Hereditary Transthyretin Amyloidosis in Israel: Genetic Landscape and Clinical Characteristics

BackgroundHereditary transthyretin (ATTRv) amyloidosis is a rare, adult-onset autosomal-dominant disorder caused by pathogenic variants in the transthyretin (TTR) gene. Data about relevant variants in specific populations and typical initial manifestations may facilitate early diagnosis and treatment. We here describe the genetic landscape of ATTRv amyloidosis in Israel.MethodsGenetic and clinical data of TTR variant carriers and ATTRv amyloidosis patients were collected from a national referral clinic and other subspecialty clinics in Israel. Genotype-phenotype correlations of the detected variants were detailed. In addition, two large Israeli exome sequence (ES) databases were screened for TTR variants.ResultsSeven heterozygous disease-causing variants in TTR were identified among 95 adults (52 males, 50.7%). The Ser77Tyr variant was found in 68 (71.6%) subjects of Jewish Yemenite ancestry. Val122Ile was found in 9 (9.4%) subjects and was the only variant detected in individuals of Arab ethnicity. Other variants were Thr60Ala, Val30Met, Val32Ala, Ala81Val, and Glu89Val. Thirty-five individuals were ATTRv amyloidosis patients (25 males, 71.4%), diagnosed at a mean age of 62.5 +/- 6.7 years, and 23 (63.7%) were due to Ser77Tyr. Initial symptoms were mostly related to carpal tunnel syndrome, and the sensitivity of scintigraphy was low for Ser77Tyr but high for Thr60Ala and Val32Ala variants. TTR pathogenic variants were detected in 14 of approximately 36,600 subjects who underwent ES, including Val122Ile in 9 subjects of Arab ethnicity.ConclusionsMost ATTRv amyloidosis cases in Israel are attributable to the Ser77Tyr variant. However, other variants also contribute to disease occurrence, and testing is warranted in clinically suspected patients.