Imprinting disorders in Estonia

Abstract

Kaasasündinud vermimishäired on vähetuntud rühm harva esinevaid pärilikke haigusi, mis on tingitud vermitud geenide ekspressiooni muutustest ning mõjutavad peamiselt kasvu, aju funktsioone ja hormonaalset süsteemi. Kuigi inimese genoomis on leitud vähemalt 100 vermitud geeni, on hetkel teada ainult 13 kliiniliselt tunnustatud kaasasündinud vermimishäiret. Nendest sagedasemad on Prader-Willi sündroom (PWS), Angelmani sündroom (AS), Beckwith-Wiedemanni sündroom (BWS) ning Silver-Russelli sündroom (SRS). Kuigi igale vermimishäirele on iseloomulik spetsiifiline kliiniline pilt, on sümptomid sageli kattuvad, ebatüüpilised või vähe väljendunud. Ka molekulaarsed põhjused võivad olla nii geneetilised kui ka epigeneetilised. Varieeruva molekulaarse etioloogia ja kliinilise avaldumise tõttu on vermimishäirete diagnostika keeruline, mistõttu osa vermimishäirete juhtudest jääb diagnoosimata. Käesoleva uuringuga selgitati sagedamini esinevate vermimishäirete esinemissagedust Eestis. Leiti, et PWS, AS ning BWS esinemissagedus Eestis on võrreldav kirjanduses publitseeritud esinemissagedusega, kuid SRS ning GNAS-geeniga seotud vermimishäirete esinemissagedus on eeldatavast oluliselt kõrgem. Demonstreeriti, et kuigi iga vermimishäire eraldi võetuna on väga harva esinev, on kõik vermimishäired koos suhteliselt levinud. Molekulaarselt kinnitati diagnoos 38%-l kliinilise SRS diagnoosiga patsientidest ning 8%-l kliinilise BWS diagnoosiga patsientidest, mis näitab, et SRS skooringusüsteem on Eesti patsientidel efektiivsem kui BWS skooringusüsteem. Juurutati laboripraktikasse selliseid uusi molekulaarseid teste nagu 6., 7., 14. ja 20. kromosoomi vermitud regioonide MS-MLPA (ingl Methylation-Specific Multiplex Ligation-dependent Probe Amplification) analüüsid, ning kirjeldati nende analüüsidega leitud haruldasi vermimishäireid Eestis. Käesoleva uurimistöö tulemusena õnnestus parandada vermimishäirete diagnostikat Eestis ning ka tõsta Eesti arstide teadlikkust vermimishäiretest.Congenital imprinting disorders (ImpDis) are a little-known group of rare hereditary diseases caused by changes in the expression of imprinted genes, mainly affecting growth, brain functions and the hormonal system. Although at least 100 imprinted genes have been found in the human genome, only 13 clinically recognizable ImpDis are currently known. The most common of these are Prader-Willi syndrome (PWS), Angelman syndrome (AS), Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). Although each ImpDis has its own specific clinical features, the symptoms are often overlapping, atypical, or mildly expressed. The molecular causes of ImpDis can be genetic as well as epigenetic. Because of the high variability of the clinical phenotype and molecular alterations, the diagnosis of ImpDis is difficult, and many ImpDis cases remain therefore undiagnosed. This study clarified the prevalence of the most frequent ImpDis in Estonia. The birth prevalence of PWS, AS and BWS in Estonia is comparable with the prevalence previously reported in the literature, but the birth prevalence of SRS and GNAS-gene-related ImpDis is significantly higher than previously estimated. It was demonstrated that although each ImpDis, taken separately, is very rare, all ImpDis together are relatively common. Molecular diagnostic tests confirmed the diagnosis in 38% of patients with clinical diagnosis of SRS and in 8% of patients with clinical diagnosis of BWS, indicating that in Estonia the clinical scoring system for SRS is more effective than those for BWS. New molecular diagnostic tests, such as MS-MLPA (Methylation-Specific Multiplex Ligation-dependent Probe Amplification) of imprinted loci in chromosomes 6, 7, 14 and 20, were introduced into the laboratory practice in Estonia, and rare ImpDis found by these analyses were described. As a result of this study, the diagnostics of ImpDis has been improved in Estonia, and the awareness of ImpDis among Estonian doctors has been increased.