Estimating the prevalence of allelic variants in the transthyretin gene by analysing large-scale sequencing data

Abstract

Transthyretin amyloidosis (ATTR amyloidosis) is a rare disease characterised by extracellular deposition of amyloid fibrils composed by transthyretin. ATTR amyloidosis can be sub-classified as wild-type ATTR (ATTR-wt) or as hereditary amyloidosis (ATTR-m); the prevalence of both types are likely underestimated. There are tools that can help us to study ATTR-m, as gnomAD database. Our primary aim was to estimate prevalence of variants, especially amyloidogenic variants, in the TTR gene using gnomAD database. We analysed TTR missense variants found in gnomAD. The variables studied were classified according to their clinical significance and according to the different populations. We found 71 missense variants in the TTR gene. Eleven variants were described as affects function variants (prevalence 1:230). The most frequently detected variant were c.424G>A (p.( Val142Ile)) (prevalence 1:332, MAF 0.00151) and c.148G>A (p.( Val50Met)) (prevalence 1:4924, MAF 0.000102), which represented 88% and 5%, respectively, of all affects function variants detected. Seventeen variants were classified as probably affects function, 29 as unknown variants, 4 as probably does not affect function and 10 as does not affect function variants. In terms of different populations, c.424G>A (p.( Val142Ile)) was especially prevalent in African population (MAF 0.01602; prevalence of 1:31) and c.148G>A (p.(Val50Met)) in European population (MAF 0.000179; prevalence of 1:2792). Prevalence of amyloidogenic variants in the general population was higher than prevalence heretofore described. This difference could be explained by incomplete penetrance of the disease, but other factors contributing to this fact, fundamentally the underdiagnosis of the disease.

Established and candidate transthyretin amyloidosis variants identified in the Saudi population by data mining

“…Of these, 28 were in coding or flanking regions. These were further reduced by removal of synonymous, nonsense and splice variants leaving 12 potentially amyloidogenic variants that were further investigated (Table 1 Two mutations are known to negatively impact function of the TTR protein, resulting in amyloidosis: c.238A>G(p.Thr80Ala) and c.424G>A(p.Val142Ile) [ 5 , 14 – 16 ]. The most frequent was c.424G>A(p.Val142Ile) (0.001), whereas c.238A>G(p.Thr80Ala) (0.00004) was less frequent (Table 1 ).…”

“…Variant c.239C>T(p.Thr80Ile) affects a hotspot for pathogenic mutations (same amino acid) and according to ACMG guidelines and Varsome should be considered as a pathogenic mutation [ 17 , 18 ]. Three variantsc.368G>A(p.Arg123His), c.370C>T (p.Arg124Cys), and c.385G>A (p.Ala129Thr) were classified as variants of uncertain significance (VUS) having no known effect on TTR function [ 14 , 17 ]. Three further variants were classified as benign/likely benign (Table 1 ).…”

“…At present, Arab populations are underrepresented in ATTR databases, thus limiting our ability to adopt such an approach in Saudi Arabia. Large-scale national genomic data mining can be very useful to establish frequency of pathological genetic variation resulting in rare diseases such as amyloidosis [ 13 , 14 ]. This type of study also 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.…”

Genomic Screening Identifies Individuals at High Risk for Hereditary Transthyretin Amyloidosis

“…Due to the nonspecific and progressive nature of its symptoms, hATTR diagnosis is frequently delayed or missed [ 11 , 12 , 13 ]. V142I is the most common pathogenic TTR variant worldwide, with recent prevalence estimates of 1 in 330 individuals [ 14 , 15 ]. Up to 4% of African Americans (AA) in the U.S. harbor the V142I variant [ 16 ], and V142I was also recently shown to be prevalent (1%) in Hispanic/Latinx (HL) populations in New York City [ 17 ].…”

Diagnostic and Treatment Approaches Involving Transthyretin in Amyloidogenic Diseases

“…More recently, the prevalence of non-amyloidogenic and amyloidogenic variants of ATTR was estimated from the gnomAD database. Eleven were shown to have effects on function, with c.424G>A as the most prevalent (88% of function-affecting variants) followed by c.148G>A (5%) [6]. The role of TTR as a carrier protein was revealed to involve the reduction of cytotoxicity by blocking the aggregation of other proteins in protein aggregation diseases [7].…”