A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening.
Deficiency of beta-hexosaminidase A (Hex A) activity typically results in Tay-Sachs disease. However, healthy subjects found to be deficient in Hex A activity (i.e., pseudodeficient) by means of in vitro biochemical tests have been described. We analyzed the HEXA gene of one pseudodeficient subject and identified both a C739-to-T substitution that changes Arg247----Trp on one allele and a previously identified Tay-Sachs disease mutation on the second allele. Six additional pseudodeficient subjects were found to have the C739-to-T mutation. This allele accounted for 32% (20/62) of non-Jewish enzyme-defined Tay-Sachs disease carriers but for none of 36 Jewish enzyme-defined carriers who did not have one of three known mutations common to this group. The C739-to-T allele, together with a "true" Tay-Sachs disease allele, causes Hex A pseudodeficiency. Given both the large proportion of non-Jewish carriers with this allele and that standard biochemical screening cannot differentiate between heterozygotes for the C739-to-T mutations and Tay-Sachs disease carriers, DNA testing for this mutation in at-risk couples is essential. This could prevent unnecessary or incorrect prenatal diagnoses.
Triggs-Raine
B L
BL
McGill University, Montreal Children's Hospital Research Institute, Quebec, Canada.
Mules
E H
EH
Kaback
M M
MM
Lim-Steele
J S
JS
Dowling
C E
CE
Akerman
B R
BR
Natowicz
M R
MR
Grebner
E E
EE
Navon
R
R
Welch
J P
JP
D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D006580:Genetic Carrier Screening; D005820:Genetic Testing; D054818:Hexosaminidase A; D006801:Humans; D007231:Infant, Newborn; D007585:Jews; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction / Q000379:methods; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D013661:Tay-Sachs Disease / Q000235:genetics*; D001619:beta-N-Acetylhexosaminidases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D009838:Oligodeoxyribonucleotides; D012313:RNA; D004247:DNA; D054818:Hexosaminidase A; D001619:beta-N-Acetylhexosaminidases