Severe phenotype of neurofibromatosis type 2 in a patient with a 7.4-MB constitutional deletion on chromosome 22: possible localization of a neurofibromatosis type 2 modifier gene?

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder predisposing to multiple neoplastic lesions with the hallmark of schwannoma arising at the eighth cranial nerve. NF2 shows a distinct clinical variability, with a mild and a severe form of the disease. The NF2 gene is mutated in constitutional DNA of affected patients from NF2 families and in sporadic cases. Comprehensive mutation analyses in patients with severe and mild phenotypes revealed mutations in only 34%-66%. In the remaining fraction, the genetic mechanism behind the development of NF2 is unknown. Analyses of germline mutations do not provide a conclusive explanation for the observed clinical heterogeneity of NF2. It can therefore be hypothesized that other factors, e.g., modifier gene(s), contribute to the development of a more severe NF2 phenotype. We report a mentally retarded patient with the severe form of NF2 who displays a 7.4 million base pair deletion on chromosome 22. We performed a full genetic characterization of this case using heterozygozity analysis of 41 markers from chromosome 22, detailed FISH mapping of deletion breakpoints, allelotyping of all other chromosomes, and sequencing of the NF2 gene in tumor DNA. Two genomically large deletions similar in size (700-800 kb), which encompass the entire NF2 gene, have been reported previously in mildly affected NF2 patients. The centromeric breakpoints of these deletions were similar to the centromeric breakpoint in the present case. However, the deletion in our patient extends over a much larger distance toward the telomere of 22q. Our results support the existence of NF2 modifier gene(s) and suggest that such a putative locus maps to a 6.5-MB interval on 22q, between D22S32 and the MB gene.