Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene

Abstract

We have identified a family afflicted over multiple generations with posterior fossa tumors of infancy, including central nervous system (CNS) malignant rhabdoid tumor (a subset of primitive neuroectodermal tumors, or PNET) and choroid plexus carcinoma. Various hereditary tumor syndromes, including Li-Fraumeni syndrome, Gorlin syndrome, and Turcot syndrome, have been linked to increased risk of developing CNS PNETs and choroid plexus tumors. Malignant rhabdoid tumors of the CNS and kidney show loss of heterozygosity at chromosome 22q11. The hSNF5 gene on chromosome 22q11 has recently been identified as a candidate tumor-suppressor gene in sporadic CNS and renal malignant rhabdoid tumors. We describe a family in which both affected and some unaffected family members were found to have a germline splice-site mutation of the hSNF5 gene, leading to exclusion of exon 7 from the mature cDNA and a subsequent frameshift. Tumor tissue shows loss of the wild-type hSNF5 allele, in keeping with a tumor-suppressor gene. These findings suggest that germline mutations in hSNF5 are associated with a novel autosomal dominant syndrome with incomplete penetrance that predisposes to malignant posterior fossa brain tumors in infancy.

Figure 1

Pedigree showing posterior fossa tumors in one family over two generations with an unaffected carrier.

Figure 2

RT-PCR of a portion of the hSNF5 cDNA, showing the expected wild-type product from normal brain and from paternal and sibling (brother) wbc cDNA. Maternal and proband wbc cDNA shows wild-type and mutant transcripts, with an intervening heteroduplex. Tumor cDNA shows only the mutant transcript, with loss of the wild-type allele.

Figure 3

Sequencing of exon 7 of hSNF5, showing a G→A mutation (double arrow) in the proband’s tumor, proband’s germline, and mother’s germline DNA. Leukocyte DNA from proband’s father and brother show the wild-type sequence. The proband’s tumor and her uncle’s tumor (Uncle) show the same G→A mutation.