A phenotypic comparison of the Romanian and French ATTRv cohorts: Glu54Gln founder pathogenic variant vs the most common variants in Western Europe.

Aim And Methods: We conducted a retrospective observational study of the ATTRv heterozygous mutation frequency, phenotype, and all-cause mortality at two cardiac amyloidosis centers in Romania and France.

Results: 291 patients were included: 26 Glu54Gln (all Romanian), 200 Val122Ile, 47 Val30Met and 18 Ser77Tyr. On diagnosis, Gu54Gln patients were younger than Val122Ile or late-onset Val30Met (median age: 46 [42-50], 76 [71-80] and 70 [61-76], respectively; p < 0.001) and had more autonomic dysfunction (50 %, 6.3 %, and 7.7 %, respectively; p < 0.001) and similar cardiac symptom profiles. They had fewer conduction disorders (11.5 %) than early-onset Val30Met (76.9 %, p < 0.001) and Ser77Tyr group, notably less cardiac pacemaker present on diagnosis: 3.8 % for Glu54Gln vs. 23.5 % for Ser77Tyr; p = 0.014. Glu54Gln, Val122Ile, late-onset Val30Met and Ser77Tyr patients had similar left ventricular mass and systolic function values. Median survival for Glu54Gln patients was 58.7 years (95 %CI 55.9 - upper bound indeterminable), significantly lower than that of Val122Ile (83.6 years 95 %CI 81.6-85.5, log-rank test p < 0.001), late-onset Val30Met (83.4 years 95 %CI 81.9-84.9, log-rank test p < 0.001) and Ser77Tyr (74.8 years 95 %CI 68.7-80.9, log-rank test p = 0.022). Median survival after diagnosis was 5.7 years for Glu54Gln patients (95 %CI 4.7-6.4).

Conclusion: We established that the Glu54Gln variant has an aggressive, mixed phenotype, with an early onset of autonomic dysfunction and heart failure symptoms. We emphasize the need for systematic genetic testing in patients with ATTR as understanding genotype-phenotype correlations is key for the management and the counseling of patients and their family members.