ClinVar Genomic variation as it relates to human health

Benson (2001) noted that the val122-to-ile mutation in transthyretin (V122I) was discovered in an individual with cardiomyopathy but no family history of amyloidosis (AMYLD1; 105210) (Gorevic et al., 1989). It was first believed to explain some cases of senile cardiac amyloidosis. Both homozygous and heterozygous patients have been described. All affected individuals have been elderly, presenting after the age of 60 with cardiomyopathy, and nearly all have been African American. The mutation has been found in nearly 4% of selected African American cohorts and may be the cause of heart failure in a significant portion of the elderly in this population (Jacobson et al., 1996). Peripheral neuropathy has been reported, but is a minor clinical manifestation of this syndrome. Because transthyretin amyloidosis is an autosomal dominant trait, the high allele frequency makes this one of the most important genetic mutations in the United States. Jiang et al. (2001) stated that the V122I variant is the most common amyloidogenic variant worldwide, with an estimated 1.3 million heterozygotes. Although the age of onset (typically older than 60 years) is similar for senile systemic amyloidosis and familial amyloidotic cardiomyopathy V122I patients, the latter are much more likely to suffer cardiac failure, especially in the case of V122I homozygotes. V122I cardiac disease penetrance approaches 100%, whereas senile systemic amyloidosis, involving wildtype TTR amyloid deposition in the heart, affects less than 25% of the population above age 80. In a case of senile systemic amyloidosis in a 68-year-old black male, Jacobson et al. (1988, 1990) found an apparently homozygous substitution of isoleucine for valine at position 122 (V122I). No family members were available for study. This change predicted a genomic G-to-A transition, destroying an MaeIII restriction site. Homozygosity was established by the demonstration that the patient's DNA was entirely resistant to MaeIII cleavage. The variant was found in none of either 24 controls or 6 other patients with senile systemic amyloidosis. The only other report of homozygosity for a transthyretin mutation causing amyloidosis is the report by Holmgren et al. (1988) concerning the val30-to-met mutation (176300.0001). Gorevic et al. (1989) found that isolated amyloid fibrils from 3 cases of systemic senile amyloidosis contained subunit proteins that were transthyretin. Complete sequence analysis of 1 (presumably the same case as that studied by Jacobson et al., 1988, 1990) showed the presence of a new variant TTR molecule with a single amino acid substitution of isoleucine for valine at position 122. Thus, systemic senile amyloidosis may, in some cases at least, be a genetically determined disease expressed late in life. Snyder et al. (1989) provided evidence for the hereditary nature of senile cardiac amyloidosis. They identified 2 brothers, both homozygous for the isoleucine-for-valine substitution at position 122. The substitution predicts a guanine-to-adenine substitution at the nucleotide corresponding to the first base of codon 122 (i.e., GTC to ATC) which would result in the loss of a MaeIII restriction endonuclease recognition site. The same change was found in the DNA of the son of 1 of the brothers in heterozygous state and was confirmed by analysis of the plasma prealbumin. Westermark et al. (1990) found that the transthyretin molecule is normal in cases of the common form of senile systemic amyloidosis that affects to some degree 25% of the population over 80 years of age. For this reason they concluded that factors other than the primary structure of TTR must be important in its pathogenesis. They suggested that the cardiomyopathy that is similar to senile systemic amyloidosis and is associated with the val122-to-ile mutation represents another rare form of amyloidosis separate from the common disorder. Using PCR around codon 122 and digestion with MaeIII, Jacobson et al. (1991) investigated the frequency of the val122-to-ile mutation in 177 black persons without amyloidosis and without overt cardiac disease. The MaeIII restriction site is eliminated by the val122-to-ile mutation. They found 4 examples of the MaeIII-negative gene among 354 chromosomes, giving a frequency of 1.1% (95% confidence interval 0.32-2.7%). Thus, the variant is relatively common in blacks. HLA genotyping did not suggest that the val122-to-ile heterozygotes were of closely related genetic background. DNA testing for this variant may be useful in the clinical evaluation of black patients with unexplained cardiomyopathy. It is useful to distinguish TTR-related cardiac amyloidosis from that due to deposition of immunoglobulin light chains, AL amyloid (Olson et al., 1987). The TTR disease has a better prognosis than does AL amyloidosis involving the heart. Chemotherapy, which is thought to be beneficial in AL amyloid (Kyle et al., 1985), may be of no value in TTR-amyloidosis. With a specific test for the val122-to-ile mutation, Jacobson (1992) confirmed that the mutation was present in heterozygous state in 4 of 177 healthy black individuals and as a homozygous variant in a person with cardiac amyloidosis. He suggested that genetic testing for this mutation would be worthwhile in the evaluation of patients with unexplained cardiomyopathy. Nichols et al. (1991) had found the val122-to-ile mutation in homozygous state in anther black patient with cardiac TTR-amyloidosis, and Saraiva et al. (1990) had found it in heterozygous state in a black patient with the same disorder. After the age of 60, isolated cardiac amyloidosis is 4 times more common among blacks than whites in the United States; 3.9% of blacks are heterozygous for the