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Prenatal diagnosis of the WAS R86H sequence variation in heterozygous twins.

To the Editor:

A healthy 28-year-old woman was heterozygous for the Wiskott-Aldrich syndrome gene (WAS) sequence variation, and the syndrome-causing variant was inherited by her first-born son (Fig. 1). The 2.5-year-old hemizygous boy developed characteristic features of the WAS, including eczema, thrombocytopenia, and recurrent infections of the lower respiratory tract from early infancy. The mother presented recently with a new pregnancy, and the abdominal ultrasound scan obtained at 7 weeks of gestation revealed that she had conceived twins. We counseled the mother on the complexity and risks of invasive prenatal diagnostic procedures and made it clear that the potential risk of disease in a male fetus is 50%; nevertheless, she decided to continue her pregnancy and to undergo invasive prenatal evaluation. At 11 weeks of gestation, chorionic villus sampling by a transabdominal approach was performed with no complications. Rapid karyotyping revealed a male and a female fetus. We then isolated genomic DNA from the chorionic villus samples and performed bidirectional DNA sequencing of the WAS gene. Neither of the fetuses carried the R86H WAS sequence variant found in the mother and her son (Fig. 1).


The WAS is a rare X-linked immunodeficiency disorder characterized by eczema, thrombocytopenia with small platelets, recurrent pyogenic infections, and high incidences of autoimmune diseases and malignancies (1). The genetic basis of the disease is a sequence variant in the WAS gene encoding a 502-amino acid protein that is expressed in the cytosol of hematopoietic cells (2,3). Sequence variations occur throughout the WAS gene and include missense, nonsense, and splice-site variants; insertions; and deletions (4). In a recent study, 141 unique sequence variations were identified in 265 patients affected with WAS or X-linked thrombocytopenia, including 4 R86H missense variants (4). The predominant WAS sequence variations were missense variants, which were typically located in exons 1 to 4.

Genomic medicine provided a powerful means to detect WAS sequence variations in this early pregnancy and to assist the mother in her decision-making on the fate of her fetuses. This report is the first to describe a case of DNA analysis in a twin pregnancy at risk for WAS. As in singleton pregnancies, chorionic villus sampling is also used as an invasive tool for early sex determination and DNA assays in multiple pregnancies (5). We decided to use chorionic villus sampling because it has considerable advantages over amniocentesis by offering rapid karyotyping and DNA studies at an early stage of pregnancy. In multifetal pregnancies, early diagnosis by chorionic villus sampling also facilitates selective termination of an affected fetus. Remarkably, fetal termination performed earlier in pregnancy may be associated with a higher survival rate of the unaffected twin (6). It is important to emphasize that only experienced centers should perform these procedures because of the technical challenges and the expertise needed.


(1.) Snapper SB, Rosen FS. A family of WASPs. N Engl J Med 2003;348:350-1.

(2.) Derry JM, Ochs HD, Francke U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell 1994; 78:635-44.

(3.) Ochs HD, Notarangelo LID. Structure and function of the Wiskott-Aldrich syndrome protein. Curr Opin Hematol 2005;12:284-91.

(4.) Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, et al. Mutations of the Wiskott-Aldrich syndrome protein (WASP): hotspots, effect on transcription, and translation and phenotype/ genotype correlation. Blood 2004;104:4010-9.

(5.) Weisz B, Rodeck CH. Invasive diagnostic procedures in twin pregnancies. Prenat Diagn 2005; 25:751-8.

(6.) Evans MI, Goldberg JD, Horenstein J, Wapner RJ, Ayoub MA, Stone J, et al. Selective termination for structural, chromosomal and Mendelian anomalies: international experience. Am J Obstet Gynecol 1999;181:893-7.

Krisztina Alapi [1] Melinda Erdos [1] Olga Torok [2] Laszlo Marodi [1]*

Departments of [1] Infectious and Pediatric Immunology and

[2] Obstetrics and Gynecology University of Debrecen Medical and Health Science Center Debrecen, Hungary

* Address correspondence to this author at: Department of Infectious and Pediatric Immunology, University of Debrecen, Medical and Health Science Center, H-4012 Debrecen, Hungary. Fax 3652-430-323; e-mail

DOI: 10.1373/clinchem.2005.064816
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Title Annotation:Letters
Author:Alapi, Krisztina; Erdos, Melinda; Torok, Olga; Marodi, Laszlo
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:May 1, 2006
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