Developing a more accurate population frequency of Marfan syndrome from predicted pathogenic FBN1 variants in the...

Marfan syndrome is an autosomal dominantly (AD)-inherited disease that results from pathogenic variants in the Fibrillin 1 (FBN1) gene, and is characterised by tall stature, elongated limbs and digits, lens abnormalities and aortic root dilatation, aneurysms and dissection, but milder forms also occur. Radiological imaging suggests that Marfan syndrome affects between one in 3000 and 5000 of the population. The aim of this study was to determine the population frequency of Marfan syndrome from the number of predicted pathogenic FBN1 changes found in a normal database. FBN1 variants were downloaded from gnomAD v2.1.1 and annotated with ANNOVAR. The population frequency was determined from the number of pathogenic null and structural variants, and the number of predicted pathogenic missense changes classified by rarity and computational scores. This population frequency was then compared with the frequencies in the control subset, and from gnomAD variants assessed as Pathogenic or Likely pathogenic in the ClinVar or LOVD databases. Our strategy identified predicted pathogenic FBN1 variants in one in 416 individuals, which was confirmed in the control subset (one in 356, p NS). Predicted pathogenic variants were most common in East Asian people (one in 243, p < 0.0001) and least common in Ashkenazim (one in 5185, p = 0.0082). The population frequencies based on pathogenic variants in the ClinVar or LOVD databases were one in 718 and one in 1014 respectively. Null variants which are associated with aortic aneurysms affected only one in 8624. Thus, Marfan syndrome is more common than previously recognised. Emergency departments and cardiac clinics in particular should be aware of undiagnosed Marfan syndrome and its cardiac risks, but many of those affected still have a milder phenotype.