Origin of mutation in sporadic cases of severe haemophilia A in Sweden

Abstract

Introduction

Many newly diagnosed Swedish severe haemophilia A (HA) patients are sporadic cases. Some genotypically non-carrier mothers have gone on to have two descendants with the same mutation, presumably due to mosaicism.

Aims

To define the origin of mutation in sporadic cases of HA, reveal possible sex-specific differences in mutagenesis and identify potential mosaics among non-carrier mothers.

Methods

Sanger sequencing characterized the mutations and microsatellite haplotyping determined the origin of the X chromosome carrying the mutation in 3 generations of 45 families with sporadic severe HA. Droplet digital polymerase chain reaction (ddPCR) was used in five cases to reveal mosaicism mutations not found on conventional DNA sequencing.

Results

In 23/45 families the mother carried the mutation and in 5/28 families the grandmother was also a carrier. The X chromosome was of grandpaternal origin in 17/23 cases. One of five tested mothers was a mosaic with a mutation frequency of 7%.

Conclusion

In 40/45 families the sporadic case resulted from a mutation in the last two generations. In 82% (23/28) the carrier mothers had a de novo mutation where the X chromosome was of paternal origin in 74% (17/23). ddPCR is a potentially powerful and promising analysis for mosaicism in HA.

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