Premium
Germline mosaicism resulting in the transmission of severe hemophilia B from a grandfather with a mild deficiency
Author(s) -
Cutler Jacqueline A.,
Mitchell Michael J.,
Smith Mark P.,
Savidge Geoffrey F.
Publication year - 2004
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.30162
Subject(s) - proband , germline mosaicism , aunt , germline , factor ix , genetics , daughter , genetic counseling , asymptomatic carrier , asymptomatic , germline mutation , x chromosome , karyotype , mutation , medicine , biology , chromosome , gene , evolutionary biology , sociology , anthropology
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. © 2004 Wiley‐Liss, Inc.