Absence of cutaneous neurofibromas in an NF1 patient with an atypical deletion partially overlapping the common 1.4 Mb microdeleted region

Abstract

The majority of neurofibromatosis type 1 (NF1) microdeletions in 17q11.2 span approximately 1.4 Mb and have breakpoints that lie within the proximal and distal NF1-low copy repeats, termed NF1-REPs. Less frequent are patients with atypical deletions and non-recurring breakpoints. NF1 patients with gross deletions have been reported to manifest a more severe clinical phenotype than NF1 patients with intragenic mutations, and display early onset and extensive growth of neurofibromas. It has been suggested that the deletion of a neighboring gene or genes in addition to the NF1 gene may modify the expression of the disease, particularly with regard to the high burden of cutaneous neurofibromas. Thus, atypical deletions partially overlapping with the common 1.4 Mb microdeletion interval could prove useful in identifying possible genetic modifiers in the NF1 gene region whose haploinsufficiency might promote neurofibroma growth. Here we report a 20-year-old female who has an atypical deletion with a proximal breakpoint in NF1 intron 21 and a distal deletion breakpoint in the ACCN1 gene. The deletion spans 2.7 Mb and was mediated by an intrachromosomal non-homology-driven mechanism, for example, non-homologous end-joining (NHEJ). Remarkably, this patient did not exhibit cutaneous neurofibromas. However, genotype-phenotype comparisons in this and other previously reported patients with atypical deletions partially overlapping the commonly deleted 1.4 Mb interval do not identify a specific deleted region that is associated with increased neurofibroma growth.