Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes

Abstract

Neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis are a group of autosomal dominant disorders that predispose to the development of nerve sheath tumors. Pathogenic variants (PVs) that cause NF1 and NF2 are located in the NF1 and NF2 loci, respectively. To date, most variants associated with schwannomatosis have been identified in the SMARCB1 and LZTR1 genes, and a missense variant in the DGCR8 gene was recently reported to predispose to schwannomas. In spite of the high detection rate for PVs in NF1 and NF2 (over 90% of non‐mosaic germline variants can be identified by routine genetic screening) underlying PVs for a proportion of clinical cases remain undetected. A higher proportion of non‐NF2 schwannomatosis cases have no detected PV, with PVs currently only identified in around 70%–86% of familial cases and 30%–40% of non‐NF2 sporadic schwannomatosis cases. A number of variants of uncertain significance have been observed for each disorder, many of them located in noncoding, regulatory, or intergenic regions. Here we summarize noncoding variants in this group of genes and discuss their established or potential role in the pathogenesis of NF1, NF2, and schwannomatosis.

Neurofibromatosis in Children: Actually and Perspectives

“…Mutations in the SMARCB1 (otherwise known as INI1 , BAF47 , or hSNF5 gene and centromeric to the NF2 gene situated on chromosome 22) and LZTR1 genes (also located on chromosome 22, close to the former gene), which suppress tumors, are associated with this type of neurofibromatosis [ 16 , 18 ]. The majority of mutations occur sporadically, however, an autosomal-dominant inheritance pattern has also been observed in familial cases [ 3 , 27 , 29 ]. Interestingly, mutations of SMARCB1 have also been incriminated for the development of rhabdoid tumors in the rhabdoid predisposition syndrome; although these syndromes have scant overlapping features [ 27 ].…”

Principles of molecular testing for hereditary cancer

“…Intronic and noncoding variants are important causes of disease in some hereditary cancer syndromes. For neurofibromatosis type 1, there are known pathogenic variants in the 5 0 UTR of NF1, 165,166 as well as NF1 intronic variants which cause splicing aberrations and require whole gene sequencing and RNA analysis to characterize. RNA analysis is routinely used in clinical genetic testing for NF1.…”

“…RNA analysis is routinely used in clinical genetic testing for NF1. 165 Noncoding pathogenic variants have been identified in NF2 for neurofibromatosis 2, and in LZTR1 for schwannomatosis, 165 and a dominantly inherited 5 0 UTR variant associated with promoter hypermethylation has been identified in BRCA1…”