Published Online
on July 16, 2009

A more recent version of this article appeared on October 1, 2009

This Article Full Text (PDF) All Versions of this Article: 2/5/436    most recent CIRCGENETICS.108.821314v1 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 Google Scholar Articles by Kaski, J. P. Articles by Elliott, P. M. PubMed Articles by Kaski, J. P. Articles by Elliott, P. M. Related Collections Clinical genetics Myocardial cardiomyopathy disease Pediatric and congenital heart disease, including cardiovascular surgery

Original Article

Prevalence of Sarcomere Protein Gene Mutations in Pre-Adolescent Children with Hypertrophic Cardiomyopathy

Juan Pablo Kaski^1,5; Petros Syrris²; Maria Teresa Tome Esteban³; Sharon Jenkins⁴; Antonios Pantazis⁴; John E. Deanfield²; William J. McKenna² and Perry M. Elliott²

¹ University College London & Great Ormond Street Hospital, London, United Kingdom;
² University College London, London, United Kingdom;
³ Great Ormond Street Hospital & University College London Hospitals, London, United Kingdom;
⁴ University College London Hospitals, London, United Kingdom

⁵ E-mail: j.kaski{at}ucl.ac.uk

Background—Hypertrophic cardiomyopathy (HCM) in infants and children is thought to be commonly associated with metabolic disorders and malformation syndromes. Familial disease caused by mutations in cardiac sarcomere protein genes, which accounts for most cases in adolescents and adults, is believed to be a very rare cause of HCM.

Methods and Results—Seventy-nine consecutive patients diagnosed with HCM aged 13 years underwent detailed clinical and genetic evaluation. The protein-coding sequences of 9 sarcomere protein genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC, and TNNC1) and the genes encoding desmin (DES) and the gamma-2 subunit of adenosine monophosphate kinase (PRKAG2) were screened for mutations. A family history of HCM was present in 48 patients (60.8%). Forty-seven mutations (15 novel) were identified in 42 (53.2%) patients (5 patients had two mutations). The genes most commonly implicated were MYH7 (48.9%) and MYBPC3 (36.2%); mutations in TNNT2, ACTC, MYL3 and TNNI3 accounted for less than 5% of cases each. 16.7% of patients with sarcomeric mutations were diagnosed before 1 year of age. There were no differences in clinical and echocardiographic features between those children with sarcomere protein gene mutations and those without, or between patients with two mutations and those with one or no mutations.

Conclusions—This study shows that familial disease is common among infants and children with HCM and that, in most cases, disease is caused by mutations in cardiac sarcomere protein genes. The major implication is that all first-degree relatives of any child diagnosed with HCM should be offered screening. Furthermore, the finding that one sixth of patients with sarcomeric disease were diagnosed in infancy suggests that current views on pathogenesis and natural history of familial HCM may have to be revised.

Key Words: cardiomyopathy • death, sudden (if surviving, use heart arrest) • genes • myocardial contraction • pediatrics