Analphoid marker chromosome in a patient with hyper-IgE syndrome, autism, and mild mental retardation

Hyper-IgE syndrome with recurrent infections (HIES) is a primary immunodefi ciency disease characterized by recurrent skin and lung abscesses and extre me elevations of serum IgE, but also involving dentition, bones, and connec tive tissue. Although the etiology of HIES is unknown, autosomal dominant i nheritance has been observed in multiple kindreds. A 17 year old male with sporadic HIES, autism, and mild mental retardation was found to have a supe rnumerary marker chromosome in peripheral blood lymphocytes and shin fibrob lasts. Microdissection and FISH analysis of the marker chromosome showed th at it was derived from a small interstitial deletion of one homologue of ch romosome 4q21. Lack of hybridization of probes specific for telomeres and a lphoid centromeres, including a centromere 4 specific probe, established th at the marker was an analphoid ring chromosome. Comparative genotyping of t ransformed B-cell subclones with (M+) and without (M-) the marker chromosom e showed loss of the maternal alleles in M- cells between markers D4S1569 a nd D4S3010. FISH using YAC clones from 4q21 confirmed the size and location of the interstitial deletion. Thus our patient's phenotypes were associate d with de novo formation of a marker chromosome containing 15-20 cM of DNA deleted from his maternally derived chromosome 4. Proximal chromosome 4q th erefore is a candidate region for disease genes for both HIES and autism. I dentification of genes disrupted or lost during the formation of the marker chromosome as well as linkage studies in kindreds with HIES or autism may help us to understand the etiology of these complex phenotypes.