title: Deletions in the 3' part of the NFIX gene including a recurrent Alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of Marshall-Smith syndrome.
abstract: Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.
authors.affiliation: Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Denny
authors.initials: D
authors.lastname: Schanze
authors.forename: Dorothée
authors.initials: D
authors.lastname: Neubauer
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Delrue
authors.forename: Anne
authors.initials: A
authors.lastname: Dieux-Coeslier
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Eva E
authors.initials: EE
authors.lastname: Holmberg
authors.forename: Rainer
authors.initials: R
authors.lastname: Koenig
authors.forename: Gabriele
authors.initials: G
authors.lastname: Krueger
authors.forename: Ina
authors.initials: I
authors.lastname: Schanze
authors.forename: Eva
authors.initials: E
authors.lastname: Seemanova
authors.forename: Adam C
authors.initials: AC
authors.lastname: Shaw
authors.forename: Julie
authors.initials: J
authors.lastname: Vogt
authors.forename: Marianne
authors.initials: M
authors.lastname: Volleth
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Peter
authors.initials: P
authors.lastname: Meinecke
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D020087:Alu Elements; D001848:Bone Diseases, Developmental / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D019465:Craniofacial Abnormalities / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D019066:Facies; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D051839:NFI Transcription Factors / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D025962:Septo-Optic Dysplasia / Q000175:diagnosis / Q000235:genetics*; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D051839:NFI Transcription Factors; C000594474:NFIX protein, human; D012333:RNA, Messenger
keywords: Marshall-Smith syndrome; NFIX; intellectual disability; nonsense-mediated decay; nuclear factor 1/X