Haploinsufficiency of NCOR1 associated with autism spectrum disorder, scoliosis, and abnormal palatogenesis

Yuri Sakaguchi, Tomoko Uehara, Hisato Suzuki, Yoshiaki Sakamoto, Mineko Fujiwara, Kenjiro Kosaki, Toshiki Takenouchi

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


NCOR1 (nuclear receptor corepressor 1) is a transcriptional coregulatory protein that regulates the balance between histone acetylation and histone deacetylation. NCOR1 is listed as one of the 3,230 dose-sensitive genes which very rarely show truncating mutations in the pediatric population without severe diseases, even in a heterozygous state. In a large cohort study of intellectual disability/autism spectrum disorder, splicing mutations were identified in two individuals, however, the truncating effects of these splicing mutations have not been examined at the transcription level. We describe a 3-year-old girl who had behavior consistent with autism spectrum disorder, a bifid uvula, and early-onset scoliosis. Trio exome analysis showed a de novo heterozygous mutation at the splice donor site in exon 19 of NCOR1, c.2182 + 1G > T (NM_00190440.1). Reverse transcription polymerase chain reaction assay confirmed that the splicing mutation results in skipping of exon 19, a shift in the reading frame and then to nonsense-mediated mRNA decay. This patient represents the first patient who has had unequivocal documentation of haploinsufficient for the NCOR1 gene. Based on our observations, we conclude that NCOR1 is indeed a human disease-causing gene. We further suggest that bifid uvula, a micro form of cleft palate, may well be causally related to de novo NCOR1 haploinsufficiency, in that a previously reported deletion mapping study of atypical Smith-Magenis syndrome patients with large deletions and cleft palate identified that NCOR1, the only loss-of-function-intolerant gene within the region, is located in the smallest region of overlap.

Original languageEnglish
Pages (from-to)2466-2469
Number of pages4
JournalAmerican Journal of Medical Genetics, Part A
Issue number11
Publication statusPublished - 2018 Nov


  • NCOR1
  • Smith-Magenis syndrome
  • autism spectrum disorder
  • bifid uvula
  • intellectual disability
  • scoliosis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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