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

Publisher Copyright: © 2023, The Author(s).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.Peer reviewe

Tumor grading.

<p>Gleason grading score of the tumors for the samples used in Experiment 1 and Experiment 2. The sample on array 5 was used repeatedly on three arrays in Experiment 3.</p

The number of Monte Carlo simulations for which each region is chosen by the selection method using arrays with the same sample.

<p>The genomic location of the regions on 8q24 is on the x-axis. The proportion of Monte Carlo simulations for which the region was chosen is on the y-axis. The graph is shown with two different colourings, representing whether the region was among the previously experiment-wise selected regions (cyan) or not (pink). Those who were selected previously in Experiment 1 are shown at the top graph, Experiment 2 in the middle and Experiment 3 at the bottom. The simulations are done on the ten repeated spots for each probe for the three arrays in Experiment 3 that contained the same sample.</p

The number of Monte Carlo simulations for which each region is chosen by the selection method using arrays with different samples.

<p>The genomic location of the regions on 8q24 is on the x-axis. The proportion of Monte Carlo simulations for which the region was chosen is on the y-axis. The graph is shown with two different colourings, representing whether the region was among the previously experiment-wise selected regions (cyan) or not (pink). Those who were selected previously in Experiment 1 are shown at the top graph, Experiment 2 in the middle and Experiment 3 at the bottom. The simulations are done on the ten repeated spots for each probe for all nine arrays in Experiment 3.</p

The proportion of regions that were selected in both Experiment 1 and Experiment 2.

<p>The underlying region was split up into equally sized regions and a fixed number of regions with the highest ratio of probes, within the region, expressed above the median, was selected. The proportion of regions that were selected in both Experiment 1 and Experiment 2 was calculated for varying length of each underlying region (y-axis) and the total number of regions to be selected (x-axis). The numbers within each cell show the exact proportions for the corresponding criteria.</p

Regions selected in first two experiments.

<p>The loci of the 20 regions selected in first and second experiments, according to hg18 and hg19 and the genes reported at these loci.</p

Multiple transmissions of de novo mutations in families.

To access publisher's full text version of this article click on the hyperlink belowDe novo mutations (DNMs) cause a large proportion of severe rare diseases of childhood. DNMs that occur early may result in mosaicism of both somatic and germ cells. Such early mutations can cause recurrence of disease. We scanned 1,007 sibling pairs from 251 families and identified 878 DNMs shared by siblings (ssDNMs) at 448 genomic sites. We estimated DNM recurrence probability based on parental mosaicism, sharing of DNMs among siblings, parent-of-origin, mutation type and genomic position. We detected 57.2% of ssDNMs in the parental blood. The recurrence probability of a DNM decreases by 2.27% per year for paternal DNMs and 1.78% per year for maternal DNMs. Maternal ssDNMs are more likely to be T>C mutations than paternal ssDNMs, and less likely to be C>T mutations. Depending on the properties of the DNM, the recurrence probability ranges from 0.011% to 28.5%. We have launched an online calculator to allow estimation of DNM recurrence probability for research purposes

Ron Clarke heads down the track with the Olympic torch, Melbourne Cricket Ground, 22 November, 1956 [picture] /

Part of the collection: Olympic Games, Melbourne, Victoria 1956.; Title devised by cataloguer from typed label on reverse.; Inscriptions: "Ron Clarke heads down the track with the Olympic torch, MCG. 22.11.1956"--Typed label on reverse.; Also available in electronic version via the Internet at: http//nla.gov.au/nla.pic-vn4278496-s44; Donated through the Australian Government's Cultural Gifts Program by Bruce Howard, 2007