Non-amiloidojenik Transtiretin Gen Varyantlarının Biyoinformatik Analizi ve His90Asn Varyantının Klinik Önemi

Yıl 2020, Cilt: 3 Sayı: 3, 102 - 113, 05.11.2020

Evrim Kömürcü Bayrak , Gizem Çelebi Elif Eroğlu Gökhan Kahveci Fatih Bayrak

Öz

Amaç: Transtiretin (TTR) amiloidozu, otozomal dominant kalıtımlı değişken penetransa sahip bir hastalıktır. TTR genindeki patojenik varyantlar, TTR proteininin yanlış katlanmasına yol açarak kardiyomiyositlerde birikime ve kalp yetmezliğine sebep olabilmektedir. Bu çalışmada, biventriküler konsantrik hipertrofisi olan hastada TTR geninde saptanan His90Asn (H90N) varyantının hastalık patogenezine etkisinin ve non-amiloidojenik varyantlarının biyoinformatik analizlerle klinik önemlerinin belirlenmesi amaçlandı. Gereç ve Yöntem: İndeks vaka, 18 yıl kardiyolojik açıdan takip edildi ve Illumina TruSight Kardiyomiyopati paneli kapsamında 46 genin ekzonik bölgelerindeki varyantlar araştırıldı. TTR geninde H90N varyantı saptanan vakadan klinik olarak amiloidoz şüphesi ile rektal biopsi örneği alındı. Bu varyant, Sanger dizileme yöntemi ile konfirme edildi. Bulgular: Onbir yıl önce tanı alan ve ICD implante edilen 32 yaşındaki bir erkek vakada TTR geninin ekzon 3'ünde H90N varyantı heterozigot olarak belirlendi. Indeks vaka, kardiyak amiloidoz açısından değerlendirildiğinde, progresif sistolik disfonksiyona sahip olduğu (sol ventrikül ejeksiyon fraksiyonu, 2013'te %60, 2016'da %35 ve 2017'de %20) ve amiloidoz ile uyumlu epikardiyal ve endokardiyal tabakalarda global longutidunal strain (GLS) skoru ve strain rate değerinin azaldığı belirlendi. Rektal biyopsininde kongo kırmızısı boyamasında amiloid birikimi gözlenmedi. Bu varyant, asemptomatik olan babasında da tespit edildi. İlk defa bu çalışmada, TTR genindeki non-amiloidojenik aminoasit değişimine neden olan tüm varyantlar biyoinformatik analizlerle karşılaştırıldı. Sonuç: Bu çalışmada, H90N varyantının infiltratif miyokard hastalığındaki patojenik etkisi kanıtlanamamış olsada TTR genindeki H90N varyantı gibi non-amiloidojenik varyantların klinik değerlendirmede dikkate alınması gerektiği ortaya konmuştur.

Anahtar Kelimeler

kardiyak amiloidoz, transtiretin, His90Asn varyantı

Destekleyen Kurum

İstanbul Üniversitesi Bilimsel Araştırma Projeleri Birimi

Proje Numarası

42173 ve TDP-2017-22581

Bioinformatic Analysis of Non-Amyloidogenic Transtyhretin Gene Variants and Clinical Importance of His90Asn Variant

Öz

Objective: Transthyretin (TTR) amyloidosis is an autosomal dominant inherited disease with variable penetration. Cardiac deposition of misfolded TTR protein due to missense pathogenic variants causes heart failure. Our aim was to determine the effect of the TTR gene His90Asn (H90N) variant on the pathogenesis of disease in a patient with biventricular concentric hypertrophy, and the clinical significance of variants defined as non-amyloidogenic with bioinformatic analysis. Materials and Methods: The index case was followed cardiologically for 18 years and pathogenic variants were investigated in the exonic regions of 46 genes using the Illumina TruSight Cardiomyopathy panel. Rectal biopsy specimen was taken from a case where the H90N variant was detected in the TTR gene, with clinical suspicion of amyloidosis. This variant was confirmed by the Sanger sequencing method. Results: Heterozygote H90N variant was determined in exon3 of the TTR gene in index case of a 32-year-old man with severe heart failure who was diagnosed 11 years ago and implanted with an ICD. He had progressive systolic dysfunction (left ventricular ejection fraction, 60% in 2013, 35% in 2016, and 20% in 2017). GLS score and strain rate were reduced in the epicardial and endocardial layers compatible with amyloidosis in the patient. In congo red staining of rectal biopsy, amyloid deposition was not observed. This variant was detected also in the patient’s father, who did not have clinical symptoms. For the first time in this study, all variants that cause non-amyloidogenic amino acid subtitutions in the TTR gene were compared with bioinformatics analyzes. Conclusion: In this study, although the pathogenic effect of the H90N variant in infiltrative myocardial disease was not proven, it was revealed that non-amyloidogenic variants such as the H90N variant in the TTR gene should be considered in clinical evaluation.

Anahtar Kelimeler

cardiac amyloidosis, transthyretin, His90Asn variant

Proje Numarası

42173 ve TDP-2017-22581

Kaynakça

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