Abstract 16937: Age at Genetic Testing is Negatively Correlated with the Number of Mutations Found in Five Cardiac Channelopathies and Cardiomyopathies
INTRODUCTION: Although dominantly inherited diseases are defined as being caused by a single mutant gene copy, other factors can affect disease expression. Here we examined the relationship between mutation count and age at genetic testing across five autosomal dominant cardiac diseases.
METHODS: We examined data for 2596 probands referred for genetic testing for arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), hypertrophic cardiomyopathy (HCM), or long QT syndrome (LQTS). Age at testing was used as a clinical correlate of age of onset. Mutations were categorized as either class I (definite or probable pathogenic) or class II (variant of uncertain significance).
RESULTS: Among mutation-positive patients, 12% had two mutations and 1% had three; these two percentages were similar across all diseases, although the overall positive rate varied considerably. In all five diseases, age at testing was lower for positive than negative probands, and even lower for those with two mutations. In three out of the four diseases where at least one patient had three mutations, those patients were even younger. While differing by disease, the average age drop from 0 mutations to 1 was 3.5 years (p=0.00013) and from 1 mutation to 2 was 5.2 years (p=0.012). The patterns held when restricting to either class I or II mutations.
CONCLUSIONS: This study found a remarkable 12% multiple-hit rate across five so-called autosomal dominant diseases and identified a correlation between mutation count and age at testing. This correlation may have multiple explanations: First, each mutation may contribute to disease severity or onset. Second, “more mutations” may reflect a higher probability that at least one is deleterious and that the patient indeed has the disease. Overall, the results point to a complexity that must continue to be explored as science and medicine grapple with the genetics of disease.
- © 2011 by American Heart Association, Inc.