Identification of a Novel Mutation in CTCF in a Family with MRD21

Abstract Background Developmental delay (DD) and intellectual disability (ID) represent one of the biggest medical and social challenges in our society with a prevalence of 1 ~ 3% worldwide. Currently, at least 50% of DD/ID cases remained unexplained. Mental retardation, autosomal dominant 21 (MRD21), caused by mutations in CTCF, is a rare DD/ID-related disease. The clinical phenotypes of MRD21 are highly variable but are not considered sufficiently distinct to be clinically recognizable. To date, only 37 pathogenic/likely pathogenic mutations in CTCF associated with MRD21 have been identified, and the pathogenesis of CTCF remains largely unknown. Methods Whole exon sequencing (WES) and bioinformatics analysis were used to identify the mutation as being responsible for an 18-month-old girl with unexplained DD, abnormality of the face and congenital heart disease. The origin of the mutation was analyzed by Sanger sequencing. The pathogenicity of the missense mutation was mainly analyzed by western blot (WB) and molecular dynamics (MD) simulations. Results We identified a novel missense mutation in CTCF (c.1115C > T, p. Ser372Phe) using WES, and Sanger sequencing indicated that the mutation was de novo. The expression levels of CTCF in 293T cells were unaltered by the missense mutation. However, MD simulations supported the pathogenicity of the p. Ser372Phe mutation, which resulted a decrease in the binding affinity of CTCF with DNA. Conclusions Our study broadens the mutational spectrum of CTCF and provides a better understanding of the pathogenicity of missense mutations in CTCF. This is the first time that MD simulations have been applied to evaluate the pathogenicity of missense mutations in CTCF.