A Novel Missense Mutation in the TGF-β-binding Protein-Like Domain 3 of FBN1 Causes Weill-Marchesani Syndrome with Intellectual Disability.

Background: Weill-Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by locus heterogeneity and variable expressivity. Patients suffering from WMS are described by short stature, brachydactyly, joint stiffness, congenital heart defects, and eye abnormalities. This disorder is inherited in two different modes; the autosomal dominant form of the disease occurs due to a mutation in FBN1, and the recessive form results from mutations in ADAMTS10, ADAMTS17, or LTP2 genes.

Materials and methods: The family recruited in this study was a consanguineous Iranian family with an intellectually disabled girl referred to the Sadra Genetics laboratory, Shahrekord, Iran. The clinical history of family members was investigated. Whole-Exome Sequencing (WES) for the proband was performed. Sanger sequencing was used to assess the segregation of candidate variants in the other family members.

Results: Whole-exome sequencing analysis revealed a novel heterozygote mutation in the proband located at the third TGF-β-binding protein-like (TB) domain of the FBN1 gene (NM000138: c.2066A>G: (p. Glu689Gly), NP_000129.3, in exon 17 of the gene). Co-segregation analysis with Sanger sequencing confirmed this mutation in the affected members of the pedigree.

Conclusion: Our findings represent an autosomal dominant form of specific WMS resulting from a substitution mutation in the FBN1 gene. In addition to the typical manifestations of the disorder, mild intellectual disability (ID) was identified in the 8-year-old proband. Given the fact that ID is primarily reported in ADAMTS10 mutated cases, this family was clinically and genetically a novel case.