Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation.
Mutations in the FBN1 gene cause Marfan syndrome (MFS) and a wide range of overlapping phenotypes. The severe end of the spectrum is represented by neonatal MFS, the vast majority of probands carrying a mutation within exons 24-32. We previously showed that a mutation in exons 24-32 is predictive of a severe cardiovascular phenotype even in non-neonatal cases, and that mutations leading to premature truncation codons are under-represented in this region. To describe patients carrying a mutation in this so-called 'neonatal' region, we studied the clinical and molecular characteristics of 198 probands with a mutation in exons 24-32 from a series of 1013 probands with a FBN1 mutation (20%). When comparing patients with mutations leading to a premature termination codon (PTC) within exons 24-32 to patients with an in-frame mutation within the same region, a significantly higher probability of developing ectopia lentis and mitral insufficiency were found in the second group. Patients with a PTC within exons 24-32 rarely displayed a neonatal or severe MFS presentation. We also found a higher probability of neonatal presentations associated with exon 25 mutations, as well as a higher probability of cardiovascular manifestations. A high phenotypic heterogeneity could be described for recurrent mutations, ranging from neonatal to classical MFS phenotype. In conclusion, even if the exons 24-32 location appears as a major cause of the severity of the phenotype in patients with a mutation in this region, other factors such as the type of mutation or modifier genes might also be relevant.
Faivre
L
L
Centre de Génétique, CHU, Dijon, France. laurence.faivre@chu-dijon.fr
Collod-Beroud
G
G
Callewaert
B
B
Child
A
A
Binquet
C
C
Gautier
E
E
Loeys
B L
BL
Arbustini
E
E
Mayer
K
K
Arslan-Kirchner
M
M
Stheneur
C
C
Kiotsekoglou
A
A
Comeglio
P
P
Marziliano
N
N
Wolf
J E
JE
Bouchot
O
O
Khau-Van-Kien
P
P
Beroud
C
C
Claustres
M
M
Bonithon-Kopp
C
C
Robinson
P N
PN
Adès
L
L
De Backer
J
J
Coucke
P
P
Francke
U
U
De Paepe
A
A
Jondeau
G
G
Boileau
C
C
D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004479:Ectopia Lentis / Q000235:genetics; D005091:Exons / Q000235:genetics*; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D008382:Marfan Syndrome / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D054392:Adipokines
D018389:Codon, Nonsense; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines