The clinical spectrum of complete FBN1 allele deletions

Abstract

The most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations. There are only a few reports of patients with marfanoid features and a molecularly proven complete deletion of a FBN1 allele. We describe the clinical features of 10 patients with a complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome.

Figure 1

Pedigree of the family with five members carrying a complete deletion of a FBN1 allele. Del –, no deletion present; del +, deletion present.

Figure 2

MLPA results of FBN1 in mother and daughter (patient 2) compared with healthy control (MLPA kit P065, MRC-Holland). The control probes are normalized to two copies. The probe signals for FBN1 relative to control probes and TGFBR2 probes show a single copy for FBN1 in patient 2. All other patients discussed in this paper show MLPA results comparable with patient 2. The healthy mother of patient 2 has reduced probe signals for all FBN1 probes, indicative of somatic mosaicism for the deletion. The mean (±SD) signals for all FBN1 probes were: 1.93±0.08 (control), 1.08±0.08 (case 2) and 1.71±0.05 (mosaic mother; P<10⁻¹⁵ compared with control, according to a two-tailed t-test). The color reproduction of this figure is available on the html full text version of the manuscript.

Figure 3

Position of the deletions on chromosome 15 (Ensemble release 53, March 2009) including the deletion described by Faivre et al The red bars underneath the chromosome depict the known protein-coding genes according to Ensemble release 53, March 2009. The names of the genes are written below. The horizontal colored lines show the size of the different deletions and their overlap. The color reproduction of this figure is available on the html full text version of the manuscript.