Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome

Pauline Arnaud (1, 2) , Nadine Hanna (1, 2) , Mélodie Aubart (2) , Bruno Leheup (3) , Sophie Dupuis-Girod (4) , Sophie Naudion (5) , Didier Lacombe (5) , Olivier Milleron (1) , Sylvie Odent (6) , Laurence Faivre (7) , Laurence Bal (8) , Thomas Edouard (9) , Gwenaëlle Collod-Béroud (10) , Maud Langeois (1) , Myrtille Spentchian (1) , Laurent Gouya (1) , Guillaume Jondeau (2, 1) , Catherine Boileau (2, 1)

1 CRMR Marfan - Centre de Référence Maladies Rares Syndrome de Marfan et Maladies Apparentées [AP-HP]
2 LVTS (UMR_S_1148 / U1148) - Laboratoire de Recherche Vasculaire Translationnelle
3 Service de Génétique Clinique Pédiatrique [CHRU Nancy]
4 Service de Génétique Clinique, Hôpital Femme Mère Enfant
5 Service de Génétique Médicale du CHU de Bordeaux
6 Service de génétique clinique [Rennes]
7 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
8 TIMONE - Hôpital de la Timone [CHU - APHM]
9 Service Cardiologie pédiatrique [CHU Toulouse]
10 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques

Background Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. Objectives Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. Methods and results In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. Conclusion Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.

Mots clés: FBN1 gene; Genetic heterogeneity; Homozygosity; Marfan syndrome

Domaines: Génétique humaine; Biologie moléculaire; Cardiologie et système cardiovasculaire

Pauline Arnaud, Nadine Hanna, Mélodie Aubart, Bruno Leheup, Sophie Dupuis-Girod, et al.. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome. Journal of Medical Genetics, 2017, 54 (2), pp.100 - 103. ⟨10.1136/jmedgenet-2016-103996⟩. ⟨hal-01670201⟩