A Case Based Approach to Clinical Genetics of Thoracic Aortic Aneurysm/Dissection

Table 2

Revised Ghent criteria for Marfan syndrome diagnosis (modified from Loeys et al. 2010) [11].

In the absence of family history of MFS
(i) Aortic dilatation (-score ≥ 2) and Ectopia lentis = MFS
(ii) Aortic dilatation (-score ≥ 2) and FBN1 mutation = MFS
(iii) Aortic dilatation (-score ≥ 2) and systemic score ≥ 7 points (Table 3) = MFS
(iv) Ectopia lentis and  FBN1 mutation with known aortic dilatation^∧ = MFS
In the presence of family history of MFS
(i) Ectopia lentis and familial history of MFS = MFS
(ii) Systemic score ≥ 7 points (Table 3) and familial history of MFS = MFS
(iii) Aortic dilatation (-score ≥ 2 above 20 years old, ≥3 below 20 years) + familial history of MFS = MFS

: aortic diameter at the sinuses of valsalva above indicated -score or aortic root dissection.
FBN1 (fibrillin 1) mutation is defined according to the following criteria:
(i) Mutation previously shown to segregate in Marfan family.
(ii) De novo (with proven paternity and absence of disease in parents) mutation belonging to one of the five following categories:
() nonsense mutation,
() in frame and out of frame deletion/insertion,
() splice site mutations affecting canonical splice sequence or shown to alter splicing on mRNA/cDNA level,
() missense affecting/creating cysteine residues,
() missense affecting conserved residues of the EGF consensus sequence ((D/N)(D/N)(E/Q)(D/N)(Y/F) with and representing variable number of residues; D aspartic acid, N asparagine, E glutamic acid, Q glutamine, Y tyrosine, and F phenylalanine).
(iii) Other missense mutations: segregation in family if possible and absence in 400 ethnically matched control chromosomes, if no, family history absence in 400 ethnically matched control chromosomes.
(iv) Linkage of haplotype for meioses to the FBN1 locus.
FBN1 mutation that has been identified in an individual with aortic aneurysm.
Caveat: without discriminating features of Sphrintzen-Goldberg syndrome, Loeys-Dietz syndrome, or vascular form of Ehlers-Danlos syndrome and after TGFBR1/2, collagen biochemistry, and COL3A1 testing if indicated.