Abstract
Marfan syndrome (MFS) is a hereditary connective tissue disease caused by heterozygous mutations in the fibrillin-1 gene (FBN1) located on chromosome 15q21.1. A complex chromosomal rearrangement leading to MFS has only been reported in one case so far. We report on a mother and daughter with marfanoid habitus and no pathogenic variant in the FBN1 gene after next generation sequencing (NGS) analysis, both showing a cytogenetically reciprocal balanced translocation between chromosomes 2 and 15. By means of fluorescence in situ hybridization of Bacterial artificial chromosome (BAC) clones from the breakpoint area on chromosome 15 the breakpoint was narrowed down to a region of approximately 110 kb in FBN1. With the help of optical genome mapping (OGM), the translocation breakpoints were further refined on chromosomes 2 and 15. Sequencing of the regions affected by the translocation identified the breakpoint of chromosome 2 as well as the breakpoint of chromosome 15 in the FBN1 gene leading to its disruption. To our knowledge, this is the first report of patients with typical clinical features of MFS showing a cytogenetically reciprocal translocation involving the FBN1 gene. Our case highlights the importance of structural genome variants as an underlying cause of monogenic diseases and the useful clinical application of OGM in the elucidation of structural variants.
Highlights
Marfan syndrome (MFS) as an autosomal-dominant disorder is the most common hereditary connective tissue disease, with a defect in the synthesis of microfibrils caused by heterozygous pathogenic variants in the fibrillin-1 gene (FBN1) located on chromosome15q21.1 [1]
For next generation sequencing (NGS) panel diagnostics DNA sequences were enriched by a SureSelect Custom Kit (Agilent Technologies, Inc., Santa Clara, CA, USA)
We report on a mother and daughter with clinical features of connective tissue disorder from the Marfan syndrome spectrum
Summary
Marfan syndrome (MFS) as an autosomal-dominant disorder is the most common hereditary connective tissue disease, with a defect in the synthesis of microfibrils caused by heterozygous pathogenic variants in the fibrillin-1 gene (FBN1) located on chromosome15q21.1 [1]. Marfan syndrome (MFS) as an autosomal-dominant disorder is the most common hereditary connective tissue disease, with a defect in the synthesis of microfibrils caused by heterozygous pathogenic variants in the fibrillin-1 gene (FBN1) located on chromosome. Pathogenic FBN1 variants lead to a disruption in the incorporation of the microfibrils into the extracellular matrix. This can affect different organ systems such as the cardiovascular system, eyes, and skeleton [2]. The clinical diagnosis of MFS is based on the 2010 revision of the Ghent nosology criteria by fulfilling at least two of the following four criteria: FBN1 mutation, lens dislocation, aorta root widening or aortic root dissection, and clinical score. In absence of either one of these two, the presence of an FBN1 mutation or a combination of systemic manifestations contributing to a systemic score ≥ 7 points is necessary [3]
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