Vogt et al. Journal of Medical Case Reports 2011, 5:577 http://www.jmedicalcasereports.com/content/5/1/577 Three types of recurrent large NF1 deletion have so far been reported: the type-1 deletion, present in 70% to 80% of all patients with NF1 with large NF1 deletions, is the most frequent [6,9]. The breakpoints of type-1 NF1 deletions are located within low-copy repeats, termed NF1-REPa and NF1-REPc [10]. Type-1 deletions encom- pass 1.4 Mb and lead to the loss of 14 genes (Figure 1). By contrast, type-2 NF1 deletions span 1.2 Mb and include only 13 genes since LRRC37B is not deleted (Figure 1). The breakpoints of type-2 deletions are located within SUZ12 and its pseudogene SUZ12P [11-13]. With an estimated frequency of 9% to 20%, type-2 deletions are less frequent than type-1 NF1 dele- tions [6,9,12]. A third type of recurrent NF1 deletion (type-3) has recently been reported which encompass 1.0 Mb and include nine genes (Figure 1) [6,14]. In addition to these three types of recurrent NF1 deletion mediated by non-allelic homologous recombination (NAHR), an amorphous group of atypical NF1 deletions has also been observed in a subset of patients. These atypical NF1 deletions are characterized by non-recur- rent breakpoints and they are highly heterogeneous in terms of their size, breakpoint position and the number of genes present within the deleted region [6,9]. It is widely assumed that genotype-phenotype correla- tions in patients with large NF1 deletions are likely to be influenced by both the number and type of deleted genes. The comprehensive clinical characterization of 29 patients with NF1 with molecularly ascertained type-1 NF1 deletions identified several features that are fre- quently associated with this type of deletion [5]. These features include dysmorphic facial features, tall stature, large hands and feet, scoliosis, developmental delay, learning disabilities and a high burden of subcutaneous, plexiform and spinal neurofibromas. cen NF1 REPa NF1 REPb SUZ12P ATAD5 C17orf42 CRLF3 ADAP2 RNF135 Page 2 of 7 In contrast to the well documented clinical phenotype associated with type-1 NF1 deletions, the detailed clini- cal investigation of patients with non-mosaic type-2 NF1 deletion has not been published so far. Type-2 deletions frequently arise during post-zygotic cell division and consequently give rise to somatic mosaicism with nor- mal cells alongside those cells harboring the deletion [11-13]. At least 44% of all patients with NF1 with type- 2 NF1 deletions exhibit somatic mosaicism [9] but their prevalence may well be under-estimated [12]. Studies of genotype-phenotype correlations in patients with mosaic type-2 NF1 deletions are inherently difficult to perform because the number of normal cells lacking the deletion in different tissues (and hence their impact on the clini- cal phenotype) is difficult to assess. Somatic mosaicism is very likely to exert a major influence on disease sever- ity since patients with mosaic large NF1 deletions often display a mild clinical phenotype [11-13]. Whereas somatic mosaicism is an issue that needs to be addressed in all cases of type-2 NF1 deletion, somatic mosaicism is rare among patients with type-1 NF1 dele- tions, occurring in only 2% to 4% of cases [9]. In order to assess the phenotype associated with type- 2 NF1 deletions, careful clinical examination of patients with non-mosaic (germline) type-2 NF1 deletions is cri- tically important. However, germline type-2 NF1 dele- tions are rare, with an estimated frequency of < 6% among patients with NF1 with gross NF1 gene deletions [9]. In a previous study, we specifically sought type-2 NF1 deletions among patients with NF1 deletion in order to explore the causative mutational mechanisms underlying these deletions [13]. We succeeded in identi- fying 18 patients with type-2 deletions, 16 of whom exhibited somatic mosaicism with normal cells. The remaining two patients with type-2 NF1 deletions in NF1 REPc tel C17orf79 UTP6 SUZ12 LRRC37B NF1 OMG EVI2B EVI2A RAB11FIP4 Type-1 NF1 deletion (1.4 Mb) Type-2 NF1 deletion (1.2 Mb) Type-3 NF1 deletion (1.0 Mb) Figure 1 Schema of the NF1 gene region and relative extents of the different deletion types. The 14 genes located within the NF1 gene region, and included within the type-1 deletion region, are indicated by horizontal arrows. The direction of each arrow denotes the transcriptional orientation of the corresponding gene. The relative locations of the low-copy repeats, termed NF1-REPa, NF1-REPb and NF1-REPc are also indicated by vertical bars. Cen, centromeric; tel, telomeric.