A population-based survey of FBN1 variants in Iceland reveals underdiagnosis Marfan syndrome

Abstract

Abstract Marfan syndrome is an autosomal dominant condition characterized by aortic aneurysm, skeletal abnormalities, and lens dislocation, and is caused by mutations in the FBN1 gene. To explore causes of Marfan syndrome and the prevalence in Iceland we collected samples and information from all living individuals with a clinical diagnosis of Marfan syndrome in Iceland (n = 35) and performed whole-genome sequencing of those who did not have a confirmed genetic diagnosis. Moreover, to assess a potential underdiagnosis of Marfan syndrome in Iceland we attempted a genotype-based approach for identifying individuals with Marfan syndrome. We interrogated deCODE genetics’ database of 35,712 whole-genome sequenced individuals to search for rare sequence variants in FBN1. Overall, we identified 15 pathogenic or likely pathogenic variants in FBN1 in 41 living individuals, only 22 of whom were previously diagnosed with Marfan syndrome. The most common of these variants, NM_000138.4:c.8038C > T (p.Arg2680Cys), is present in a multi-generational pedigree, and was found to stem from a single forefather born around 1840. The p.Arg2680Cys associates with a form of Marfan syndrome that seems to have an enrichment of abdominal aortic aneurysm, suggesting that this may be a particularly common feature of p.Arg2680Cys-associated Marfan syndrome. Based on these combined genetic and clinical data, we estimate a Marfan syndrome prevalence of at least 1/6,000 in Iceland, compared to 1/10,000 based on clinical diagnosis alone, which indicates underdiagnosis of this actionable genetic disorder.