title: Germline mosaicism resulting in the transmission of severe hemophilia B from a grandfather with a mild deficiency.
abstract: We report a family in which the normal pattern of X-linked inheritance of hemophilia B (Factor IX deficiency) is complicated by mosaicism in the proband's maternal grandfather. The proband, an infant with severe Factor IX deficiency, was initially thought to be a sporadic case. Testing of other family members identified his mother as a carrier of the disorder, and his asymptomatic maternal grandfather as having very mild FIX deficiency. The causative familial mutation was identified as a two base pair deletion (AG within codons 134-135) in the Factor IX gene. The grandfather was shown to be "heterozygous" for the deletion. Karyotype analysis confirmed him to be 46XY thereby ruling out Klinefelter syndrome. The proband's aunt, who as the daughter of a man with hemophilia is theoretically an obligate carrier, was found not to carry this familial mutation, and thus not to be a carrier of hemophilia B. The grandfather must therefore be an X chromosome somatic and germline mosaic, with consequent segregation of the affected and non-affected Factor IX genes. This observation underlines the importance of confirming carrier status even in those individuals assumed to be obligate carriers, and has implications for genetic counseling.
authors.affiliation: The Haemophilia Reference Centre, Centre for Thrombosis and Haemostasis, St. Thomas' Hospital, Lambeth Palace Road, London, United Kingdom. jacqueline.cutler@gstt.sthames.nhs.uk
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Cutler
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mitchell
authors.forename: Mark P
authors.initials: MP
authors.lastname: Smith
authors.forename: Geoffrey F
authors.initials: GF
authors.lastname: Savidge
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005164:Factor IX / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D018095:Germ-Line Mutation; D002836:Hemophilia B / Q000097:blood / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D040582:Inheritance Patterns; D008297:Male; D009030:Mosaicism; D010375:Pedigree; D017384:Sequence Deletion
chemical_list: D005164:Factor IX; D004247:DNA