Abstract
BackgroundFamilial transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease with significant phenotypic heterogeneity. Its prevalence in Saudi Arabia has not previously been investigated. An existing exome variant database of Saudi individuals, sequenced to globally investigate rare diseases in the population, was mined for TTR variants and filtered for missense mutations resulting in single amino acid changes. A total of 13,906 Saudi exomes from unrelated individuals were analyzed blindly.ResultsThree TTR variants known to be associated with ATTR amyloidosis were identified. Additionally, three novel TTR mutations were identified. Structural analysis of the three novel variants suggests that at least two could be amyloidogenic. The most common variant associated with amyloidosis was p.Val142Ile (allele frequency 0.001). Further investigation of these variants and their translation to clinical practice may help to diagnose, monitor, and manage patients with ATTR amyloidosis.ConclusionMultiple TTR variants potentially associated with systemic ATTR amyloidosis were identified in the Saudi population. Early diagnosis and intervention, facilitated by familial genetic testing of patients with ATTR amyloidosis, may benefit in the management of this disease. Early diagnosis could be enhanced through inclusion of ATTR variants in existing population-based screening programs.
Highlights
Familial transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease with significant phenotypic heterogeneity
The tetrameric transthyretin (TTR) protein is stabilized by the binding of thyroid hormone or retinol-binding protein 4 (RBP4), preventing its dissociation into monomers that can aggregate into amyloid fibrils [1,2,3]
The objectives of this study are (1) to analyze a national exome database in order to identify the incidence of known and candidate pathogenic variants associated with amyloid TTR (ATTR) in Saudi Arabia, and (2) to investigate the amyloidogenic potential of novel candidate TTR variants
Summary
Familial transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease with significant phenotypic heterogeneity. A recent review recommended genetic screening of at-risk family members of patients with ATTR amyloidosis to identify pre-symptomatic individuals with pathogenic TTR variants, in order to allow early diagnosis and possibly early therapeutic intervention [12]. Such an approach requires a good understanding of the prevalence of hereditary ATTR and of the clinical manifestations of TTR variants in the local population. This type of study offers the opportunity to identify novel variants that are potentially unique to the studied population and may have important epidemiologic, diagnostic and potentially therapeutic implications
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