Abstract 5277

Hereditary spherocytosis (HS) is the commonest hereditary hemolytic anemia due to a red cell membrane defect. Multiple proteins of the vertical component of the cytoskeleton are implicated. They include ankyrin-1, protein 4.2, band 3 protein, alpha and beta spectrin. Previous studies in Caucasians (Eber et al Nat Genet 1996) and Japanese (Nakanishi et al Int J Hematol 2001) showed that mutations in ANK1, the gene coding for ankyrin-1, was the most prevalent defect in HS. There is no published data on mutations in Chinese patients with HS.

Thirteen Chinese HS patients from 9 unrelated families and 28 normal Chinese subjects were studied. Fourteen of the 42 exons of ANK1 (exon 1, 2, 4, 5, 6, 16, 17, 20, 21, 22, 26, 33, 38, 39) were screened for mutation using direct nucleotide sequencing. Selection of exons for study was based on the frequencies of mutation detected in a large study in an Asian population (Nakanishi et al Int J Hematol 2001). Two novel nonsense mutations were detected in 2 unrelated patients in heterozygous state – codon 968 GAG>TAG and codon 1762 TGG>TAG. Family studies showed that 1 was a de novo mutation and the other was autosomal dominant. The overall prevalence of ANK1 mutations in this cohort was 22%. The actual prevalence may be higher as pathogenic mutations may also lie in the unscreened promoter and exons. Ten benign polymorphisms were detected in 8 of the 14 exons screened. Nine were synonymous mutations and 1 was a reported missense mutation. All but 1 were seen in our normal controls, including the missense mutation.

Our study shows that ANK1 mutation is a genetic cause of HS in Chinese but other candidate genes are definitely implicated. In consistence with published data in Caucasians pathogenic mutations are usually private. Many benign polymorphisms exist and they are commonly found in the general population. These features present significant challenges for screening of mutations and their interpretation in HS patients.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.