Genetic testing in patients with aortic aneurysms/dissections: a novel genotype/phenotype correlation?
OBJECTIVE
Mutations in the genes encoding fibrillin-1 (FBN1) and transforming growth factor beta receptor type II (TGFBR2) are known causes of Marfan syndrome (MFS) and related disorders. However, a sound correlation between the genotype and the cardiovascular phenotype has not yet been established. The objective of the present study was to identify novel mutations in FBN1 and TGFBR2 and to assess whether the type of mutation is linked to a particular clinical subtype of the cardiovascular condition.


METHODS
The clinical records of 36 patients referred to us for molecular genetic diagnosis were reviewed to assess the course and severity of the vascular deterioration. A semiautomatic protocol was established enabling a rapid and cost-effective screening of the genes FBN1 and TGFBR2 by direct sequencing of all coding exons and flanking intronic regions.


RESULTS
Novel mutations in FBN1 and TGFBR2 were detected in 12 and 2 patients, respectively. Four individuals carried a recurrent mutation in FBN1. Throughout the study cohort, the incidence of aortic dissections per se did not depend on the type of mutation. However, we found that mutations affecting the calcium-binding epidermal growth factor-like domain were more frequently associated with a dissection of distal parts of the aorta than mutations that lead to a premature termination codon (chi(1)(2): p=0.013), suggesting that the spatio-temporal pattern of vascular deterioration may vary with the type of mutation.


CONCLUSIONS
Detecting a mutation in the genes FBN1 and TGFBR2 proves the genetic origin of vascular findings and allows the identification of family members at risk who should undergo preventive checkups. Routine genetic testing of patients with suspected MFS or thoracic aortic aneurysms/dissections could provide further insight into genotype/phenotype correlations related to aortic dissection.
Waldmüller
Stephan
S
Institure for Heart and Curculation Research, University of Witten/Herdecke, Heinstueck 11, D-44225 Dortmund, Germany. waldmueller@herz-kreislaufforschung.de
Müller
Melanie
M
Warnecke
Henning
H
Rees
Wolfgang
W
Schöls
Wolfgang
W
Walterbusch
Gerhard
G
Ennker
Jürgen
J
Scheffold
Thomas
T
D000293:Adolescent; D000328:Adult; D000784:Aortic Dissection / Q000235:genetics* / Q000601:surgery; D001011:Aorta / Q000601:surgery; D001014:Aortic Aneurysm / Q000235:genetics* / Q000601:surgery; D002135:Calcium-Binding Proteins / Q000235:genetics; D015331:Cohort Studies; D004815:Epidermal Growth Factor / Q000235:genetics; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005838:Genotype; D006351:Heart Valves / Q000601:surgery; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000150:complications / Q000235:genetics / Q000601:surgery; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010865:Pilot Projects; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D054392:Adipokines
D002135:Calcium-Binding Proteins; D004815:Epidermal Growth Factor; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines