Fine mapping of IGAD1 in IgA deficiency and common variable immunodeficiency: Identification and characterization of haplotypes shared by affected members of 101 multiple-case families

To limit the region containing a mutation predisposing to selective IgA def iciency (IgAD) and common variable immunodeficiency (CVID), 554 informative members of 101 multiple-case families were haplotyped at the IGAD1 candida te locus in the MHC. Microsatellite markers were placed onto the physical m ap of IGAD1 to establish their order and permit rapid haplotype analyses. L inkage analysis of this extended family set provided additional support for a strong susceptibility locus at IGAD1 with a maximum multipoint nonparame tric linkage score in excess of 3, Although the transmission of maternal IG AD1 haplotypes from unaffected heterozygous parents to the affected offspri ng was in excess, this was not apparent in multiple-case families with a pr edominance of affected mothers, suggesting that this parental bias is influ enced by the affection status of transmitting parents and supporting a mate rnal effect in disease susceptibility, Of 110 haplotypes shared by 258 affe cted family members, a single haplotype (H1) was found in 44 pairs of affec ted relatives, accounting for the majority of the IGAD1 contribution to the development of IgAD/CVID in our families. The H1 allelic variability was h igher in the telomeric part of the class III region than in the distal part of the class II region in both single- and multiple-case families. Incompl ete H1 haplotypes had most variant alleles in the telomeric part of the ana lyzed region in homozygous IgAD/CVID patients, whereas this was not observe d in unaffected homozygotes, These data suggest that a telomeric part of th e class II region or centromeric part of the class III region is the most l ikely location of IGAD1.