Approximately one third of the patients with haemophilia appears to have no affected relatives. The proportion of cases due to a new mutational event as well as the gamete origin of the mutation has been much debated. The objective of this study was to define the origin of the mutation in families with an isolated case by DNA analysis. We investigated 22 families with an isolated case of haemophilia A. Intragenic (Bell, Xbal) and extragenic (BglII/DX13, Taql/Stl4) RFLPs were investigated for. If necessary, paternity was tested by DNA fingerprint patterns obtained with the 33.15 mini satellite probe.In seven of the 22 families it could be demonstratedthat the abnormal X-chromosome of the haemophiliac was derived from the normal maternal grandfather. In six of these 7 families the mother of the patient had a high probability of carriershio on the basis of clotting factor VIII assays, so that, probably, the mutation had occurred in the paternal gamete. As a consequence, carriership could be excluded for aunts, nieces and more distant female relatives of the patient.In three families the abnormal X-chromosome was derived from the maternal grandmother, while, sofar, in the remaining 12 families no conclusions as to the origin of the mutation could be drawn.In contrast with earlier findings, these results illustrate that at least thirty percent of the isolatedcases of haemophilia A are due to a recent de novo mutation.
Use of an automated DNA analysis system (DARAS®) for sequence-specific recognition of Neisseria meningitidis DNA