Homozygosity for the V122I mutation in transthyretin is associated with earlier onset of cardiac amyloidosis in the african american population in the seventh decade of life

Individuals heterozygous for the V122I mutation in transthyretin (TTR) tend to develop cardiac amyloidosis, often after the seventh decade of life. Although homozygotes have been reported, these have typically been single case reports. We report a cohort of 13 V122I homozygotes. TTR gene sequencing results from the Mayo Clinic Molecular Genetics Laboratory between September 2004 and January 2013 were reviewed; 177 heterozygotes and 13 homozygotes for the V122I alteration were identified. Detailed clinical history was available for the 24 heterozygotes seen at Mayo Clinic. We compared age at onset of disease for this group to homozygotes, both alone and pooled with the 11 homozygotes from the literature. Individuals with homozygous V122I manifested symptoms a mean of 10 years earlier than heterozygotes (63.8 ± 5.7 versus 72 ± 8.1 yrs, P = 0.0002). Further, males were significantly overrepresented in both heterozygous and homozygous individuals. There was a trend for an even higher male bias in the homozygous group. All 24 homozygotes were African American, whereas four of the heterozygotes were reported as white. Two novel V122I compound heterozygotes were also identified, with clinical presentation in the late fifth or early sixth decade of life. This study is the largest homozygous V122I cohort reported and demonstrates association with earlier age at onset. It also highlights the uncertain penetrance, particularly with respect to sex.