TY - JOUR
T1 - A population-based survey of FBN1 variants in Iceland reveals underdiagnosis of Marfan syndrome
AU - Klemenzdottir, Elin Ola
AU - Arnadottir, Gudny A
AU - Jensson, Brynjar Orn
AU - Jonasdottir, Adalbjorg
AU - Katrinardottir, Hildigunnur
AU - Fridriksdottir, Run
AU - Jonasdottir, Aslaug
AU - Sigurdsson, Asgeir
AU - Gudjonsson, Sigurjon Axel
AU - Jónsson, Jón Jóhannes
AU - Stefánsdóttir, Vigdís Fjóla
AU - Danielsen, Ragnar
AU - Palsdottir, Astridur
AU - Jonsson, Hakon
AU - Helgason, Agnar Sturla
AU - Magnusson, Olafur Thor
AU - Thorsteinsdottir, Unnur
AU - Björnsson, Hans Tómas
AU - Stefansson, Kari
AU - Sulem, Patrick
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85170083159&partnerID=8YFLogxK
U2 - 10.1038/s41431-023-01455-0
DO - 10.1038/s41431-023-01455-0
M3 - Article
AN - SCOPUS:85170083159
SN - 1018-4813
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
ER -