amyloidogenic V122I (ile122) allele. Jacobson et al. (1997) presented evidence that a high prevalence of transthyretin ile122 is at least partially responsible for the increased frequency of senile cardiac amyloidosis among blacks. They studied cardiac tissue from 32 blacks and 20 whites over 60 years of age with isolated cardiac amyloidosis. Transthyretin amyloidosis was identified in 31 of the 32 cardiac tissue samples from the black patients and in 19 of the 20 samples from the white patients. In 6 of the 26 analyzable DNA samples (23%) from the black patients and none of the 19 samples from the white patients, heterozygosity for the ile122 variant was found. In a second, age-matched cohort of blacks without amyloidosis at the same institution, 4 of 125 DNA samples obtained at autopsy (3.2%) were heterozygous for the ile122 allele. On reexamination, the cardiac tissue from these 4 patients contained small amounts of amyloid not detected at the initial autopsies. All subjects with the ile122 variant had ventricular amyloid. Jacobson et al. (1997) concluded that the assessment of elderly black patients with unexplained heart disease should include a consideration of transthyretin amyloidosis, particularly that related to the ile122 allele. Benson (1997) stated that the best way to detect cardiac amyloidosis is with echocardiography. By the time a patient presents with symptoms of heart failure, the intraventricular septum and left ventricular posterior wall are thickened and the left atrium is often enlarged, an indication of the presence of restrictive cardiomyopathy of the left ventricle. Endomyocardial biopsy is also a valuable means of diagnosing cardiac amyloidosis and is recommended for patients scheduled to undergo cardiac catheterization because of a restrictive hemodynamic pattern. DNA testing is useful to confirm the hereditary nature of the disease and in counseling patients and their families. In the treatment of heart failure due to amyloidosis the avoidance of negative inotropic agents (including most antiarrhythmic medications) and overdiuresis and the maintenance of normal sinus rhythm contribute to a better outcome. Askanas et al. (2003) reported a 70-year-old African American man with sporadic inclusion body myositis (147421) and cardiac amyloidosis associated with the V122I mutation. Cultured skeletal muscle fibers from the patient showed vacuolar degeneration, congophilic inclusions, and clusters of colocalizing beta-amyloid and TTR immunoreactivities, none of which were found in normal cultured muscle fibers. Overexpression of the amyloid precursor protein gene (APP; 104760) resulted in accelerated fiber degeneration, greater congophilic inclusions, and accumulation of heavy beta-amyloid oligomers. Askanas et al. (2003) suggested that the V122I mutation may have predisposed the patient to inclusion body myositis by increasing beta-amyloid deposition in skeletal muscle. Jiang et al. (2001) demonstrated that the V122I variant, producing familial amyloidotic cardiomyopathy primarily in individuals of African descent, increases the velocity of rate-limiting tetramer dissociation, thus resulting in accelerated amyloidogenesis. Chakrabartty (2001) pointed out that the in vitro studies of Jiang et al. (2001) provided a biophysical explanation of how disease-associated mutations in TTR affect the course of TTR amyloidoses, thus strengthening the amyloid hypothesis. In 2 Afro-Caribbean patients with cardiac amyloidosis, aged 63 and 74 years, respectively, Lachmann et al. (2002) identified heterozygosity for the V122I mutation in the TTR gene. Cardiomyopathy was the predominant clinical feature in both patients, and 1 of them also displayed neuropathy. To assess the effect of the V122I variant on long-term morbidity and mortality, Quarta et al. (2015) genotyped 3,856 black participants in the Atherosclerosis Risk in Communities study and assessed cardiac structure and function as well as features suggestive of cardiac amyloidosis in participants older than 65 years of age. The authors identified carrier status for the V122I variant in 124 participants (3%). After 21.5 years of follow-up, Quarta et al. (2015) did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1,382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval, 0.73-1.36; p = 0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% confidence interval, 1.03-2.10; p = 0.04). On echocardiography at visit 5, carriers had worse systolic and diastolic function, as well as a higher level of N-terminal pro-brain natriuretic peptide, than noncarriers, although carriers had a low prevalence of overt manifestations of amyloid cardiomyopathy. Quarta et al. (2015) did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasted with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. Buxbaum and Ruberg (2017) reviewed the TTR V122I allele. The frequency of this amyloidogenic allele is 0.0173, and it is carried by 3.5% of community-dwelling African Americans. Genotyping across Africa indicated that the origin of the allele is in the West African countries that were the major source of the slave trade to North America. Genotyping of tissues from 112 consecutive autopsies of African Americans age 65 or over identified 4 samples (3.9%) positive for the V122I allele; heart tissues from all 4 carriers showed some degree of cardiac amyloid deposition. However, the clinical penetrance varied, resulting in substantial heart disease in some carriers and few symptoms in others. The allele has been found in 10% of African Americans older than age 65 with severe congestive heart failure. The authors reported potential forms of therapy in clinical trials and suggested testing for this variant in older African Americans with heart disease. (less)