Homozygous mutation of MYBPC3 associated with severe infantile hypertrophic cardiomyopathy at high frequency amongst the Amish

Kenneth Zahka ¹, Kamini Kalidas ², Michael A Simpson ², Harold Cross ³, Bradley Keller ⁴, Csaba Galambos ⁴, Kay Gurtz ⁵, Michael A Patton ² and Andrew H Crosby ^2*

¹ Rainbow Babies and Children's Hospital, Case Western Reserve University, United States
² St George's University of London, United Kingdom
³ University of Arizona School of Medicine, United States
⁴ Children's Hospital of Pittsburgh of UPMC, United States
⁵ Windows of Hope Genetic Studies, United States

^* To whom correspondence should be addressed. E-mail: acrosby{at}sgul.ac.uk.

Accepted 8 April 2008

Abstract

Background Familial hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death amongst young and apparently healthy individuals. Mutations within genes encoding sarcomeric proteins have so far been defined and act in an autosomal dominant fashion. We have identified an autosomal recessive form of HCM within a group of Amish children that is associated with very poor prognosis and death within the 1st year of life. Affected patients experienced progressive cardiac failure despite maximal medical therapy. Post-mortem histology revealed myofiber disarray and myocyte loss consistent with refractory clinical deterioration in affected infants.

Methods and results Assuming that a founder mutation was responsible we conducted a genome-wide screen for linkage and identified an autozygous region of chromosome 11 which cosegregates with the infant cardiac phenotype. This region contained the MYBPC3 gene, which has previously been associated with autosomal dominant adult onset HCM. Sequence analysis of the MYBPC3 gene identified a splice site mutation in intron 30 which was homozygous in all affected infants. All surviving patients with the homozygous MYBPC3 gene mutations (3330+2T>G) have been treated by orthotopic heart transplantation.

Conclusions We define homozygous mutations in the MYBPC3 gene as the cause of severe infantile hypertophic cardiomyopathy amongst the Amish.