Abstract
Patients with neurofibromatosis type 1 (NF1) and type 1 NF1 deletions often exhibit more severe clinical manifestations than patients with intragenic NF1 gene mutations, including facial dysmorphic features, overgrowth, severe global developmental delay, severe autistic symptoms and considerably reduced cognitive abilities, all of which are detectable from a very young age. Type 1 NF1 deletions encompass 1.4 Mb and are associated with the loss of 14 protein-coding genes, including NF1 and SUZ12. Atypical NF1 deletions, which do not encompass all 14 protein-coding genes located within the type 1 NF1 deletion region, have the potential to contribute to the delineation of the genotype/phenotype relationship in patients with NF1 microdeletions. Here, we review all atypical NF1 deletions reported to date as well as the clinical phenotype observed in the patients concerned. We compare these findings with those of a newly identified atypical NF1 deletion of 698 kb which, in addition to the NF1 gene, includes five genes located centromeric to NF1. The atypical NF1 deletion in this patient does not include the SUZ12 gene but does encompass CRLF3. Comparative analysis of such atypical NF1 deletions suggests that SUZ12 hemizygosity is likely to contribute significantly to the reduced cognitive abilities, severe global developmental delay and facial dysmorphisms observed in patients with type 1 NF1 deletions.
Highlights
It has been estimated that 5–11% of all neurofibromatosis type 1 (NF1) patients have large deletions which include the NF1 gene and its flanking regions at 17q11.2 [1,2,3,4]
More informative with regard to genotype/phenotype correlations are those atypical NF1 deletions, which are smaller than 1.4 Mb, each encompassing only a subset of the 14 protein-coding genes located in the type 1 NF1 microdeletion region
Group #2 atypical NF1 deletions, encompassing only a subset of the 14 proteincoding genes located within the type 1 NF1 microdeletion region, have the potential to inform genotype/phenotype correlations and facilitate the identification of modifying genes
Summary
It has been estimated that 5–11% of all NF1 patients have large deletions which include the NF1 gene and its flanking regions at 17q11.2 [1,2,3,4]. These so called ‘NF1 microdeletions’ are frequently associated with severe clinical manifestations, giving rise to the NF1 microdeletion syndrome (MIM#613675), which occurs with an estimated incidence of 1:60,000 (reviewed by [5]). 70–80% of all large NF1 deletions are of type 1, and in most instances, they occur as germline deletions that are present in all cells of the affected patients [9,10]. NAHR causing type 1 NF1 deletions occurs between the low-copy repeats NF1-REPa and NF1-
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