyndromic British white patients with TOF together with 717 unaffected parents of patients and 183 unrelated healthy controls. Single nucleotide polymorphisms with suggestive evidence of association in the test cohort (P < 0.01) were taken forward for genotyping in an independent replication cohort comprising 392 cases of TOF, 218 unaffected parents of patients, and 1319 controls. Significant association was observed for 1 single nucleotide polymorphism, rs11066320 in the PTPN11 gene, in both the test and the replication cohort. Genotype at rs11066320 was associated with a per-allele odds ratio of 1.34 (95% confidence interval [CI], 1.19 to 1.52; x 10(-6)) in the total cohort of TOF cases and controls; this remained highly significant after Bonferroni correction for 207 analyses (corrected P=0.00061). Genotype at rs11066320 was responsible for a population-attributable risk of TOF of approximately 10%. Conclusions-Common variation in the linkage disequilibrium block including the PTPN11 gene contributes to the risk of nonsyndromic TOF. Rare mutations in PTPN11 are known to cause the autosomal dominant condition Noonan syndrome, which includes congenital heart disease, by upregulating Ras/mitogen-activated protein kinase (MAPK) signaling. Our results suggest a role for milder perturbations in PTPN11 function in sporadic, nonsyndromic congenital heart disease. (Circ Cardiovasc Genet. 2012;5:287-292.)

Publication metadata

Author(s): Goodship JA, Hall D, Topf A, Mamasoula C, Griffin H, Rahman TJ, Glen E, Tan H, Doza JP, Relton CL, Bentham J, Bhattacharya S, Cosgrove C, Brook D, Granados-Riveron J, Bu'Lock FA, O'Sullivan J, Stuart AG, Parsons J, Cordell HJ, Keavney B

Publication type: Article

Publication status: Published

Journal: Circulation: Cardiovascular Genetics

Year: 2012

Volume: 5

Issue: 3

Pages: 287-292

Print publication date: 13/04/2012

ISSN (print): 1942-325X

ISSN (electronic): 1942-3268

Publisher: Lippincott Williams & Wilkins


DOI: 10.1161/CIRCGENETICS.111.962035


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Funder referenceFunder name
British Heart Foundation, Heart Research UK
085475Wellcome Trust
HEALTH-F2-2008-223040European Union's Seventh Framework Programme contract CHeartED