The clinical spectrum of missense mutations of the first aspartic acid of cbEGF-like domains in fibrillin-1 including a recessive family

Yvonne Hilhorst-Hofstee (1) , Marry Eb Rijlaarsdam (2) , Arthur Jha Scholte (3) , Marietta Swart-van den Berg (4) , Michel Im Versteegh (5) , Iris van Der Schoot-van Velzen (6) , Hans-Joachim Schäbitz (7) , Emilia Bijlsma (6) , Marieke J Baars (8) , Wilhelmina S. Kerstjens-Frederikse (9) , Jacques C Giltay (10) , Ben C Hamel (11) , Martijn H Breuning (6) , Gerard Pals (12)

1 Clinical Genetics
2 Pediatric Cardiology
3 Cardiology
4 Ophthalmology
5 Cardiothoracic surgery
6 Clinical Genetics
7 Allgemeinmedizin
8 Clinical Genetics
9 Medical Genetics
10 Medical Genetics
11 Human Genetics
12 Clinical Genetics

Marfan syndrome (MFS) is a dominant disorder with a recognizable phenotype. In most patients with the classical phenotype mutations are found in the fibrillin-1 gene (FBN1) on chromosome 15q21. It is thought that most mutations act in a dominant negative way or through haploinsufficiency. In 9 index cases referred for MFS we detected heterozygous missense mutations in FBN1 predicted to substitute the first aspartic acid of different calcium-binding Epidermal Growth Factor-like (cbEGF) fibrillin-1 domains. A similar mutation was found in homozygous state in 3 cases in a large consanguineous family. Heterozygous carriers of this mutation had no major skeletal, cardiovascular or ophthalmological features of MFS. In the literature 14 other heterozygous missense mutations are described leading to the substitution of the first aspartic acid of a cbEGF domain and resulting in a Marfan phenotype. Our data show that the phenotypic effect of aspartic acid substitutions in the first position of a cbEGF domain can range from asymptomatic to a severe neonatal phenotype. The recessive nature with reduced expression of FBN1 in one of the families suggests a threshold model combined with a mild functional defect of this specific mutation.

Mots clés: Life Sciences

Yvonne Hilhorst-Hofstee, Marry Eb Rijlaarsdam, Arthur Jha Scholte, Marietta Swart-van den Berg, Michel Im Versteegh, et al.. The clinical spectrum of missense mutations of the first aspartic acid of cbEGF-like domains in fibrillin-1 including a recessive family. Human Mutation, 2010, 31 (12), ⟨10.1002/humu.21372⟩. ⟨hal-00613753⟩