Pathogenic variants affecting the TB5 domain of the fibrillin-1 protein: not only in geleophysic/acromicric dysplasias but also in Marfan syndrome.
J Med Genet
; 61(5): 469-476, 2024 Apr 19.
Article
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| MEDLINE
| ID: mdl-38458756
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 TGFß-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.Palabras clave
Texto completo:
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Enfermedades del Desarrollo Óseo
/
Deformidades Congénitas de las Extremidades
/
Síndrome de Marfan
Límite:
Humans
Idioma:
En
Revista:
J Med Genet
Año:
2024
Tipo del documento:
Article
País de afiliación:
Francia