Genetic Linkage of the Dehydrated Hereditary Stomatocytosis Locus to Chromosome 16 in Two Kindreds and Refinement of the Candidate Gene Region to 16q24.2 - 16qter,

Blood - Tập 118 - Trang 3170 - 2011
Brett L. Houston, Teresa Zelinski1, Donald S Houston2, Sara J. Israels3, Gail Coghlan4, Bernie N. Chodirker1, Patrick G. Gallagher5, Ryan Zarychanski6
1Departments of Biochemistry & Medical Genetics and Pediatrics & Child Health, University of Manitoba, Winnipeg, MB, Canada
2Department of Internal Medicine, Section of Hematology & Medical Oncology, CancerCare Manitoba, Winnipeg, MB, Canada
3Department of Pediatrics and Child Health and the Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, MB, Canada
4Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
5Pediatrics and Genetics, Yale University School of Medicine, New Haven, CT, USA
6Department of Community Health Sciences, University of Manitoba

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Abstract Abstract 3170 BACKGROUND: The hereditary stomatocytoses are a rare, diverse group of clinical conditions associated with chronic red blood cell hemolysis and increased erythrocyte membrane permeability to monovalent cations. The most common form of hereditary stomatocytosis is dehydrated stomatocytosis (DHSt, also called hereditary xerocytosis) first reported by Miller et al. (Blood 38:184, 1971). We studied two genetically unrelated kindreds with DHSt, one from Western Canada and the other, the original DHSt kindred reported by Miller et al., from upstate New York. Although the DHSt causative gene is unknown, previous studies have mapped the DHSt locus to 16q23 – 16qter. OBJECTIVES: To define the chromosomal region carrying the disease locus in these two families using DNA linkage analysis. METHODS: PCR-based genotyping was performed on genomic DNA according to standard methods. Fine mapping was performed using markers on the telomeric end of chromosome 16. Linkage data was generated from both paternal and maternal meioses. LOD scores (logarithm (base 10) of odds) were determined at assumed recombination fractions (theta) 0.00, 0.05, 0.10, 0.20, 0.30 and 0.40. Continuous allelic alignments were manually generated. RESULTS: Based on reticulocyte count, MCHC, and osmotic fragility, disease phenotypes were identified in 29 individuals of the Canadian kindred, and 27 individuals of the New York kindred. Linkage data from both families confirmed that the disease-causing locus mapped to chromosome 16. In the Canadian kindred, significant LOD scores (> +3.00) were established between the disease-causing locus (DHSt) and D16S3074, D16S2621 and D16S3026. Three recombinants were observed between DHSt:D16S3074, two between DHSt:D16S2621 and none between DHSt:D16S3026. Significant LOD scores were also established between DHSt and D16S3074, D16S476, and D16S413 in the New York kindred, and recombination between DHSt:D16S3074 was also observed. Definition of critical recombination events allowed us to define the centromeric boundary of the region containing the disease-causing locus as D16S2621, a 2.4 cM region containing 51 known or predicted genes. CONCLUSIONS: Genetic linkage analysis has confirmed DHSt linkage to chromosome 16 in two unrelated kindreds and has refined the assignment of DHSt to chromosome 16q24.2 – 16qter. Disclosures: No relevant conflicts of interest to declare.

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Blood

Tập 118

3170

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