Marfan syndrome (MFS) is an autosomal dominant condition characterized by aortic aneurysm, skeletal abnormalities, and lens dislocation, and is caused by variants in the FBN1 gene. To explore causes of MFS and the prevalence of the disease in Iceland we collected information from all living individuals with a clinical diagnosis of MFS in Iceland (n = 32) and performed whole-genome sequencing of those who did not have a confirmed genetic diagnosis (27/32). Moreover, to assess a potential underdiagnosis of MFS in Iceland we attempted a genotype-based approach to identify individuals with MFS. 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 44 individuals, only 22 of whom were previously diagnosed with MFS. The most common of these variants, NM_000138.4:c.8038 C > 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) variant associates with a form of MFS that seems to have an enrichment of abdominal aortic aneurysm, suggesting that this may be a particularly common feature of p.(Arg2680Cys)-associated MFS. Based on these combined genetic and clinical data, we show that MFS prevalence in Iceland could be as high as 1/6,600 in Iceland, compared to 1/10,000 based on clinical diagnosis alone, which indicates underdiagnosis of this actionable genetic disorder.

马凡综合征 (MFS) 是一种常染色体显性遗传疾病，以主动脉瘤、骨骼异常和晶状体脱位为特征，由FBN1基因变异引起。为了探索 MFS 的原因以及该疾病在冰岛的流行情况，我们收集了冰岛所有临床诊断为 MFS 的在世个体 ( n = 32) 的信息，并对那些没有确诊的基因诊断的个体进行了全基因组测序 ( 27/32）。此外，为了评估冰岛 MFS 诊断不足的可能性，我们尝试采用基于基因型的方法来识别 MFS 患者。我们询问了包含 35,712 个全基因组测序个体的 deCODE Genetics 数据库，以寻找FBN1中的罕见序列变异。总体而言，我们在 44 名个体的FBN1中发现了 15 种致病性或可能致病性变异，其中只有 22 人之前被诊断患有 MFS。这些变体中最常见的是 NM_000138.4:c.8038 C > T p.(Arg2680Cys)，存在于多代谱系中，并且被发现源自 1840 年左右出生的单个祖先。p.(Arg2680Cys) ) 变异与某种形式的 MFS 相关，这种 MFS 似乎富含腹主动脉瘤，表明这可能是 p.(Arg2680Cys) 相关 MFS 的一个特别常见的特征。基于这些综合遗传和临床数据，我们发现冰岛的 MFS 患病率可能高达 1/6,600，而仅根据临床诊断的患病率为 1/10,000，这表明对这种可治疗的遗传性疾病诊断不足。