title: 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.
authors: Department of Neurogenetics, Academic Medical Center, Amsterdam, The Netherlands.
authors: A C J
authors: AC
authors: Ammerlaan
authors: A
authors: A
authors: Ararou
authors: M P W A
authors: MP
authors: Houben
authors: F
authors: F
authors: Baas
authors: C C
authors: CC
authors: Tijssen
authors: J L J M
authors: JL
authors: Teepen
authors: P
authors: P
authors: Wesseling
authors: T J M
authors: TJ
authors: Hulsebos
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D040582:Inheritance Patterns; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D010375:Pedigree; D019683:Penetrance; D018335:Rhabdoid Tumor / Q000235:genetics* / Q000401:mortality; D000071796:SMARCB1 Protein; D012727:Sex Characteristics; D016019:Survival Analysis; D013577:Syndrome; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors