The clinical significance of transthyretin gene variant homozygosity in variant ATTR-CM
Authors: Razvi Y , Porcari A , Patel R , Ioannou A , Starr N , Rauf M U , Rowczenio D , Venneri L , Martinez-Naharro A , Whelan C , Lachmann H , Wechelakar A , Hawkins P , Fontana M , Gillmore J D 
Published: November 2023

Abstract

Background
Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is a progressive condition characterised by the infiltration of the myocardial extracellular space resulting in progressive heart failure and mortality. Owing to advances in imaging and diagnostics, ATTR-CM is an increasingly recognised form of heart failure worldwide. ATTR-CM can be hereditary (hATTR) and associated with a pathogenic TTR gene variant which exhibits an autosomal dominant pattern of inheritance. Studies have shown that homozygosity in Mendelian diseases confers a more severe clinical phenotype. This has yet to be determined for hATTR-CM.

Purpose
To determine the clinical significance of TTR gene variant homozygosity in hATTR-CM.

Methods
All patients whom were diagnosed with hATTR-CM at a single UK national referral centre for amyloidosis were identified retrospectively. TTR gene zygosity, clinical, biochemical and echocardiographic parameters were obtained from patient clinical records.

Results
Only patients that were homozygous for the V122I TTR gene variant were identified in sufficient numbers for meaningful analysis. Twenty three patients with hATTR-CM whom were homozygous for the V122I variant were identified. Three hundred and ninety heterozygous V122I hATTR-CM patients were identified as a control group. There were no statistically significant differences in echocardiographic parameters (heterozygous vs homozygous means were as follows: IVSd 16.9mm v 16.6mm, LVEF 43.8% v 44.8%, stroke volume 30.7ml v 34.4ml, TAPSE 14.4mm v 15.3mm and GLS -9.7% vs -9.0%). Median NT-proBNP was lower in the homozygotes compared to heterozygotes (2480ng/L v 3179ng/L, p&lt;0.05). Median survival from baseline was similar between the two groups (Figure 1), with homozygous and heterozygous patients having median survivals of 28.7 months and 24.5 months, respectively. However, homozygous patients were significantly younger at baseline diagnosis (mean age 66.4 years v 76.3 years, p&lt;0.01) and therefore died at a much younger age (mean age at death 72.5 years v 79.9 years, p&lt;0.01).

Conclusions
To our knowledge, this is the first study reporting outcomes in hATTR-CM patients whom are homozygous TTR gene variant carriers. Whilst the cardiac phenotype, natural history and length of survival were not substantially different between heterozygotes and homozygotes, the mean age at first diagnosis was substantially younger. Given the natural course of the disease was relatively similar between the groups, this resulted in a significantly younger age at death in hATTR patients whom are homozygous TTR variant carriers. Larger studies are required to confirm if this is applicable across all TTR variants. Nonetheless our study suggests that hATTR patients whom are homozygous carriers of TTR variants should be afforded closer clinical surveillance from a younger age than their heterozygous counterparts.Figure 1