Investigation on the high recurrence of the ATTRv-causing transthyretin variant Val142Ile in central Italy

Abstract

The p.Val142Ile variant in transthyretin (encoded by the TTR gene) is the most common genetic cause of transthyretin-related amyloidosis. This allele is particularly prevalent in communities ofAfrican descent compared with populations of different ancestries, where its frequency is two orders of magnitude lower. For this reason, p.Val142Ile has always been considered an "African" variant, with limited studies performed on individuals of European descent. However, recent reports of higher-than-expected prevalence in European-ancestry populations question the African specificity of this allele. Here we show that the high recurrence of p.Val142Ile in central Italy is due to a founder effect and not to recent admixture from African populations, highlighting how this may be the case in other communities. This suggests a probable underestimate of the global prevalence of p.Val142Ile, and further emphasizes the importance of routine inclusion of TTR in gene panels used for clinical genetic testing in hypertrophic cardiomyopathy (independently of the patient's geographical origin), that transthyretin-related amyloidosis can mimic.

Fig. 1. Pedigrees of the analyzed families where p.Val142Ile-related ATTRv segregates.

The pedigree structure of families from which multiple individuals have been included in the study is displayed in panels (A–J).

Fig. 2. Principal component analysis (PCA) of the 16 probands together with the 2504 individuals of the 1000 Genomes Project (Phase 3).

Individual NA10851 is plotted twice for quality control purposes, having been genotyped both within the 1000 Genomes Project (NA10851_1KG) and in-house (NA10851_internal). The proband clustering within the smear of native Americans is A228.

Fig. 3. Linkage disequilibrium (LD) structure.

LD structure of a 17 kb region comprising the TTR gene in 107 Tuscans (TSI) comprised by the 1000 Genomes Project (a, on the left) and in the maximum unrelated subset selected by Haploview from the study subjects (N = 29; b, on the right). In both cases, a unique LD block is detected across this region (chr18:29165918-29183812). Numbers in the LD squares represent D’ values, and the red color represents full LD (D′ = 100). The light blue bars above the LD plots represent real relative distances between the displayed SNPs (selected for having a frequency >5% in Europeans in the 1000 Genomes Project) within the 17 kb region. The four SNPs in black rectangular frames are the haplotype-defining (tag) SNPs, and the resulting haplotype frequencies are reported in the table below, with the 4 letters representing the alleles of the tag SNPs in the same order as they are represented in the LD plots. Of note, the T-A-T-G haplotype is found on 39.7% chromosomes in the study subjects (with all 15 probands of European ancestry being T-A-T-G carriers, with proband A204 being homozygous) and only on a minority 12.6% of TSI chromosomes. Details of all the variants represented in the figure are reported in Supplementary Table 3.

Fig. 4. Median-joining haplotype network constructed on a total of 136 individuals (N = 107 TSI and N = 29 comprising the maximum unrelated subset extracted from the study subjects), obtained including variants at all frequencies for finer dissection (including p.Val142Ile).

Ancestral haplotypes (forming the network torso) are represented in light blue (or purple). Ancestral haplotypes not detected in the analyzed sample set, but of which the existence is hypothesized are represented as “median vectors” (mv), in red. The two haplotypes with the p.Val142Ile variant are represented in yellow (VAR1 and VAR2) and the unique ancestral haplotype on which p.Val142Ile appeared in Tuscany is represented in purple (HAP16). Circle areas are proportional to the number of chromosomes carrying the haplotype, with HAP16 detected on 3 chromosomes in the TSI set and HAP1 (the most prevalent haplotype in TSI) found on 93. The full haplotype sequence is displayed for the most prevalent ancestral haplotype (HAP1) and for the two haplotypes with the p.Val142Ile variant. In the former, alleles that are different from those defining HAP1 are highlighted in red. The p.Val142Ile allele is displayed with a light blue background. Ticks along the network edges represent the number of differing alleles between the connected haplotypes. The full sequence of all haplotypes is provided in Supplementary Table 2 and details of all the haplotype-defining variants are reported in Supplementary Table 3.