Hereditary Transthyretin Amyloidosis in Patients Referred to a Genetic Testing Program

Abstract

Background: Diagnosis of hereditary amyloid transthyretin (hATTR) amyloidosis with cardiomyopathy is frequently delayed, in large part because of symptom overlap with other cardiovascular diseases and limited provider knowledge of this disease. The sponsored and provider referred hATTR Compass Genetic Testing Program (Ionis, Carlsbad, CA; Ambry Genetics, Aliso Viejo, CA) provided no-cost genetic testing to adults with a family history or clinical suspicion of hATTR amyloidosis. This study aims to characterize patients with hATTR amyloidosis and increase awareness of genetic testing for hATTR.

Methods and results: Patients were referred to the hATTR genetic testing program, and a cross-sectional post hoc analysis was performed. A pathogenic TTR variant was identified in 1503 (6.6%) of 22 886 patients referred for genetic testing between June 2018 and March 2022. Patients were identified in all US states, 3 US territories, and Canada. Median age at testing was 63 years, and 44% were female. The p.V142I TTR variant was the most common (n=1263, 84.0%). Only 32% of patients with a pathogenic TTR variant reported a known family history; a lower percentage of Black individuals reported a known family history compared with other racial and ethnic groups. Black patients accounted for 23.7% of all patients referred and 81.9% of patients with the p.V142I variant.

Conclusions: This sponsored genetic testing program identified a large number of patients with a pathogenic TTR variant, notably, in geographic regions not previously reported, and demographic groups that are historically underrepresented in the literature.

Keywords: amyloidosis; cardiomyopathy; genetic testing; prevalence; transthyretin.

Figure 1. Pathogenic TTR variants.

A, Breakdown of TTR variants identified. B, Age at testing in patients with a pathogenic TTR variant. C, Comparison of age at testing in women and men within each TTR variant. *P<0.0001. ^† P<0.05. ^‡Red line denotes median age. The dashed lines represent the first and third quartiles (25th and 75th percentiles). Comparisons were made between TTR variants; age at testing for male and female patients was compared within TTR variants. ^§Median (IQR) age, years: p.V142I Het All, 72 (59–78); p.V142I Hom All, 66 (62–70); p.T80A All, 57 (46–67); p.V50M All, 57 (42–66). ^||Median (IQR) age, years: p.V142I Het male vs female, 71 (61–77) vs 72 (56–79); pV142I Hom male vs female, 65 (61–69) vs 67 (63–72); p.T80A male vs female, 58 (47–69) vs 54 (43–66); p.V50M male vs female, 65 (44–73) vs 45 (39–63). Het indicates heterozygous; Hom, homozygous; IQR, interquartile range; ns, not significant; TTR, transthyretin gene; and TTR+, patient with a pathogenic TTR variant.

Figure 2. Self‐reported race and ethnicity of patients with a pathogenic TTR variant (A) by identified pathogenic TTR variant and (B) by self‐reported family history.

*n=5413. ^†n=1760; racial and ethnic groups other than Black or White, includes Ashkenazi Jewish; Asian; Caribbean; Hispanic; Middle Eastern; Multiracial: Asian, Black; Multiracial: Black, Hispanic; Multiracial: Black, Native American; Multiracial: Black, Native American, White; Multiracial: Black, White; Multiracial: Caribbean, White; Multiracial: Hispanic, White. ^‡n=12 219; ^§n=3494. TTR indicates transthyretin gene.

Figure 3. TTR VUS.

A, TTR VUS identified in the overall population. B, TTR variants classified as VUS and likely pathogenic or pathogenic based on position on protein reference. *Denotes location of VUS occurring in the same position as substitutions classified as P or LP. LP indicates likely pathogenic; P, pathogenic; TTR, transthyretin gene; and VUS, variants of uncertain significance.

Figure 4. Comparison of patients with pathogenic TTR variants or pathogenic variants of other genes, by self‐reported race and ethnicity.

*n=392. ^†n=5413. ^‡n=870. ^§n=498; Alaska Native; Ashkenazi Jewish; Caribbean; Middle Eastern; Multiracial: Ashkenazi Jewish, Hispanic; Multiracial: Asian, Black; Multiracial: Asian, Black, Hispanic; Multiracial: Asian, Pacific Islander; Multiracial: Asian, White; Multiracial: Black, Hispanic; Multiracial: Black, Native American; Multiracial: Black, Native American, White; Multiracial: Black, Pacific Islander; Multiracial: Black, White; Multiracial: Caribbean, White; Multiracial: Hispanic, Native American; Multiracial: Hispanic, White; Multiracial: Middle Eastern, White; Multiracial: Native American, White; Multiracial: Pacific Islander, White; Multiracial: South Asian, White, Native American, Other, Pacific Islander, Portuguese, Sephardic Jewish, South Asian. ^||n=12 219. ^#n=3494. non‐TTR+ indicates patient with a pathogenic variant for a gene other than TTR; TTR, transthyretin gene; and TTR+, patient with a pathogenic TTR variant.

Figure 5. Cardiogenetics panel testing*.

A, Panel testing results. B, Number of patients with a cardiomyopathy‐related pathogenic non‐ TTR variant. C, Age at testing. D, Age at testing in patients with a pathogenic TTR variant only vs patients with a pathogenic TTR variant and a pathogenic variant of another gene. E, Pathogenic variants by racial and ethnic group. F, Race and ethnicity of patients identified as having a pathogenic TTR variant and 1 pathogenic non‐ TTR variant or 2 pathogenic non‐ TTR variants. *10 845 patients referred for cardiogenetics panel testing. ^† P<0.0001. ^‡Red line denotes median age. The dashed lines represent the first and third quartiles (25th and 75th percentiles). Comparisons were made between variants. ^§Median (IQR) age, years: TTR +: 71 (58–77); TTN +: 53 (40–62); MYBPC3 +: 56 (40–67); MYH7 +: 52 (35–62); DMD +: 43 (30–58); DSP : 54 (42–63). ^||Cardiogenetics panel only. ^#Median (IQR) age, years: TTR + only: 72 (61–78); TTR + and non‐ TTR +: 58 (47–67). **Includes Alaska Native; Ashkenazi Jewish; Asian; Caribbean; Latinx; Middle Eastern; Multiracial: Asian, Black; Multiracial: Asian, Black, Hispanic; Multiracial: Asian, Pacific Islander; Multiracial: Asian, White; Multiracial: Black, Hispanic; Multiracial: Black, Pacific Islander; Multiracial: Black, White; Multiracial: Hispanic, Native American; Multiracial: Hispanic, White; Multiracial: Middle Eastern, White; Multiracial: Native American, White; Multiracial: Pacific Islander, White; Multiracial: South Asian, White; Native American; Other; Pacific Islander; Portuguese; South Asian. IQR indicates interquartile range; non‐TTR+, patient with a pathogenic variant for a gene other than TTR; ns, not significant; TTR , transthyretin gene; and TTR +, patient with a pathogenic TTR variant.