POSTER NO: 470

Haemochromatosis Gene Mutations in Familial Hypertrophic Cardiomyopathy (FHC)

¹Bing Yu, ¹Indira Taylor, ²Jeremy Richmond, ²David Richmond, ¹Ronald J. Trent
¹Dept. of Molecular and Clinical Genetics, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia, ²Dept. of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia

FHC is a common autosomal dominant disorder, characterised by left ventricular hypertrophy and myocyte disarray. The phenotype in affected individuals can range from asymptomatic to sudden death as the first presenting symptom. FHC is considered a 'disease of the sarcomere' since > 140 mutations have been reported in 9 genes coding for cardiac contractile proteins. However, the development of myocardial hypertrophy and/or sudden death in FHC is likely to represent a complex process involving the interaction of other modifying genes and/or the environment. Mutations in the HFE cause haemochromatosis, and so this gene becomes a potential modifier in FHC. The 2 common mutations in HFE include C282Y and H63D and these are found in populations of North European background. Subjects with one or more mutant alleles have significantly higher mean serum or tissue iron contents. Although the liver assumes the main iron burden, cardiac myocytes, especially in the ventricles, will become iron loaded with time. The potential for iron overload to cause hypertrophy is demonstrated in Friedrich's ataxia. In this disorder there is mitochondrial iron overload due to dysfunction of the frataxin gene, and hypertrophic cardiomyopathy is its major non-neurological sign. The severity of the latter relates to the length of the GAA triplet repeat. Excessive cellular iron molecules can also significantly enhance the generation of reactive oxygen species, which could act as signalling molecules for hypertrophic response and modulated cardiac hypertrophy. Hence, we studied HFE mutations in 152 Caucasian FHC index cases and compared them with 298 Caucasian controls. Six genotypes (CCHH, CCHD, CCDD, CYHH, CYHD and YYHH) and four genotypes (CCHH, CCHD, CYHH and CYHD) were found in the control and case groups respectively, but there was no statistical difference between the two groups. The allele frequencies for the mutant Y and D alleles in the control group were 6.2% and 16.4%; and in case group 7.0% and 10.5% respectively (P > 0.05). However, the frequencies of CY genotypes and Y allele were significantly increased in female index cases (23.6% and 11.8%) in comparison with female controls (7.8% and 4.8%) (P = 0.014 and P = 0.027, respectively). The thickness of the left ventricular wall was not different between female index cases with the Y allele and those without the Y allele. But the former group tended to be older since 8 of 13 female index cases carrying the Y allele came to clinical attention at post-menopausal ages. Among 152 index cases, there were 18 cases involving sudden cardiac death. These were significantly younger than other index cases (26.1 ± 14.9 vs. 45.6 ± 17.4, P < 0.001). Since iron deposition can be pro-arrhythmic, and left ventricular dysfunction due to iron overload can predispose to ventricular arrhythmia, we compared the frequency of HFE mutations. However, this was an unlikely association as there were no significant differences in the distribution of various HFE genotypes or alleles in those with sudden death and the control group. In conclusion, the 2 common HFE mutations C282Y and H63D are unlikely to be a major genetic modifier in FHC, including the complication of sudden cardiac death. On the other hand, in females, CY genotypes or the Y allele appears to contribute to the FHC phenotype, especially in post-menopausal women.