Genetic testing and evidence of a founder mutation in a hotspot for hereditary transthyretin amyloidosis

Abstract

Abstract Variant transthyretin (ATTRv) amyloidosis is a rare, inherited disorder caused by mutations in the TTR gene, leading to amyloid fibril deposition. The Balearic Islands are a known endemic focus for the NP_000362.1:p.Val50Met (V30M) variant, one of the most prevalent pathogenic mutations. We analysed 23 years of genetic testing data from the Balearic Islands’ public health system to determine the prevalence and distribution of ATTR pathogenic variants, with a focus on V30M. A total of 1,478 individuals underwent genetic testing, with 319 positive tests for ATTRv: 308 carried the V30M variant (96.4%) and 11 carried other pathogenic variants. The V30M prevalence was highest in Mallorca and Menorca (1 in 2,900 and 4,700, respectively), with lower rates in Ibiza and Formentera. The co-occurrence of V30M and NP_000362.1:p.Gly26Ser (G6S) on the same chromosome in 93% of V30M carriers suggests a common origin. This study becomes the first registry of ATTRv in the Balearic Islands, aiming to raise awareness among clinicians across all areas and services while enabling more accurate diagnostics, informed genetic counselling, and targeted clinical follow-ups. We also postulate the Balearic Islands as a major global focus for the V30M variant, with a distinct genetic profile suggesting a unique founder effect within the region.