ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000016.9) (NC_000016.10)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
23746550 Gregor et al. performed exome sequencing in an individual with mild intellectual disability, short stature, microcephaly, cleft palate and congenital heart defects. Sequencing detected 2 de novo mutations on in the CTCF gene which is a frame shift mutation c.375dupT. This variant was not detected in dbSNP, 1000 genomes, exome variant server or inhouse database of 1500 exomes, or 820 molecularly karyotyped healthy controls. Authors followed by screening 399 individuals with intellectual disability and identified two mutations in two boys. Both mutations were de novo one a frameshift mutation and other missense. Clinical phenotype shared among all three patients include variable intellectual disability, head circumference and/or body height either low normal or below -2std, and feeding difficulties. Gregor et al. also looked in the Decipher database and found a patient with a de novo 280 kb deletion encompassing 8 genes including CTCF with intellectual disability. In order to test the consequences of the mutation authors looked at CTCF mRNA expression and protein levels performed on lymphocyte cDNA from the three patients (frameshift mutations and missense). Reduced expression of CTCF was seen in both patients with frameshifts and sequencing of the cDNA showed almost complete absence of mutated allele suggesting loss of function or haploinsufficiency as possible disease mechanism. Expression of CTCF in the individual with a missense mutation was detectable in cDNA, and CTCF mRNA expression levels and protein levels were not altered. The missense mutation occurs in the splice donor site of exon 9. Prediction programs indicate a deleterious effect of the missense mutation . Molecular modeling indicate that the missense that the mutation does not cause steric problems in the CTCF structure suggesting the mutation does not have any effect on protein stability. However, authors do discuss the possibility of the c.1699C>T mutation might effect DNA binding affinity and specificity which is compatible with a disease model of either functional haploinsufficiency or dominant negative effect.
25363768 Iossifov et al. sequenced exomes from more than 2,500 simplex families each having a child with an autistic spectrum disorder (ASD). The study identified a single de novo frame shift mutation patient 14346 in the CTCF gene.

Haploinsufficiency phenotype comments:

A haploinsufficiency score of 2 was given at this time based on having 3 patients with de novo frame shift mutations and the difference in phenotype seen in Gregor et al and Issifov et al papers. Gregor et al. had two frameshift mutations and expression studies and Iossifov et al. identified a single patient with a de novo frame shift. All the remaining patients described in the literature are either large deletions encompassing additional genes including CTCF or missense mutations. Additional missense mutations were discussed in papers PMID: 28619046 Bastaki et al. identified a de novo 4bp deletion in the CTCF gene in a patient born to first cousin parents . The 4 bp deletion results in a frameshift that is predicted to cause an out of frame shift and premature stop. This variant was not reported in dbSNP, EXaC, 1000 genomes, or GalaXC allele frequency database which contains >2.5 million unique Middle Eastern pathogenic mutations and variants. Patient was also found to have two additional mutations, a de novo heterozygous mutation in SH3PXD2B and a paternally inherited SETD5. The clinical phenotype in this patient include stunted growth, microcephaly, developmental delay, congenital heart defects, and facial dysmorphism which are similar to those described in PMID 23746550. However, this patient had additional features affecting the skeletal system PMID: 28848059 Hori et al. describe two patients with de novo deletions that include the CTCF gene (as well as additional genes). Pt1 with a 1.1 MB deletion and Pt2 with a 1.6 Mb deletion. The clinical phenotype is similar to those described in PMID 23746550 including developmental delay, feeding difficulties, dysmorphic facial features, microcephaly and growth retardation. Hori et al. suggest that based on this observation the haploinsufficiency of the CTCF gene may be a major determinant of phenotype an other deleted genes may not have significant dosage effects. Authors attempted to determine the underlying photomechanism by investigating XCI patterns, DNA methylation levels at multiple imprinted differentially methylated regions (DMRs) and genome wide methylation patterns. Authors showed that patients with CTCF gene deletions show normal random XCI pattern. DNA methylation levels in the patients appear to be higher than in controls at DNA binding sites while imprinted DMRs methylation was normal. The results suggest that CTCF haploinsufficiency could induce aberrant methylation of CTCF binding sites, altering gene expression, which may be the underlying mechanism of the disorder. Authors also suggest that the CTCF gene deletion may affect the methylation of CTCF binding site, and discussing the PRKCZ gene as a possible candidate gene for phenotypic effects.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity