TY - JOUR
T1 - Haploinsufficiency of NCOR1 associated with autism spectrum disorder, scoliosis, and abnormal palatogenesis
AU - Sakaguchi, Yuri
AU - Uehara, Tomoko
AU - Suzuki, Hisato
AU - Sakamoto, Yoshiaki
AU - Fujiwara, Mineko
AU - Kosaki, Kenjiro
AU - Takenouchi, Toshiki
N1 - Funding Information:
information Japan Agency for Medical Research and Development, Grant/Award Number: Initiative on Rare and Undiagnosed Diseases (JP17ek0109151); Ministry of Health, Labour and Welfare, Grant/Award Number: Research on rare and intractable diseasesWe thank Ms. Chika Kanoe, Yumi Obayashi, and Keiko Tsukue for their technical assistance in the preparation of this article. This work was supported by Research on rare and intractable diseases from the Ministry of Health, Labour and Welfare, Japan, and Initiative on rare and undiagnosed diseases [Grant number JP17ek0109151] from Japan Agency for Medical Research and Development.
Publisher Copyright:
© 2018 Wiley Periodicals, Inc.
PY - 2018/11
Y1 - 2018/11
N2 - 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.
AB - 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.
KW - NCOR1
KW - Smith-Magenis syndrome
KW - autism spectrum disorder
KW - bifid uvula
KW - intellectual disability
KW - scoliosis
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U2 - 10.1002/ajmg.a.40354
DO - 10.1002/ajmg.a.40354
M3 - Article
C2 - 30289594
AN - SCOPUS:85054499100
VL - 176
SP - 2466
EP - 2469
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
IS - 11
ER -