Autosomal dominant Marfan syndrome caused by a previously reported recessive FBN1 variant

• Published in: Molecular genetics & genomic medicine Vol. 7; no. 2; pp. e00518 - n/a
• Main Authors: Overwater, Eline, Efrat, Rifka, Barge‐Schaapveld, Daniela Q. C. M., Lakeman, Phillis, Weiss, Marjan M., Maugeri, Alessandra, van Tintelen, J. Peter, Houweling, Arjan C.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.02.2019; John Wiley and Sons Inc
• Subjects: abdominal aortic aneurysm; Adult; Aneurysms; Aortic aneurysms; autosomal dominant inheritance; autosomal recessive inheritance; clinical heterogeneity; FBN1; Female; Fibrillin-1 - genetics; Genes, Dominant; Humans; Male; Marfan syndrome; Marfan Syndrome - genetics; Marfan Syndrome - pathology; Middle Aged; Mutation, Missense; Original; Pedigree; Phenotype; Phenotypes; clinical heterogeneity; autosomal recessive inheritance; Marfan syndrome; abdominal aortic aneurysm; autosomal dominant inheritance; FBN1
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.518

Background Pathogenic variants in FBN1 cause autosomal dominant Marfan syndrome but can also be found in patients presenting with apparently isolated features of Marfan syndrome. Moreover, several families with autosomal recessive Marfan syndrome caused by pathogenic variants in FBN1 have been described. The aim of this report was to underline the clinical variability that can be associated with the pathogenic variant c.1453C>T, p.(Arg485Cys) in FBN1. Methods We provide the clinical details of two autosomal dominant families with this specific FBN1 variant, which was previously associated with autosomal recessive Marfan syndrome. Results Clinical data of 14 individuals carrying this variant from these two families were collected retrospectively. In both families, the diagnosis of autosomal dominant Marfan syndrome was established based on the characteristics of the variant and the phenotype which includes aortic aneurysms and dissections. Of interest, in one of the families, multiple relatives were diagnosed with early onset abdominal aortic aneurysms. Conclusion In conclusion, FBN1 variant c.1453C>T, p.(Arg485Cys) is a pathogenic variant that can cause autosomal dominant Marfan syndrome characterized by a high degree of clinical variability and apparently isolated early onset familial abdominal aortic aneurysms. This study corroborates the high degree of clinical variability associated with variants in FBN1 and provides novel insights into the pattern of inheritance of FBN1 variant c.1453C>T, p.(Arg485Cys). Homozygosity for this variant was previously reported to cause autosomal recessive Marfan syndrome (MFS) in a consanguineous family. As illustrated by these two pedigrees, we provide the clinical details of two autosomal dominant families with MFS with this specific FBN1 variant.