Analiza varioma izgube sluha v slovenski populaciji

Pirnat, Aljaž (avtor), Trebušak Podkrajšek, Katarina (mentor), DEBELJAK, MARUŠA (komentor)

Izguba sluha je najpogostejša motnja senzoričnih sistemov, saj na svetu za njo trpi skoraj pol milijarde ljudi. Zanjo je značilna velika genetska raznolikost, odkritih je bilo namreč že več kot 6000 različnih vzročnih sprememb v nukleotidnem zaporedju v več kot 110 genih. Izgubo sluha delimo na več skupin glede na različne kriterije. Ena izmed najpogostejših delitev je glede na anatomsko mesto okvare, in sicer poznamo konduktivno, senzorinevralno in mešano izgubo sluha. Senzorinevralna izguba sluha predstavlja 90 % vseh oblik in je praviloma posledica nepravilnosti in poškodb dlačnic Cortijevega organa. Nesindromska izguba sluha predstavlja 70 % vseh senzorinevralnih izgub sluha in se glede na način dedovanja deli na avtosomno recesivno, avtosomno dominatno, X-vezano in mitohondrijsko. Največji delež predstavlja avtosomno recesivna oblika, za katero so najpogosteje odgovorne spremembe v genih GJB2, GJB6, SLC26A4, OTOF, CDH23 in TMC1. V evropski in slovenski populaciji so najpogostejši vzrok predvsem genetske spremembe v genu GJB2, ki kodira koneksin 26, ki sestavlja presledkovne stike. Namen magistrske naloge je bil na podlagi podatkov, pridobljenih s sekvenciranjem po Sangerju in sekvenciranjem naslednje generacije, ovrednotiti in analizirati genetske spremembe, ki so prisotne pri bolnikih z izgubo sluha v slovenski populaciji. Z analizo varioma smo želeli preveriti možnost prisotnosti potencialno novih kandidatnih sprememb in genov v populaciji, ki bi lahko bili povezani z razvojem izgube sluha. V magistrsko nalogo so bile vključene 103 osebe z izgubo sluha in 167 oseb kot kontrolna skupina. Genetske spremembe v genu GJB2 so bile vzrok izgube sluha pri 23 preiskovancih. Najpogostejša sprememba v omenjenem genu je bila NM_004004.6: c.35delG (NP_003995.2:p.Gly12Valfs), saj je predstavljala 64 % vseh opredeljenih sprememb v genu GJB2. S sekvenciranjem naslednje generacije smo uspešno opredelili genetski vzrok izgube sluha pri dodatnih 5 % preiskovancev. Določili smo majhno število sprememb v genu TMPRSS3, ki naj bi bile sicer drugi najpogostejši vzrok izgube sluha v slovenski populaciji. Z analizo varioma smo prepoznali kandidatne gene, ki bi morda lahko bili povezani z izgubo sluha, in sicer so to geni MIAT, GSTT1, TBL1Y, ACSL4, ACVR2B, ZMYND11 in NEUROD1. V genu ACSL4 smo pri enem preiskovancu določili spremembo, ki bi lahko bila vzrok njegove izgube sluha.

• Jezik: Slovenski jezik
• Ključne besede: izguba sluha, genetika, sekvenciranje po Sangerju, sekvenciranje naslednje generacije, analiza varioma
• Vrsta gradiva: Magistrsko delo/naloga
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2019
• PID: 20.500.12556/RUL-111225
• Datum objave v RUL: 26.09.2019

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Hearing loss variome analysis in Slovenian population

Izvleček

Hearing loss is the most common sensory defect, affecting more than 500 million people worldwide. Genetically it is very heterogenous disease with more than 6000 variants in more than 110 genes. It is most often classified based on ear anatomy, where ear is divided into the outer and middle ear (conductive hearing loss) and into inner ear (sensorineural hearing loss). Sensorineural hearing loss is the most common type of hearing loss, accounting for more than 90 % of all hearing loss cases and is caused by damaged hair or nerve cells in the cochlea. It can be further divided into 4 types based on the inheritance mode: autosomal recessive, autosomal dominant, X-linked and mitochondrial. Autosomal recessive sensorineural hearing loss is mostly the consequence of mutations in genes SLC26A4, OTOF, CDH23, TMC, GJB6 or GJB2, the latter being the main cause of hearing loss in European and Slovenian population. The aim of this study was to find and evaluate causal genetic variants in people with hearing loss using Sanger sequencing and next generation sequencing. Furthermore, with the hearing loss variome analysis we wanted to identify novel disease causing variants or genes that are potentially involved in development of hearing loss. We enrolled 103 people with hearing loss and 167 individuals without hearing loss, representing our control group. Disease causing variants in GJB2 were the cause of hearing loss in 23 patients and the most common variant was NM_004004.6:c.35delG (NP_003995.2:p.Gly12Valfs) present in 64 % of all GJB2 mutated alleles. With the next generation sequencing hearing loss was genetically resolved in additional 5 % of the individuals. We identified a very small number of disease causing variants in TMPRSS3 gene, although it was previously reported that variants in this gene are the second most common cause of hearing loss in Slovenian population. With the hearing loss variome analysis we recognized few new candidate genes that could be related to the etiology of hearing loss, namely MIAT, GSTT1, TBL1Y, ACSL4, ACVR2B, ZMYND11 and NEUROD1. In addition, in one subject we identified a ACSL4 gene variant which could potentially be the cause of hearing loss.

• Ključne besede: hearing loss, genetics, Sanger sequencing, next generation sequencing, variome analysis