SMARCB1/INI1 maternal germ line mosaicism in schwannomatosis

Abstract

Schwannomatosis is characterized by the development of multiple schwannomas of the nervous system, but without the occurrence of vestibular schwannomas. Most cases of schwannomatosis are thought to be sporadic, representing the first case in a family due to a new mutation in the causative gene. We recently identified SMARCB1/INI1 as a schwannomatosis-predisposing gene. Here, we analyzed this gene in a schwannomatosis family with two affected children, but with clinically unaffected parents. Both affected individuals carried a constitutional SMARCB1 mutation, c.1118+ 1G>A, that changes the donor splice site sequence of intron 8, causing skipping of exon 8 and resulting in the in-frame deletion of 132 nucleotides in the transcript. The mutation was not evident in constitutional DNA of the parents. Haplotyping revealed that the chromosome 22 segment that carries the mutant SMARCB1 allele originated from the mother. She transferred the same chromosome 22 segment, however, with a wild-type SMARCB1 copy, to a third unaffected child. Our findings indicate that the mother is germ line mosaic for the SMARCB1 mutation. In conclusion, our study shows for the first time that germ line mosaicism may occur in schwannomatosis, which has implications for genetic counseling in this disease.

Frequent hSNF5/INI1 Germline Mutations in Patients with Rhabdoid Tumor

“…Indeed, splice sites mutations are predominantly observed in schwannomatosis (12/20 reported; refs. [21][22][23][24]27), whereas they are rare in RTs and particularly associated with asymptomatic carriers (3/5 heritable mutations of hSFN5/INI1; refs. 7,14).…”

“…1). Secondly, as germline hSNF5/INI1 mutation is known to predispose not only to early aggressive RTs with rapid fatal outcome but also to late-onset indolent multiple schwannomas (21)(22)(23)(24)(25)(26)(27) and meningiomas (21,28), predicting the outcome of a mutation carrier seems somewhat hazardous. Indeed, different tumor types may selectively affect the members of a family carrying the same mutation in a so far unpredictable manner (26).…”

Selected topics in the pathology of epithelioid soft tissue tumors

“…13 Germline SMARCB1 alterations also appear to underlie schwannomatosis. [47][48][49] Very rare instances of MRT and epithelioid MPNST arising in schwannomatosis have been reported, presumably reflecting second somatic mutations. 50,51 Epithelioid malignant peripheral nerve sheath tumor Malignant peripheral nerve sheath tumors are relatively rare, accounting for roughly 5% of all soft tissue sarcomas.…”

SMARCB1 Deficiency in Tumors From the Peripheral Nervous System

“…Moreover, we unexpectedly observed some features compatible with benign nervous proliferation within or near the rhabdoid components. Given the recent works showing the links between SMARCB1 germline mutations, acquired NF2 somatic inactivation in Schwann cells, and development of schwannomas, 9,11,20,25,26,35,37,39 a potential genetic relationship between common PNS tumors-that is, neurofibromas, schwannomas, and MPNST-and our cases actually required further investigation. Although NF2 constituted an attractive candidate gene, we found only 3 hemizygous deletions and no mutation.…”

“…24 Strikingly, recent studies also showed that SMARCB1 germline mutations are the underlying cause of a subset of familial and sporadic schwannomatosis and rare forms of familial meningiomas. 9,11,20,25,26,35,37,39 Schwannomatosis is a genetic disorder characterized by the development of multiple schwannomas in the fourth to fifth decade of life. The occurrence of both RT and schwannomas within families with a unique SMARCB1 germline mutation confirms that a common genetic disorder could be shared by these 2 types of tumors.…”