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

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.