Abstract 25

Both parents of about 25% of HS patients are clinically and hematologically normal. These patients could have either the autosomal recessive form of the disease or a de novo mutation and constitute an unsolved problem during genetic counseling. Eighty unrelated Italian HS children with normal parents have been investigated. These patients were screened for the presence of a-spectrinLEPRA, a synthetically partially deficient a-spectrin allele, as well as for the -108 T->C mutation of the ankyrin promoter. Both alleles have been recently identified in some cases of genuinely recessive HS. The patients were also screened for the occurrence of ankyrin or β-spectrin de novo mutations. In about one half of the subjects we were able to detect the molecular alterations underlying HS and consequently to identify the true manner of inheritance. Six patients showed a genuinely recessive pattern of inheritance (i.e. 5 a-spectrinLEPRA and 1 ankyrin -108 T->C mutation). The de novo inactivation of one ankyrin allele was found in 25 patients (31%) and the de novo inactivation of one β-spectrin allele was found in 11 HS subjects (14%) Our data show an increasing proportion of apparently recessive HS due to the high incidence of ankyrin or β-spectrin de novo mutations. The de novo events may have a parental origin with occurrence of a germline mutation even if a somatic mutation in a very early stage of the embryological development of the HS children cannot be excluded. A recurrence risk at most of 4.8% has been calculated for a next child in the case of germline de novo mutation. Only a few cases instead appear to be genuinely recessive.