JAG1 MUTATION SPECTRUM IN CASES WITH ALAGILLE SYNDROME FROM TURKIYE

Öz

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 gross 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 heterozy gous 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.

Anahtar Kelimeler

• Alagille syndrome
• JAG1
• arteriohepatic dysplasia

Destekleyen Kurum

ISTANBUL UNIVERSITY SCIENTIFIC RESEARCH PROJECT FOUNDATION

Proje Numarası

Project number of TSA-2022-39315.

TÜRKİYE'DE ALAGILLE SENDROMLU OLGULARDA JAG1 MUTASYON SPREKTRUMU

Öz

Amaç: Arteriyohepatik displazi olarak da bilinen Alagille sendromu (ALGS), çoğunlukla JAG1 genindeki mutasyonların neden olduğu otozomal dominant kalıtılan bir multisistem hastalığıdır. Karaciğer, kalp, göz, vertebra ve yüz morfolojisinde belirgin anomaliler içerir. Gereç ve Yöntem: Çalışmamıza Ocak 2016-Aralık 2022 tarihleri arasında ALGS tanısı alan ve İstanbul Tıp Fakültesi Tıbbi Genetik Anabilim Dalı'na sevk edilen hastalar dahil edildi. Hastalar ve ailelerinin klinik, radyolojik, sitogenetik ve moleküler bulguları retrospektif olarak yeniden değerlendirildi. Karyotip, floresan in situ hibridizasyon (FISH), karşılaştırmalı genomik hibridizasyon (aCGH) yöntemi ile yeni nesil ve Sanger dizileme teknolojisi kullanılarak yapılan JAG1 geni moleküler ve moleküler sitogenetik sonuçları incelendi. Bulgular: Tüm vakalarda Alagille sendromuyla ilişkili büyük delesyon veya nokta mutasyonlarının varlığı tespit edildi. Karyotip ve aCGH analizi ile tek bir vakada de novo büyük 20p delesyonu saptadı. JAG1 geninin yeni nesil dizileme analizi aşağıdaki bulguları ortaya çıkardı; heterozigot patojenik c.2122_2125del/p.(Gln708Valfs*34), heterozigot olası patojenik c.1754_1755del/p.(Asn585Argfs*4), heterozigot patojenik c.2026del/p.(Cys676Alafs*67), heterozigot patojenik c.753C>A/p.(Cys251*), heterozigot olası patojenik c.2458+2_2458+4delTAAinsGAC/p.(?) varyantları olduğu anlaşıldı. Bir vakada ise FISH analizi ile anneden kalıtılan 20p delesyonu saptandı. Mevcut aile üyelerinin analizi sonrasında üç varyantın ailesel olduğunu anlaşıldı. İki novel varyanttan biri olan c.1754_1755del varyantı de novo olarak tanımlanırken, diğer c.2458+2_2458+4delTAAinsGAC novel varyantının ailesel olduğu belirlendi. Sonuç: Özetle, araştırmamız farklı JAG1 geni varyantlarını tanımlamakla birlikte ve doğru genetik tanı ve genetik danışmanlık için JAG1 geninin dizi analizi ile birlikte moleküler sitogenetik analizi birleştirmenin önemli olduğunun altını çizdi. Ayrıca çalışmamız, ALGS'li hastalarda dikkate değer aileler arasında ve aile içi fenotipik değişkenlik olduğundan, genetik etiyopatogenezi netleştirmek için ebeveynleri, kardeşleri ve çocukları taramanın katkısını vurgulamaktadır.

Anahtar Kelimeler

• Alagille sendromu
• JAG1
• arteriyohepatik displazi

Proje Numarası

Project number of TSA-2022-39315.

Kaynakça

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