BACKGROUND: Hemophilia A (HA) in females is a rare observation. Here we describe various genetic mechanisms that result in phenotypic expression of HA in seven females. METHODS: The F8 gene was examined in all patients and relatives by direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) was performed for large deletion screening. X chromosome inactivation was studied by PCR analysis of a polymorphic CAG repeat in the first exon of the human androgen receptor (HUMARA) gene. RESULTS: In two females sequencing of the F8 gene revealed homozygous missense mutations (Arg593Cys and Tyr1680Phe) as a consequence of consanguineous marriage. The third case was due to compound heterozygosity comprising the missense mutation Leu412Phe inherited from the carrier mother, together with a de novo large deletion spanning exon 9-22, probably originating from the germ cells of the healthy father. Three further cases shared a common mechanism representing heterozygous mutations in the F8 gene (Arg1781His, Arg327His, small deletion in exon 10) combined with non-random inactivation of the X chromosome. The final case describes a coincidental inheritance of HA and Coffin-Lowry syndrome in the same family. The HA phenotype results from a heterozygous small deletion affecting the F8 gene (c.6872 del CT leading to Thr2272fs) and a complete inactivation of the maternal X chromosome, which segregates with Coffin-Lowry syndrome in the two brothers of the proposita. CONCLUSIONS: In conclusion, molecular genetic analysis represents an essentially valuable tool in elucidating the nature of the molecular mechanisms underlying the HA phenotype in females.
BACKGROUND:Hemophilia A (HA) in females is a rare observation. Here we describe various genetic mechanisms that result in phenotypic expression of HA in seven females. METHODS: The F8 gene was examined in all patients and relatives by direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) was performed for large deletion screening. X chromosome inactivation was studied by PCR analysis of a polymorphic CAG repeat in the first exon of the humanandrogen receptor (HUMARA) gene. RESULTS: In two females sequencing of the F8 gene revealed homozygous missense mutations (Arg593Cys and Tyr1680Phe) as a consequence of consanguineous marriage. The third case was due to compound heterozygosity comprising the missense mutation Leu412Phe inherited from the carrier mother, together with a de novo large deletion spanning exon 9-22, probably originating from the germ cells of the healthy father. Three further cases shared a common mechanism representing heterozygous mutations in the F8 gene (Arg1781His, Arg327His, small deletion in exon 10) combined with non-random inactivation of the X chromosome. The final case describes a coincidental inheritance of HA and Coffin-Lowry syndrome in the same family. The HA phenotype results from a heterozygous small deletion affecting the F8 gene (c.6872 del CT leading to Thr2272fs) and a complete inactivation of the maternal X chromosome, which segregates with Coffin-Lowry syndrome in the two brothers of the proposita. CONCLUSIONS: In conclusion, molecular genetic analysis represents an essentially valuable tool in elucidating the nature of the molecular mechanisms underlying the HA phenotype in females.
Authors: Jill M Johnsen; Shelley N Fletcher; Haley Huston; Sarah Roberge; Beth K Martin; Martin Kircher; Neil C Josephson; Jay Shendure; Sarah Ruuska; Marion A Koerper; Jaime Morales; Glenn F Pierce; Diane J Aschman; Barbara A Konkle Journal: Blood Adv Date: 2017-05-18
Authors: Jane A Mason; Hnin T Aung; Adayapalam Nandini; Rickie G Woods; David J Fairbairn; John A Rowell; David Young; Rachel D Susman; Simon A Brown; Valentine J Hyland; Jeremy D Robertson Journal: Mol Genet Genomic Med Date: 2018-02-28 Impact factor: 2.183