Klinička vrijednost analize epigenetičkog potpisa u neurorazvojnim poremećajima

master's thesis

• Title (english): Clinical value of episignature analysis in neurodevelopmental disorders
• Author: Matej Dobrošević
• Mentor: Ana Katušić Bojanac (mentor)
• Committee member: Nino Sinčić (predsjednik povjerenstva)
• Committee member: Ljiljana Šerman (član povjerenstva)
• Committee member: Ana Katušić Bojanac (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Medical Biology); Zagreb
• Defense date and country: 2024-07-12, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Human Genetics, Genomics and Proteomics

Abstract

Neurorazvojni poremećaji skupina su poremećaja s teškoćama u osobnom, socijalnom,
akademskom i/ili okupacijskom funkcioniranju, a za sve više njih se otkriva povezanost s
promjenama u epigenomu pojedinca koje potom utječu na fenotip. Općenito, epigenetički
mehanizmi omogućuju da se više različitih fenotipa ispolji kao produkt jednog genotipa. Promjena
u metilaciji DNA pa tako i aktivnosti gena, dovodi se u vezu s nastankom raka i mnogih drugih
bolesti. Epigenetički potpis uključuje, između ostalog, skup diferencijalno metiliranih citozina i
specifičan je za točno određenu stanicu. Specifičan je s obzirom na tkivo, dob te prisutnu
patologiju. Analiza obrasca metilacije DNA, odnosno epigenetičkog potpisa, može neizravno
ukazati na promjene u ekspresiji raznih gena i promjene u efikasnosti raznih enzima i ostalih
proteina uključenih u proces metilacije, te tako, bez sekvenciranja same patološke varijante, točno
ukazati na njenu prisutnost i efekt. Kod velikog broja rijetkih neurorazvojnih poremećaja
zamijećena je podliježuća patološka varijanta gena uključenih u proces metilacije DNA. Analiza
metilacije DNA kvantificira stupanj metilacije DNA, te točno određuje koji CpGovi su metilirani
ili nemetilirani. Dosadašnjim analizama epigenetički potpis je definiran za mnoge rijetke
neurorazvojne poremećaje. Uspoređivanje epigenetičkog potpisa nedijagnosticiranih pacijenata s
definiranim potpisima može pomoći postavljanju kliničke dijagnoze. Stoga se počeo koristiti u
klasifikaciji varijanti nejasnog značaja i inicijalnom postavljanu dijagnoze, a potencijalno i kao
metoda ranog probira, identifikacije mogućih meta za razvoj novih lijekova i korak ka
personaliziranoj medicini.

Abstract (english)

Neurodevelopmental disorders are a group of disorders with difficulties in personal, social,
academic and/or occupational functioning, and for more and more of them, a connection with
changes in the epigenome of the individual is being discovered, which then affects the phenotype.
In general, epigenetic mechanisms allow multiple different phenotypes to manifest as a product of
a single genotype. Changes in methylation, and thus gene activity, are linked to the development
of cancer and many other diseases. The epigenetic signature includes a set of differentially
methylated cytosines specific to a particular cell. It is specific with respect to tissue, age, and the
presence of pathology. Analysis of DNA methylation levels, or the epigenetic signature, can
indirectly indicate changes in the expression of various genes and changes in the efficiency of
various enzymes and proteins involved in the methylation process, and in this way, without
sequencing the pathological variant itself, accurately indicate its presence and effect. In a large
number of rare neurodevelopmental disorders, an underlying pathological variant of genes
involved in the methylation process has been observed. Methylation analysis quantifies the degree
of methylation and precisely determines which CpGs are methylated or unmethylated. Previous
analyses have defined the epigenetic signature for many rare neurodevelopmental disorders.
Comparison of the epigenetic signature of undiagnosed patients with defined signatures can help
establish a clinical diagnosis. Thus, it has started to be used in the classification of variants of
uncertain significance (VUS) and initial diagnosis. Also, potentially, as a method for early
screening, identification of possible targets for the development of new drugs, and a step towards
personalized medicine.

• Keywords: epigenetički potpis; neurorazvojni poremećaji; metilacija DNA
• Keywords (english): epigenetic signature; neurodevelopmental disorders; DNA methylation
• Language: croatian
• URN:NBN: urn:nbn:hr:105:286881
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-07-02 12:36:38