COMBINED ANALYSIS OF LINKAGE AND WHOLE EXOME SEQUENCING REVEALS CIC AS A CANDIDATE GENE FOR ISOLATED DYSTONIA/BAGLANTI VE TUM EKZOM DIZILEME ANALIZLERININ BIRLIKTE DEGERLENDIRILMESIYLE CIC GENININ IZOLE DISTONI ADAYI OLARAK BELIRLENMESI

Objective: To explore the underlying genetic variations and mechanisms in a family affected by isolated dystonia. Material and Method: We employed whole genome Single Nucleotide Polymorphism (SNP) based linkage analysis along with whole exome sequencing (WES) in a consanguineous family presenting with isolated dystonia. An in-house pipeline compiled for WES analysis along with in-depth in silico prediction algorithms were used to assess the associated data produced in this study. Sanger sequencing was used for variant confirmation and segregation. Results: Data analysis included locus oriented WES variant prioritization and cryptic splicing predictions. We detected a homozygous and synonymous variation rs748449895 (NM_015125.4: c.4143C>T; p.(Thr1381=)) in the capicua transcriptional repressor, CIC. This variation disrupts the YB-1 RNA recognition motif and creates an alternative SRp20 RNA recognition motif. Conclusion: The resulting variant might cause the dystonia phenotype by affecting the alternative splicing of CIC transcript and altering the exon inclusion motif which may disrupt the ATXN1- CIC complex. Keywords: Autosomal recessive dystonia, whole genome genotyping, linkage analysis, whole exome sequencing, alternative splicing Amac: Izole distoni hastaligindan etkilenmis bir ailede hastaliga neden olan genetik varyasyonlari ve mekanizmalari kesfetmek. Gerec ve Yontem: Izole distoni hastaligi tanisi konmus ve akraba evliligi bulunan bir ailede, tum genom Single Nucleotide Polymorphism (SNP) temelli baglanti analizi ile beraber tum ekzom dizileme (TED) gerceklestirildi. TED analizleri icin laboratuvarimizda gelistirilen akis hatti ve in siliko tahmin algoritmalari bu calismada uretilen verinin iliskilendirilmesinde kullanildi. Sanger dizileme varyantlarin dogrulanmasi ve ayrimi icin kullanildi. Bulgular: SNP dizimi ile genotipleme, baglanti analizi ve ekzom dizileme analizleri sonucu rs748449895 (NM_015125.4: c. 4143C>T;p.(Thr1381=)) homozigot sinonim varyanti tespit edildi. Devamindaki biyoinformatik analizler varyantin YB-1 RNA tanima motifi oldugunu gosterdi. Bu varyant YB-1 RNA tanima motifini bozarak, SRp20 RNA tanima motifi olusturmaktadir. Sonuc: Bulunan varyant, ekzon katilma motifini degistirerek CIC transkriptinin alternatif kirpilmasini etkileyip ATXN1-CIC kompleksini bozarak distoni fenotipine yol acabilir. Anahtar Kelimeler: Otozomal resesif distoni, tum genom genotipleme, baglanti analizi, tum ekzom dizileme, alternatif kirpilma