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

Increased use of genetic health care in Iceland 2012-2017

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadINNGANGUR Formleg erfðaráðgjafareining hefur verið starfrækt á Landspítala við Hringbraut frá árinu 2006. Samhliða hefur áhugi og þörf á erfðalæknisfræði í almennri heilbrigðisþjónustu aukist til muna. Í þessari grein er starfsemi og útkoma erfðarannsókna hjá erfða- og sameindalæknisfræðideild Landspítala á 5 ára tímabili (2012-2017) tekin saman. Sérstaklega var horft til fjölda einstaklinga, ástæðu komu, ástæðu erfðarannsókna án aðkomu erfðaráðgjafar Landspítala og eins var nýtni (heildarhlutfall rannsókna sem skila jákvæðri niðurstöðu) erfðarannsókna skoðuð. AÐFERÐIR Gögn um komur voru fengin upp úr sjúkraskrárkerfi erfðaráðgjafar, Shire og Sögu/Heilsugátt. NIÐURSTAÐA Fjöldi þeirra sem sóttu þjónustu erfðaráðgjafareiningarinnar jókst árlega allt tímabilið. Ástæður fyrir erfðaráðgjöf reyndust vera krabbameinstengdar í tveimur þriðju hlutum tilfella. Aðrir komu vegna fjölskyldulægra sjúkdóma sem eru algengir á Íslandi, ýmist sjúkdóma sem erfast ríkjandi (dæmi: vöðvaspennuvisnun og ofvaxtarhjartavöðvasjúkdómur) eða vegna víkjandi sjúkdóma (dæmi: mænuvöðvarýrnun og GM1-ganglio-síðkvilli). Algengast var að fólk færi í erfðarannsókn án aðkomu erfðaráðgjafar Landspítala vegna meðhöndlanlegra sjúkdóma, svo sem arfgengrar járnofhleðslu og bláæðasegatilhneigingar. Nýtni erfðarannsókna var metin fyrir a) leit að þekktum meinvaldandi breytingum, b) leit að meinvaldandi breytingum í stökum genum (eingenarannsóknir), c) fjölgenarannsóknir og d) tákn- og heilerfðamengisrannsóknir. Leit að þekktri breytingu skilaði jákvæðri niðurstöðu í 33% tilvika og leit í stöku geni í 46% tilvika. Nýtni fjölgenarannsókna vegna krabbameina var lægri (20%) samanborið við aðrar fjölgenarannsóknir (40%). Þá var nýtni tákn- og heilerfðamengisrannsókna 46%.INTRODUCTION: A genetic counselling unit at Landspitali hospital (LSH) was established in 2006. Meanwhile, genetic testing has become an integral part of general health care. In this article we detail the outcome of genetic testing at the Department of Genetic and Molecular Medicine (DGM) at Landspitali over a five year period (2012-2017). Factors that were analyzed for the time period were: Number of patients, reason for referral, reason for genetic testing without genetic counselling and yield (proportion of positive tests) of genetic testing. METHODS: Data was analysed from two medical record databases, Shire and Saga, used by the DGM in the time period. RESULTS: The number of individuals coming for genetic counselling increased every year over the time period. Reasons for referral were cancer-related in two-thirds of cases. Other reasons for referral included various other familial disorders. Most common were autosomal dominant disorders like myotonic dystrophy, hypertrophic cardiomyopathy and autosomal recessive disorders like spinal muscular atrophy (SMA) and GM1- gangliosidosis. Most common reasons for genetic testing outside of the LSH GC unit was because of managable diseases like hemochromatosis and F5/Prothrombin-related thrombophilia. Yield of genetic testing was assessed for a) known mutation testing / carrier testing, b) single gene testing, c) gene panel testing and d) whole genome and whole exome sequencing. Known mutation testing was positive in 33% of cases and single gene testing in 46% of cases. The yield of gene panel testing for cancer was found to be lower (20%) than gene panel testing for other disorders (40%). The yield of whole exome and whole genome sequencing was 46%