Tay-Sachs disease is caused by mutations in the hexosaminidase A gene (HEXA) that lead to destruction of nerve cells in the brain. About 1 in 300 people carries a mutation in the HEXA gene; the rate among Ashkenazi Jews and people of French-Canadian or Cajun ancestry is ten times higher. Tay-Sachs disease also appears at a higher rate among people with Irish ancestry.
Carriers of a single mutation in the HEXA gene do not develop Tay-Sachs disease. Some researchers suspect that carriers (heterozygotes) may have some biological advantage over non-carriers. There are more than 100 mutations that can cause Tay-Sachs. The classic type causes death in childhood, but some forms do not appear until adulthood and do not lead to early death. Genetic testing is important because false positive results can be obtained from a Tay-Sachs blood test that measures activity of the hexosaminidase A enzyme. False negatives are also possible; see "Notes From a Dragon Mom."
SNPs in the HEXA gene that cause Tay-Sachs disease include the following; note that 23andMe often but not always reports results from the opposite strand as dbSNP:
- rs121907954 or i4000436; adult form; G269S (risk allele A in dbSNP, but T in 23andMe data)
- rs387906309 or i4000391; infantile form; 1278insTATC (risk allele +TATC, or in 23andMe data, I)
- rs147324677 or i4000393; infantile form; IVS12+1G>C (risk allele G in both dbSNP and 23andMe data)
- rs76173977 or i4000438; infantile form; IVS9+1G>A (risk allele T in both dbSNP and 23andMe data)
- rs138058578 or i4000440; causing blood test false positive; R249W (risk allele A in both dbSNP and 23andMe data)
- rs121907970 or i4000442; causing blood test false positive; R247W (risk allele T in dbSNP, or in 23andMe data, A)
In Ashkenazi Jews, the three mutations that are thought to comprise 98% of the disease alleles in the population are rs387906309, rs121907954 and rs147324677.[PMID 24498621]