Glanzmann thrombasthenia is an autosomal recessive bleeding disorder caused by mutations in the genes encoding platelet GPIIb or GPIIIa. Both genes map to chromosome 17q21 and polymorphisms within this chromosomal region have been identified. In the current study, prenatal diagnosis was performed for a family that already had one affected child, patient 1, who had a compound heterozygous mutation in GPIIb. At the time of prenatal diagnosis, the maternal GPIIb mutation had been identified but the paternal GPIIb mutation was unknown. By sequence analysis, the fetus was identified as a carrier of the mother's mutation. To determine the probability of the fetus inheriting the father's mutation, haplotype analysis of DNA samples from the fetus, mother, father and affected child were performed using polymorphic markers on chromosome 17q12‐q21. These markers included polymorphisms within the thyroid hormone receptor α1 gene (THRA1), the breast cancer gene (BRCA1), GPIIb, GPIIIa, and an anonymous marker D17S579. Heterozygosity within the THRA1, BRCA1 and GPIIIa polymorphic markers predicted that the fetus carried the father's normal allele. Based on genetic linkage studies, no recombination was identified with any of the informative markers, and from the map distance between GPIIb and BRCA1 the accuracy of diagnosis was predicted to be >98%. The father's mutation was subsequently identified and direct sequence analysis of fetal DNA confirmed that the fetus did not inherit the fathers' mutant allele.
FABRY'S DISEASE is an X-linked recessive disorder resulting from deficient activity of the lysosomal hydrolase α-galactosidase A.1-3 The enzymatic defect leads to the progressive accumulation of neutral glycosphingolipids with terminal α-galactosyl moieties (particularly globotriaosylceramide) in the lysosomes of vascular endothelial and smooth-muscle cells throughout the body. In classically affected males, who have no detectable α-galactosidase A activity, the onset of disease manifestations occurs in childhood or adolescence and is characterized by severe acroparesthesias, angiokeratoma, corneal opacities, and hypohidrosis. The cardiac manifestations result from the accumulation of globotriaosylceramide in the myocytes, leading to myocardial failure; in coronary endothelial cells, resulting . . .
Journal Article Fabry disease: twenty-three mutations including sense and antisense CpG alterations and identification of a deletional hot-spot in the α-galactosidase A gene Get access Christine M. Eng, Christine M. Eng 1Departments of Human Genetics, Mount Sinai School of MedicineFifth Avenue and 100th Street, New York, NY 10029, USA2Departments of Pediatrics, Mount Sinai School of MedicineFifth Avenue and 100th Street, New York, NY 10029, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Dana J. Niehaus, Dana J. Niehaus 1Departments of Human Genetics, Mount Sinai School of MedicineFifth Avenue and 100th Street, New York, NY 10029, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Annette L. Enriquez, Annette L. Enriquez 1Departments of Human Genetics, Mount Sinai School of MedicineFifth Avenue and 100th Street, New York, NY 10029, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Tania S. Burgert, Tania S. Burgert 1Departments of Human Genetics, Mount Sinai School of MedicineFifth Avenue and 100th Street, New York, NY 10029, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Mark D. Ludman, Mark D. Ludman 3Department of Pediatrics, Dalhousie UniversityHalifax, Nova Scotia, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar RobertJ. Desnick RobertJ. Desnick * 1Departments of Human Genetics, Mount Sinai School of MedicineFifth Avenue and 100th Street, New York, NY 10029, USA2Departments of Pediatrics, Mount Sinai School of MedicineFifth Avenue and 100th Street, New York, NY 10029, USA *To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Human Molecular Genetics, Volume 3, Issue 10, October 1994, Pages 1795–1799, https://doi.org/10.1093/hmg/3.10.1795 Published: 01 October 1994 Article history Received: 25 May 1994 Revision received: 02 August 1994 Accepted: 02 August 1994 Published: 01 October 1994
Fabry disease (FD) is an X-linked recessive disorder caused by the deficient activity of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). Affected males are reliably diagnosed by demonstration of deficient alpha-Gal A activity in plasma or leukocytes. However, identification of female carriers is problematic due to Lyonization, requiring mutation identification and/or linkage studies for accurate carrier detection. Here, we describe a large Brazilian kindred with Fabry disease that permitted comparison of biochemical and molecular diagnostic techniques. Initially, the plasma alpha-Gal A activities were determined in at-risk affected males and potential female carriers; affected males were readily diagnosed, while the females had variable results. To detect carrier females, haplotype analysis using 10 polymorphic markers adjacent to the gene was performed. Subsequently, solid-phase direct sequencing of the alpha-Gal A gene demonstrated a novel single base deletion in exon 1 (30delG). Discrepancies were observed between the enzymatic and molecular diagnoses in two at-risk females. These findings emphasize the need for precise heterozygote diagnosis by mutation and/or haplotype analyses in all families with Fabry disease.
