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Evidence for haploinsufficiency phenotype
PubMed ID Description
23746550 Gregor et al. (2013) performed exome sequencing in an individual with mild intellectual disability, short stature, microcephaly, cleft palate and congenital heart defects and identified two de novo variants: one missense in POLR2A and one frameshift in CTCF. The CTCF variant was a single base duplication (c.375dupT) not observed in control databases. The authors then performed mutational screening of an additional 399 individuals with intellectual disability and identified CTCF variants in an additional two boys. Both variants were de novo: one frameshift variant (c.1186dupA) and the other a missense variant (c.1699C>T, p.Arg567Trp). The authors confirmed reduced mRNA expression and protein levels in both patients with frameshift variants and sequencing of the cDNA showed almost complete absence of the mutated allele suggesting loss of function or haploinsufficiency as possible disease mechanism. The missense variant did not impact CTCF mRNA expression or protein levels and at this time there is insufficient evidence to determine whether this variant leads to loss of function. Clinical phenotypes shared among all three patients include variable intellectual disability, lower head circumference and/or body height, and feeding difficulties.
30893510 Chen et al. (2019) describe 3 patients of Chinese ancestry that harbor de novo CTCF variants identified via exome sequencing. All three patients share clinical features consistent with those reported by Gregor et al (2013) and Bastaki et al (2017), which include neonatal hypotonia and feeding difficulties, global developmental delay, intellectual disability, short stature and microcephaly. Only 2 of the 3 patients reported by Chen et al. harbor truncating variants: patient 1 is heterozygous for a frameshift variant in CTCF (c.615_618del) and patient 3 is heterozygous for a different frameshift variant in CTCF (c.329dupT). Both variants were confirmed to be de novo after Sanger sequencing parental samples and confirming paternity.
31239556 Konrad et al (2019) report on the clinical phenotype of 39 individuals harboring CTCF variants that were identified by various methods. The spectrum of CTCF variants identified in these individuals is as follows: six frameshift, two nonsense, two splice site variants, and 20 missense. Of the truncating variants, six were found to be de novo. The authors also found that knocking down the CTCF gene in Drosophila resulted in ?impaired gross neurological functioning and learning and memory deficits, further corroborating haploinsufficiency as the disease mechanism. While the missense variants did not impact gene/protein, patients with CTCF variants (including several missense) showed altered regulation of genes implicated in neurodevelopment disorders, presumed to be related to altered DNA binding (although that was not directly tested).
25363768 Iossifov et al. (2014) 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 CTCF variant (c.1053_1054insA) in patient 14346.
33004838 Wang et al (2020) performed sequencing for 125 genes in more than 16,000 patients with neurodevelopmental disorders and identified 13 probands with CTCF variants (8 missense, 3 frameshift, 1 nonsense and 1 splice site). Of the 5 potentially truncating variants, 2 were confirmed de novo (c.778_781del and c.1037delC), 2 unknown inheritance and 1 paternally inherited without description of the father's phenotype. The authors also provide a comprehensive review of the published cases and corresponding phenotypes (through 2020) in Figure 3. All patients across the studies exhibit dysmorphic facial features and nearly all exhibit developmental delay and/or intellectual disability. Other commonly observed features are ocular abnormalities, behavioral problems, feeding difficulties, and microcephaly.

Haploinsufficiency phenotype comments:

The CTCF gene encodes a transcriptional regulator that binds DNA through the 11 zinc finger domains located throughout the gene and is important for regulating chromatin organization and gene expression. More than 65 individuals with pathogenic variants in the CTCF gene have been reported in the literature to have a neurodevelopmental disorder characterized by dysmorphic facial features, developmental delay and/or mild ?intellectual disability, feeding difficulty, and microcephaly. Other common features include ocular abnormalities and behavioral problems. The mutation spectrum includes predicted truncating variants (at least 19 cases) and missense variants, which typically cluster in the DNA binding domains and are therefore thought to disrupt function (however this has not been formally demonstrated). Drosophila studies knocking down the CTCF gene show impaired gross neurological function and learning and memory deficits, further supporting haploinsufficiency as the disease mechanism for this gene (PMID: ?33004838). RNA expression and methylation studies demonstrate that CTCF variants appear to alter methylation patterns and expression of other genes implicated in neurodevelopment disorders (PMIDs: ?33004838 and 28848059). Larger deletions of the CTCF gene have also been observed in affected individuals, however all reported deletions include additional genes (PMIDs: 28848059, 31239556, 23746550).

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