Impact of genetic testing family screening in hereditary transthyretin amyloidosis

Background Hereditary transthyretin amyloidosis (ATTRv), is an autosomal dominant, multisystem, adult-onset, genetic disease, caused by pathogenic variants in the transthyretin (TTR) gene. Although genetic testing is recommended for at-risk family members, there have been no studies addressing the uptake and clinical impact of genetic testing in relatives. Purpose To assess the uptake and clinical impact of genetic testing in ATTRv families. Methods Genetic screening uptake and its clinical impact was analyzed in relatives at-risk of probands with ATTRv evaluated between 2010 and 2023 at a Spanish amyloid center located in a non-endemic area. Results ATTRv cascade genetic screening was conducted in 464 relatives (50% male, 46 [IQR 34-57] years) from 86 families (38 Val50Met, 26 Val142Ile, 22 other variants). The median number of screened relatives per family was 5 (range 0-22). A total of 201 (43%) subjects at-risk (50% male, 45 [34-57] years) were identified as genetic carriers (median 2 individuals per family, Range 0-13). Clinical evaluation revealed that 67 (33%) carriers (55% male, median age 53 [45-61]) showed ATTRv manifestations (79% neurologic, 64% cardiac, 12% ophthalmologic). Of these, 95% initiated disease-modifying therapies. Affected relatives were diagnosed and were able to initiate disease-modifying therapies at a younger age compared to probands (53 [45-61] vs. 66 [56-73] years; p<0.001 and 56.5 [49-63] vs. 66 [58-74] years; p<0.001, respectively). Additionally, seven relatives opted for preimplantation genetic testing. Independent predictors of absence of genetic screening in relatives included: older age of the proband at diagnosis, an incidental diagnosis in the proband, living in a different province or country than the proband, older age, male sex and distant relationship with the proband (second or third-degree relative). Conclusions Structured systematic cascade genetic screening identifies a median of two genetic carriers per proband in families with ATTRv. Familial genetic screening should be actively pursued in ATTRv, as it enables earlier diagnosis and treatment initiation in affected relatives.Family Genetic screening in ATTRv Factors linked to absence of screening