Somatic/Germinal Mosaicism of a F8 Promoter Deletion Confounds Clinical Predictions in a Family with Haemophilia A: Key Role of Genotype Quantitation

Large F8 deletions cause 10 to 15% of severe-haemophilia A (HA) cases and associate with the highest clinical/biochemical severity and with significantly augmented risks for developing inhibitors against therapeutic factor VIII (FVIII).[1]

Only 45 to 50% of severe-HA cases present family history of the disease.[2] In the remnant cases (sporadic HA), the mutation origin defines different clinical scenarios in which the risk of recurrence and thus genetic counselling significantly vary. The origin of the causative mutation may be either prezygotic or postzygotic generating a genetic mosaicism affecting, partially or totally, one or more tissue/organs including the gonads. Furthermore, the technical features of the genotyping approach for detecting and measuring an eventual genetic mosaicism critically affect its diagnosis.[3]

The quali-quantitative extent of somatic and germinal mosaicisms is passively assumed to be associated with the phenotypic expression of haemophilia severity and inheritance pattern, respectively.

We present a case of a family affected with HA in which the clinical/biochemical severity and inheritance patterns associate with the observed fraction of mosaic cells bearing a F8-promoter deletion.

Authors' Contribution

All authors confirmed they have contributed to the intellectual content of this article and have met the following three requirements: (1) significant contributions to the conception and design, acquisition of data or analysis and interpretation of data; (2) drafting or revising the article for intellectual content and (3) final approval of the article.

^* Both these authors have equally contributed to this work and should be considered as first authors.

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