Researchers found a high recurrence of the hereditary transthyretin amyloidosis (hATTR)-causing transthyretin (TTR) gene variant p.Val142Ile in central Italy. They believe it is likely associated with a founder effect rather than a result of recent admixture from African populations.

“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,” the researchers wrote in the European Journal of Human Genetics.

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Principal component analysis (PCA) showed that most (70.5%) of the total variance was explained by the first 2 principal components and confirmed the European ancestry of 15 out of 16 probands. The other sample was classified by the PCA as Native American, which was confirmed by the patient’s clinical record, so it was excluded from further analysis.

Moreover, the researchers found that the entire TTR gene lied within a linkage block that was subject to complete linkage disequilibrium. This was observed for both the samples from families enrolled in the study and those of Tuscans in the 1000 Genomes Project, which confirmed their genetic similarity. Hence, the results of the linkage disequilibrium analysis of the study cohort excluded the occurrence of major recombination events involving the TTR locus.

The researchers identified 4 haplotype-defining tag single-nucleotide polymorphisms and found that all p.Val142Ile carriers shared the T-A-T-G haplotype. Furthermore, the p.Val142Ile variant appeared on a specific ancestral Tuscan haplotype found in less than 3% of Tuscans in the 1000 Genomes Project.

The study enrolled 46 individuals from 16 families residing in Tuscany, Italy at the time of the study who were patients at the Tuscan Regional Amyloidosis Centre in Florence. The families were unrelated in recent generations, and the researchers were not aware of any consanguinity.


Mazzarotto F, Argirò A, Zampieri M, et al. Investigation on the high recurrence of the ATTRv-causing transthyretin variant Val142Ile in central Italy. Eur J Hum Genet. Published online November 15, 2022. doi:10.1038/s41431-022-01235-2