GROSS DELETIONS OF THE NEUROFIBROMATOSIS TYPE-1 (NF1) GENE ARE PREDOMINANTLY OF MATERNAL ORIGIN AND COMMONLY ASSOCIATED WITH A LEARNING-DISABILITY, DYSMORPHIC FEATURES AND DEVELOPMENTAL DELAY

Mutation screening in neurofibromatosis type 1 (NF1) families has long been hampered by the complexity of the NF1 gene. By using a novel mul ti-track screening strategy, 67 NF1 families (54 two-generation, 13 th ree-generation) with a de novo mutation in the germline of the first g eneration were studied with two extragenic and 11 intragenic markers. The pathological lesion was identified in 31 cases. Loss of heterozygo sity (LOH) in the affected individual revealed a gross gene deletion i n 15 of the two-generation families; in 12 (80%) of them, the deletion was maternally derived. Eleven patients with a gross deletion exhibit ed developmental delay, ten had dysmorphic features and six manifested a learning disability. No gross deletion was apparent in any of the 1 3 three-generation families, suggesting that such lesions are subject to more intense selection. In these families, the new mutation was of paternal origin in 11 kindreds and the underlying mutational event cou ld be characterised in three of them.