TYPE-2 GAUCHER-DISEASE WITH HYDROPS-FETALIS IN AN ASHKENAZI JEWISH FAMILY RESULTING FROM A NOVEL RECOMBINANT ALLELE AND A RARE SPLICE JUNCTION MUTATION IN THE GLUCOCEREBROSIDASE LOCUS

Gaucher disease, the deficiency of the lysosomal enzyme glucocerebrosi dase (EC 3,2.1.45), is frequently encountered in the Ashkenazi Jewish population, Carrier screening for Gaucher disease by enzyme analysis p erformed during a routine pregnancy indicated that both Ashkenazi pare nts were carriers, Screening for four common Gaucher mutations was sub sequently performed on fetal and parental DNA. None of the common Ashk enazi mutations were identified. However, when exons 9-11 were amplifi ed and digested with NciI to detect the L444P mutation, it appeared th at the mother and the fetus had an unusual allele and that the expecte d paternal allele was not present. When the fetal amniocytes were foun d to have less than 2% of the normal glucocerebrosidase activity and a fetal sonogram revealed hydrops fetalis, the pregnancy was terminated . The diagnosis of severe type 2 Gaucher disease was confirmed at auto psy. Ultrastructural studies of epidermis from the fetus revealed the characteristic disruption of lamellar bilayers, diagnostic for type 2 Gaucher disease. In subsequent studies of the fetal DNA, long-template polymerase chain reaction amplification revealed one appropriately si zed band (similar to 6,5 kb) and one smaller (similar to 5.2 kb) band. Sequencing of the similar to 5.2-kb fragment identified a novel fusio n allele resulting from recombination between the glucocerebrosidase g ene and its pseudogene beginning in intron 3, This fusion allele was i nherited from the father, The result was confirmed by Southern blot an alysis using the enzyme SstII, Sequencing of the 6.5-kb fragment ident ified a previously described, although rare, T-to-G; splice junction m utation in intron 10 of the maternal allele, which introduced an NciI site, The couple had a subsequent pregnancy which was also found to be affected. This case study identifies a novel recombinant allele and a n unusual splice junction mutation, and demonstrates that even in the Ashkenazi population, screening for common mutations may not accuratel y identify the most severe forms of the disease. (C) 1998 Academic Pre ss.