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Neurofibromatosis type 1 (NF1) is caused by NF1 gene mutations. The phenotype is highly variable, with ‘modifiers’ being discussed as potential determinants. Mismatch repair deficiency was shown to cause NF1 mutations, but constitutional mutation of mismatch repair genes was identified only once in a NF1 patient. We aimed to analyze whether DNA methylation of mismatch repair gene promoters, known to lead to transcriptional silencing, is associated with increased tumor load in NF1 defined by the number of cutaneous neurofibromas. Leukocyte DNA of 79 controls and 79 NF1 patients was investigated for methylation of mismatch repair genes MLH1, MSH2, MSH6, and PMS2 by methylation-specific PCR and pyrosequencing. MLH1, MSH6, and PMS2 promoters were not methylated. By contrast, we found promoter methylation of MSH2 with a higher rate of methylation in NF1 patients compared with controls. Furthermore, when comparing NF1 patients with a low vs those with a high number of cutaneous neurofibromas, MSH2 promoter methylation was significantly different. In patients with a high tumor burden, methylation of two (out of six) CpGs was enhanced. This finding was not confounded by age. In conclusion, enhanced methylation involving transcription start points of mismatch repair genes, such as MSH2 in NF1, has not been described so far. Methylation-induced variability of MSH2 gene expression may lead to variable mismatch repair capacity. Our results may point toward a role of MSH2 as a modifier for NF1, although the amount of DNA methylation and subsequent gene expression in other cell types of NF1 patients needs to be elucidated. [ABSTRACT FROM AUTHOR]

Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. NS is associated with mutations in the genes PTPN11, SOS1, RAF1, or KRAS, whereas CFCS can be caused by mutations in BRAF, MEK1, MEK2, or KRAS. The NS phenotype is rarely accompanied by multiple giant cell lesions (MGCL) of the jaw (Noonan-like/MGCL syndrome (NL/MGCLS)). PTPN11 mutations are the only genetic abnormalities reported so far in some patients with NL/MGCLS and in one individual with LEOPARD syndrome and MGCL. In a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. Mutations in BRAF or MEK1 were identified in these patients. All mutations detected in these seven patients with syndromic MGCL had previously been described in NS or CFCS without apparent MGCL. This study demonstrates that MGCL may occur in NS and CFCS with various underlying genetic alterations and no obvious genotype–phenotype correlation. This suggests that dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant cell lesion formation in patients with NS and CFCS rather than specific mutation effects.European Journal of Human Genetics (2009) 17, 420–425; doi:10.1038/ejhg.2008.188; published online 15 October 2008 [ABSTRACT FROM AUTHOR]

Congenital central hypoventilation syndrome (CCHS), a rare disorder typically presenting in the newborn period, results in over 90% of cases from PHOX2B polyalanine repeat mutations. It is characterized by alveolar hypoventilation, symptoms of autonomic nervous system dysregulation, and in a subset of cases Hirschsprung’s disease and, later, tumors of neural crest origin. We describe a preterm infant with severe phenotype of CCHS and hyperinsulinism. A novel de novo heterozygote missence mutation (Gly68Cys) in the PHOX2B gene could be identified. Based on the observation of three patients presenting with the combination of congenital hyperinsulinism and CCHS, hyperinsulinism might represent an additional clinical feature of CCHS. [ABSTRACT FROM AUTHOR]

Purpose: Germline mutations in either BRCA1 or BRCA2 genes are responsible for the majority of hereditary breast and ovarian cancers. At present, over thousand distinct BRCA1 and BRCA2 mutations have been identified. Specific mutations are found to be common within particular populations, resulting from genetic founder effects. To investigate the contribution of germline mutations in these two genes to inherited breast cancer in Iran, we performed BRCA1/BRCA2 mutation analyses in ten Iranian high risk breast cancer families. This is the first study analysing the complete coding sequences of both genes that concerns the Iranian population. Methods: BRCA1/BRCA2 mutation detection included sequencing of the coding and the 3′ and 5′ untranslated regions. To detect large genomic rearrangements in the BRCA1 gene semi-quantitative multiplex PCR was performed. Results: Two pathogenic mutations in the BRCA2 gene were detected: a novel deletion c.4415_4418delAGAA and a previously described insertion c.6033_6034insGT. In addition, one intronic variation g.5075–53C>T and a deletion/insertion g.*381_389del9ins29 in the 3′ untranslated region of BRCA1 were found in two of the investigated families. Both sequence alterations were absent in an age matched Iranian control group. The BRCA2 homozygous variation p.N372H, previously associated with an increased risk for developing breast cancer, was not identified in this study. We did not detect large genomic rearrangements in BRCA1 in patients tested negatively for disease causing mutations in both genes by standard sequencing. Conclusions: At present, the BRCA2 mutations c.4415_4418delAGAA and c.6033_6034insGT have not been identified in any investigated population except the Iranian. Whether both mutations are specific for the Iranian population or a special subgroup remains to be investigated in larger studies. The absence of BRCA1 mutations in the analysed families may suggest that penetrance or prevalence of BRCA1 mutations may be lower in Iran. [ABSTRACT FROM AUTHOR]

We screened a total of 92 unrelated patients with neurofibromatosis type 1 (NF1) for mutations in exon 37 of the NF1 gene, by using temperature gradient gel electrophoresis. Two novel mutations were found: a 4 bp deletion in a so-called quasi-symmetric element (6789delTTAC) and a recurrent nonsense mutation, which was identified in two unrelated patients, at codon 2264 (C6792A). The independent origin of the latter mutation in two families was confirmed by haplotype analysis. The nonsense mutation and the 4 bp deletion are both predicted to lead to a truncated protein product lacking the Cterminal 20% (aproximately) of its sequence. The occurrence of three independent mutations among 92 NF1 patients at codons 2263-2264 (exon 37) suggests that a specific search for mutations in this area should be undertaken in screening programs for NF1 mutations. [ABSTRACT FROM AUTHOR]

Cherubism (MIM 118400) is an autosomal dominant inherited syndrome characterized by excessive bone degradation of the upper and lower jaws followed by development of fibrous tissue masses, which causes a characteristic facial swelling. Here we describe seven mutations in the SH3-binding protein SH3BP2 (MIM 602104) on chromosome 4p16.3 that cause cherubism. [ABSTRACT FROM AUTHOR]