Background Heterozygous mutations in CTCF have been reported in patients with distinct clinical features including intellectual disability. However, the precise pathomechanism underlying the phenotype remains to be uncovered, partly because of the diverse function of CTCF. Here we describe extensive clinical and genetic investigation for two patients with a microdeletion encompassing CTCF.
Methods We performed genetic examination including comprehensive investigation of X chromosome inactivation and DNA methylation profiling at imprinted loci and genome-wide.
Results Two patients showed comparable clinical features to those in a previous report, indicating that haploinsufficiency of CTCF was the major determinant of the microdeletion syndrome. Despite the haploinsufficiency of CTCF, X chromosome inactivation was normal. DNA methylation at imprinted loci was normal, but hypermethylation at CTCF binding sites was demonstrated, of which PRKCZ and FGFR2 were identified as candidate genes.
Conclusions This study confirms that haploinsufficiency of CTCF causes distinct clinical features, and that a microdeletion encompassing CTCF could cause a recognisable CTCF deletion syndrome. Perturbed DNA methylation at CTCF binding sites, not at imprinted loci, may underlie the pathomechanism of the syndrome.
- X chromosome inactivation
- DNA methylation
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Contributors SS was responsible for the concept and design of the study. IH and SS drafted the main manuscript. IH, RK, KN, HW, KenH, JT, KO, KW, KeniH, HS and KK analysed and interpreted the data. DI, KO, YN, AH, YS, KK and SS contributed clinical data. RK, KN, KW, HS and KK revised the manuscript and made comments on the structure, details and grammar of the article.
Funding This study was partially supported by the Program for an Integrated Database of Clinical and Genomic Information from the Japanese Agency for Medical Research and Development (AMED) (SS).
Competing interests None declared.
Patient consent Parental/guardian consent obtained.
Ethics approval This study was approved by the institutional review board of Nagoya City University Graduate School of Medical Sciences.
Provenance and peer review Not commissioned; externally peer reviewed.
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