Algorithm for molecular diagnosis of the Neurofibromatosis NF1, NF2 and NF3 (Schwannomatosis)

Abstract

Neuropathological evaluation of CNS tumors is increasingly dependent on molecular genetic tests for proper classification, prediction of biological behavior and patient management. The neurofibromatoses (NFs) consist of at least three autosomal dominant inherited disorders: neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis (NF3). The molecular diagnosis is still difficult due to: 1) absence of hotspots in NF1/NF2 genes, 2) ≥50% of sporadic cases for NF1/NF2, 3) NF1 gene large size and the existence of several pseudogenes. NF3 the newly recognized form is poorly understood: 1) only 15% of cases are inherited, 2) is caused by concomitant loss of several tumor suppressor genes by a single mutational event, 3) the 2 predisposition genes (SMARCB1 and LZTR1) identified do not explain all cases. Our aim is to show the diagnostic algorithms for molecular genetic testing for the NFs. We have used segregation analysis of STRs, mutational screening by DNA sequencing and exome sequencing (WES).The analysis of a family with NF1 numerous patients revealed the at-risk haplotype in one on the unaffected probands and a recombination event in two individuals (one affected and one asymptomatic). In four out of 11 NF2 patients tree small novel germinal mutations (2 frameshift and 1 splice-site) and one partial deletion of the maternal NF2 copy were identified, as well as a loss of heterozygosity (LOH) in the fifth patient. Molecular analysis of four patients with NF3 showed no mutations in SMARCB1 gene. One of the patients with family history studied by WES, did not show alterations in the predisposing genes. Analysis of four of this patient´s tumors did not display the frequently observed LOH. Evaluation of abnormalities in these genes was performed using a diagnostic algorithm which depends on the type of NF, family history and sample availability.