Deletions in the 3 %26apos; 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

作者：Schanze Denny; Neubauer Dorothee; Cormier Daire Valerie; Delrue Marie Ange; Dieux Coeslier Anne; Hasegawa Tomonobu; Holmberg Eva E; Koenig Rainer; Krueger Gabriele; Schanze Ina; Seemanova Eva; Shaw Adam C; Vogt Julie; Volleth Marianne; Reis Andre; Meinecke Peter; Hennekam Raoul C M; Zenker Martin^*

来源：Human Mutation, 2014, 35(9): 1092-1100.

DOI：10.1002/humu.22603

• Marshall-Smith syndrome
• nuclear factor 1/X
• NFIX
• nonsense-mediated decay
• intellectual disability

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-mediatedmRNAdecay. 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.

• 出版日期2014-9