Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome

Abstract

Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G>A mutation in the donor splice site of exon 4 (c.500+1G>A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsense-mediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.

Figure 1

Haplotyping of family members and LOH analysis of tumours using microsatellite markers from chromosome 22. Patients with the germline INI-mutation are represented by black symbols and proven nonexpressing carriers of this mutation by dotted symbols. Haplotypes were constructed assuming minimal numbers of recombinations. Haplotypes for the grandfather (between brackets) were inferred. N: noninferred marker allele. MBT-1, MBT-3, and MBT-4(R) are the marker alleles retained in the MBT of patients III-1, III-3, and III-4 (R, recurrent tumour), respectively. M-1 and My-1 represent marker alleles retained in meningioma and myoepithelioma of patient III-1, respectively.

Figure 2

Sequence analysis of the exon 4–intron 4 boundary of INI1. Constitutional heterozygosity for the G>A mutation in blood DNA of patient III-1 (B) but not in normal DNA (A) and retention of the mutant A-allele in MBT DNA of patient III-1 (MBT-1) (C).

Figure 3

Immunohistochemical INI1-staining of the recurrent MBT of patient III-4 (MBT-4R) (A) and the meningioma (M-1) (B) and myoepithelioma (My-1) (C) of patient III-1. Note absence of nuclear staining of tumour cells in MBT-4R and myoepithelioma. In contrast, the nuclei of endothelial cells of the blood vessels in both tumours and the nuclei of all cells in the meningioma show unequivocal staining. Original magnification × 200.

Figure 4

Microsatellite analysis with intragenic NF2 markers nf2C3.1 (A) D22S929 (B) and nf2CAV (C) of constitutional DNAs of patient III-1, mother II-1, and father II-2, and of tumour DNAs of patient III-1. Positions of alleles are indicated on the left. MBT-1, M-1, and My-1 represent retained alleles in the MBT, meningioma, and myoepithelioma of patient III-1, respectively.