DELETIONS SPANNING THE NEUROFIBROMATOSIS-I GENE - IDENTIFICATION AND PHENOTYPE OF 5 PATIENTS

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder chara cterized by marked variation in clinical severity. To investigate the contribution to variability by genes either contiguous to or contained within the NF1 gene, we screened six NF1 patients with mild facial dy smorphology, mental retardation, and/or learning disabilities, for DNA rearrangement of the NF1 region. Five of the six patients had NF1 gen e deletions on the basis of quantitative densitometry, locus hemizygos ity, and analysis of somatic cell hybrid lines. Analyses of hybrid lin es carrying each of the patient's chromosomes 17, with 15 regional DNA markers, demonstrated that each of the five patients carried a deleti on >700 kb in size. Minimally, each of the deletions involved the enti re 350-kb NF1 gene; the three genes-EVI2A, EV12B, and OMG-that are con tained within an NF1 intron; and considerable flanking DNA. For four o f the patients, the deletions mapped to the same interval; the deletio n in the fifth patient was larger, extending farther in both direction s. The remaining NF1 allele presumably produced functional neurofibrom in; no gene rearrangements were detected, and RNA-PCR demonstrated tha t it was transcribed. These data provide compelling evidence that the NF1 disorder results from haploid insufficiency of neurofibromin. Of t he three documented de novo deletion cases, two involved the paternal NF1 allele and one the maternal allele. The parental origin of the sin gle remaining expressed NF1 allele had no dramatic effect on patient p henotype. The deletion patients exhibited a variable number of physica l anomalies that were not correlated with the extent of their deletion . All five patients with deletions were remarkable for exhibiting a la rge number of neurofibromas for their age, suggesting that deletion of an unknown gene in the NF1 region may affect tumor initiation or deve lopment.