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

Abstract

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.