Genetic heterogeneity in X‐linked agammaglobulinemia complicates carrier detection and prenatal diagnosis

Abstract

X‐linked agammaglobulinemia (XLA) is a severe antibody deficiency disease reflecting an arrest of B lymphocyte differentiation at the level of precursor B cells. The disease is inherited in an X‐linked recessive mode. In a single eight‐generation pedigree the XLA gene was mapped to the Xq21.3‐Xq22 area of the X chromosome. The data establish close linkage of the XLA locus to the DXS17 restriction fragment length polymorphic (RFLP) marker locus (the lodscore exceeding 6 at = 0). A series of RFLP markers around the DXS17 locus provided an RFLP haplotype of use in genetic counselling within this pedigree. In one other pedigree a phenotypically identical disease was inherited but was accompanied by a high frequency of recombination with the DXS17 locus, which made localisation of the gene at the DXS17 locus highly unlikely (lod score < –3). This genetic heterogeneity complicates genetic counselling within particular pedigrees, especially when the localization of the XLA gene involved in those pedigrees has not been established.