GENOTYPE-PHENOTYPE CORRELATION IN PATIENTS WITH FIBRILLIN-1 GENE MUTATIONS

摘要

Fibrillin-1 (FBN1) gene mutations are clinically associated with the Marfan syndrome (MFS), an autosomal dominant connective tissue disorder with prominent clinical manifestations in the cardiovascular, musculoskeletal and ocular system. Data of molecular genetic analysis and a catalogue of clinical symptoms were mined in order to discover novel correlations between MFS's genotype and phenotype using hierarchical cluster analysis and logistic regression analysis. A score measure describing the similarity between a patient's clinical symptoms and a characteristic phenotype was introduced. Four different phenotype classes were clustered in patients with classic or suspected MFS. A probabilistic model built on clinical symptoms was established to predict the presence of a FBN1 missense mutation. Highest correlation between a missense mutation, which manifested as ectopia lentis, skeletal major and skin minor criteria, and two out of four clustered phenotypes was found. The probability for the presence of a missense mutation in both phenotype classes is approximately 70%. Genotype-phenotype correlation between FBN1 gene mutations and clinical manifestations may contribute to anticipate the clinical consequences of specific mutations more comprehensively and may be helpful to identify and treat at-risk patients at an early stage of disease.