Pathogenic variants affecting the TB5 domain of the fibrillin-1 protein: not only in geleophysic/acromicric dysplasias but also in Marfan syndrome

Abstract

Background: Marfan syndrome (MFS) is a multisystem disease with a unique combination of skeletal, cardiovascular and ocular features. Geleophysic/acromicric dysplasias (GPHYSD/ACMICD), characterised by short stature and extremities, are described as 'the mirror image' of MFS. The numerous FBN1 pathogenic variants identified in MFS are located all along the gene and lead to the same final pathogenic sequence. Conversely, in GPHYSD/ACMICD, the 28 known heterozygous FBN1 pathogenic variants all affect exons 41-42 encoding TGFβ-binding protein-like domain 5 (TB5).

Methods: Since 1996, more than 5000 consecutive probands have been referred nationwide to our laboratory for molecular diagnosis of suspected MFS.

Results: We identified five MFS probands carrying distinct heterozygous pathogenic in-frame variants affecting the TB5 domain of FBN1. The clinical data showed that the probands displayed a classical form of MFS. Strikingly, one missense variant affects an amino acid that was previously involved in GPHYSD.

Conclusion: Surprisingly, pathogenic variants in the TB5 domain of FBN1 can lead to two opposite phenotypes: GPHYSD/ACMICD and MFS, suggesting the existence of different pathogenic sequences with the involvement of tissue specificity. Further functional studies are ongoing to determine the precise role of this domain in the physiopathology of each disease.

Keywords: Cardiovascular Diseases; Diagnosis; Genetic Diseases, Inborn; Musculoskeletal Diseases.

Figure 1

Schematic representation of the variants identified in TB5 domain in fibrillin-1 protein. Cysteine residues are shown in yellow, with disulfide bonds illustrated as yellow lines. Residues in purple correspond to highly conserved residues in human TB domains (conserved in at least four out of seven TB domains in fibrillin-1). Pathogenic variants previously reported in Weill-Marchesani syndrome are shown in blue, pathogenic variants previously reported in geleophysic dysplasia or acromicric dysplasia are shown in grey. Missense variants from this report associated with MFS are shown in red. In-frame deletions from this report associated with MFS are shown in green. The figure was adapted from Robertson et al.

Figure 2

Protein structure predictions of the variants impacting p.Cys1719 and p.Cys1721 residues. (A) Using NovaFold AI, protein structure predictions were obtained using the WT cb-EGF-like 14/TB5/cb-EGF-like 15 peptidic sequences (FBN1 WT), introducing the variations, respectively, leading to MFS (FBN1 MFS–p.(Cys1719Tyr)), GPHYSD [FBN1 GPHYSD-1–p.(Cys1719Trp); and FBN1 GPHYSD-2: p.(Cys1721Gly)] and WMS (FBN1 WMS–p.(Cys1721Ser)). (B) Karplus-Schulz flexibility plot, depicting the rigidity of a residue, was obtained using the corresponding protein structure predictions. A zoom on the differences is shown at the bottom right of the graph. The substitutions occur at the 67^th and 69^th residues (see supplementary data for peptidic sequences used).