부산대학교 도서관

INTRODUCTION Alagille syndrome (ALGS), is an autosomal-dominant, multisystem disorder caused by a defective NOTCH signaling pathway with a broad spectrum of clinical variability, spanning from severe life-threatening cardiac or liver [...]
Objective: Alagille syndrome (ALGS), known as arteriohepatic dysplasia, is an autosomal dominant multisystem disorder primarily linked to JAG1 gene variants. It features distinctive anomalies in the liver, heart, eyes, spine, and facial morphology. Material and Method: Patients diagnosed with ALGS and referred to Istanbul Faculty of Medicine, Department of Medical Genetics between January 2016 and December 2022 were included in the study. The clinical, radiological, cytogenetic, and molecular findings of the patients as well as their families were re-assessed retrospectively. Karyotype, fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and JAG1 gene sequencing utilizing next-generation and Sanger sequencing methodologies were conducted. Result: The presence of both large deletion and small variants associated with Alagille syndrome was detected in all cases. In karyotype and aCGH analysis of a single case, a 20p deletion was identified. Subsequent next-generation sequencing (NGS) of the JAG1 gene revealed the following findings: a heterozygous pathogenic variant c.2122_2125del/p.(Gln708Valfs*34), a heterozygous likely pathogenic variant c.1754_1755del/p.(Asn585Argfs*4), a heterozygous pathogenic variant c.2026del/p.(Cys676Alafs*67), a heterozygous pathogenic variant c.753C>A/p.(Cys251*), and a heterozygous likely pathogenic variant c.2458+2_2458+4delTAAinsGAC/p. (?). In one case, FISH analysis revealed a 20p deletion inherited from the mother. Analysis of available family members further indicated that three variants were inherited within the family. One of the two novel truncating variants, the c.1754_1755del variant was identified as de novo, while the other c.2458+2_2458+4delTAAinsGAC variant was determined to be familial. Conclusion: In summary, the research effectively identified various JAG1 gene alterations and underlined the significance of incorporating molecular cytogenetic analysis in conjunction with sequence analysis of the JAG1 gene for accurate genetic diagnosis and counseling. Furthermore, study highlights the valuable outcome of screening parents, siblings, and children to clarify the genetic etiopathogenesis, as there is a remarkable intra- and inter-familial phenotypic variability in patients with ALGS. Keywords: Alagille syndrome, JAG1, arteriohepatic dysplasia Amac: Arteriyohepatik displazi olarak da bilinen Alagille sendromu (ALGS), cogunlukla JAG1 genindeki mutasyonlarin neden oldugu otozomal dominant kalitilan bir multisistem hastaligidir. Karaciger, kalp, goz, vertebra ve yuz morfolojisinde belirgin anomaliler icerir. Gerec ve Yontem: Calismamiza Ocak 2016-Aralik 2022 tarihleri arasinda ALGS tanisi alan ve Istanbul Tip Fakultesi Tibbi Genetik Anabilim Dali'na sevk edilen hastalar dahil edildi. Hastalar ve ailelerinin klinik, radyolojik, sitogenetik ve molekuler bulgulari retrospektif olarak yeniden degerlendirildi. Karyotip, floresan in situ hibridizasyon (FISH), karsilastirmali genomik hibridizasyon (aCGH) yontemi ile yeni nesil ve Sanger dizileme teknolojisi kullanilarak yapilan JAG1 geni molekuler ve molekuler sitogenetik sonuclari incelendi. Bulgular: Tum vakalarda Alagille sendromuyla iliskili buyuk delesyon veya nokta mutasyonlarinin varligi tespit edildi. Karyotip ve aCGH analizi ile tek bir vakada de novo 20p delesyonu saptadi. JAG1 geninin yeni nesil dizileme analizi asagidaki bulgulari ortaya cikardi; heterozigot patojenik c.2122_2125del/p. pathogenic variant c.1754_1755del/p.(Asn585Argfs*4), a heterozygous pathogenic variant c.2026del/p.(Cys676Alafs*67), a heterozygous pathogenic variant c.753C>A/p.(Cys251*), and a heterozygous likely pathogenic variant c.2458+2_2458+4delTAAinsGAC/p. (Gln708Valfs*34), heterozigot olasi patojenik c.1754_1755del/p.(Asn585Argfs*4), heterozigot patojenik c.2026del/p.(Cys676Alafs*67), heterozigot patojenik c.753C>A/p.(Cys251*), heterozigot olasi patojenik c.2458+2_2458+4delTAAinsGAC/p.(?) varyantlari oldugu anlasildi. Bir vakada ise FISH analizi ile anneden kalitilan 20p delesyonu saptandi. Mevcut aile uyelerinin analizi sonrasinda uc varyantin ailesel oldugunu anlasildi. Iki novel varyanttan biri olan c.1754_1755del varyanti de novo olarak tanimlanirken, diger c.2458+2_2458+4delTAAinsGAC novel varyantinin ailesel oldugu belirlendi. Sonuc: Ozetle, arastirmamiz farkli JAG1 geni varyantlarini tanimlamakla birlikte ve dogru genetik tani ve genetik danismanlik icin JAG1 geninin dizi analizi ile birlikte molekuler sitogenetik analizi birlestirmenin onemli oldugunun altini cizdi. Ayrica calismamiz, ALGS'li hastalarda dikkate deger aileler arasinda ve aile ici fenotipik degiskenlik oldugundan, genetik etiyopatogenezi netlestirmek icin ebeveynleri, kardesleri ve cocuklari taramanin katkisini vurgulamaktadir. Anahtar Kelimeler: Alagille sendromu, JAG1, arteriyohepatik displazi