Clinical and molecular evaluation of non-dominant hereditary spherocytosis

About 75% of hereditary spherocytosis (HS) patients have the autosomal domi nant form of the disease, whereas both parents of the remaining HS patients are clinically and haematologically normal. These patients could have eith er the autosomal recessive form of the disease or a de novo mutation. We st udied 80 randomly chosen, Italian HS children with normal parents. They had different clinical phenotypes (16 mild, 40 moderate, 16 moderately severe and eight severe). These patients were screened for the occurrence of ankyr in or beta -spectrin de novo mutations. To search for ankyrin de novo mutat ions affecting mRNA accumulation, we studied a (AC)(n) microsatellite locat ed in the non-coding sequence of the last exon of the ankyrin gene, and fou r different exonic polymorphisms in the beta -spectrin gene were utilized f or the detection of de novo mutations influencing beta -spectrin mRNA stabi lity. They were also screened for the presence of alpha -spectrin(LEPRA) as well as for the mutation -108T -->C in the ankyrin promoter, two variants previously found in some cases of genuinely recessive HS. Twenty-five patie nts showed ankyrin de novo mutations and 10 HS subjects had beta -spectrin de novo mutations. Furthermore, we found five patients to be heterozygous f or alpha -spectrin(LEPRA) and one heterozygous for the mutation in the anky rin promoter. Therefore, a molecular diagnosis was achieved in about 50% of the cases. Our data demonstrate that, among HS patients with normal parent s, de novo dominant mutants are six times more common than recessive mutati ons. These results should be considered in view of the genetic counselling of a normal couple with a HS child.