Tay-Sachs disease is an autosomal recessive genetic disorder resulting from 
mutation of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme, 
beta-N-acetylhexosaminidase A (ref. 1). A relatively high frequency of carriers 
(1/27) of a lethal, infantile form of the disease is found in the Ashkenazi 
Jewish population, but it is not yet evident whether this has resulted from a 
founder effect and random genetic drift or from a selective advantage of 
heterozygotes. We have identified a single-base mutation in a cloned fragment of 
the HEXA gene from an Ashkenazi Jewish patient. This change, the substitution of 
a C for G in the first nucleotide of intron 12 is expected to result in 
defective splicing of the messenger RNA. A test for the mutant allele based on 
amplification of DNA by the 'polymerase chain rection and cleavage of a DdeI 
restriction site generated by the mutation revealed that this case and two other 
cases of the Ashkenazi, infantile form of Tay-Sachs disease are heterozygous for 
two different mutations. The occurrence of multiple mutant alleles warrants 
further examination of the selective advantage hypothesis.