TY - JOUR T1 - Homozygous and compound heterozygous mutations in the <em>FBN1</em> gene: unexpected findings in molecular diagnosis of Marfan syndrome JF - Journal of Medical Genetics JO - J Med Genet SP - 100 LP - 103 DO - 10.1136/jmedgenet-2016-103996 VL - 54 IS - 2 AU - Pauline Arnaud AU - Nadine Hanna AU - Mélodie Aubart AU - Bruno Leheup AU - Sophie Dupuis-Girod AU - Sophie Naudion AU - Didier Lacombe AU - Olivier Milleron AU - Sylvie Odent AU - Laurence Faivre AU - Laurence Bal AU - Thomas Edouard AU - Gwenaëlle Collod-Beroud AU - Maud Langeois AU - Myrtille Spentchian AU - Laurent Gouya AU - Guillaume Jondeau AU - Catherine Boileau Y1 - 2017/02/01 UR - http://jmg.bmj.com/content/54/2/100.abstract N2 - 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. ER -