title: A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening.
abstract: 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.
authors.affiliation: McGill University, Montreal Children's Hospital Research Institute, Quebec, Canada.
authors.forename: B L
authors.initials: BL
authors.lastname: Triggs-Raine
authors.forename: E H
authors.initials: EH
authors.lastname: Mules
authors.forename: M M
authors.initials: MM
authors.lastname: Kaback
authors.forename: J S
authors.initials: JS
authors.lastname: Lim-Steele
authors.forename: C E
authors.initials: CE
authors.lastname: Dowling
authors.forename: B R
authors.initials: BR
authors.lastname: Akerman
authors.forename: M R
authors.initials: MR
authors.lastname: Natowicz
authors.forename: E E
authors.initials: EE
authors.lastname: Grebner
authors.forename: R
authors.initials: R
authors.lastname: Navon
authors.forename: J P
authors.initials: JP
authors.lastname: Welch
mesh_terms: 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
chemical_list: D009838:Oligodeoxyribonucleotides; D012313:RNA; D004247:DNA; D054818:Hexosaminidase A; D001619:beta-N-Acetylhexosaminidases