Idiopathic Restrictive Cardiomyopathy in Children is Caused by Mutations in Cardiac Sarcomere Protein Genes

Juan Pablo Kaski ¹, Petros Syrris ², Michael Burch ³, Maria-Teresa Tome-Esteban ³, Matthew Fenton ³, Michael Christiansen ⁴, Paal S Andersen ⁴, Neil Sebire ³, Michael Ashworth ³, John E Deanfield ³, William J McKenna ³ and Perry M Elliott ^3*

¹ Institute of Child Health, United Kingdom
² University College London, United Kingdom
³ Great Ormond Street Hospital, United Kingdom
⁴ Statens Serum Institut, Denmark

^* To whom correspondence should be addressed. E-mail: pelliott{at}doctors.org.uk.

Accepted 15 April 2008

Abstract

Aim To determine the prevalence of sarcomere protein gene mutations in children with idiopathic restrictive cardiomyopathy (RCM).

Background RCM is rare in childhood, but has a grave prognosis. The cause of disease in most cases is unknown.

Methods Twelve patients (9 females, mean age 5.1 years) with idiopathic RCM referred between 1991 and August 2006 underwent detailed clinical and genetic evaluation. Nine had received cardiac transplants at the time of the study. The entire coding sequences of the genes encoding eight cardiac sarcomere proteins and desmin were screened for mutations. Familial evaluation was performed on first-degree relatives.

Results Four patients (33%) had a family history of cardiomyopathy: RCM (n=2); dilated cardiomyopathy (n=1); and left ventricular noncompaction (n=1). Sarcomere protein gene mutations were identified in four patients (33%): 2 in the cardiac troponin I gene (TNNI3) and 1 each in the troponin T (TNNT2) and -cardiac actin (ACTC) genes. Two were de novo mutations and 3 were novel mutations. All mutations occurred in functionally important and conserved regions of the genes.

Conclusions Sarcomere protein gene mutations are an important cause of idiopathic RCM in childhood. We describe the first mutation in ACTC in familial RCM. The identification of RCM in a child should prompt consideration of sarcomere protein disease as a possible cause and warrants clinical evaluation of the family.