A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-21 (MRD21) is caused by heterozygous mutation in the CTCF gene (604167) on chromosome 16q22.

Gregor et al. (2013) reported 3 patients with an intellectual developmental disorder and mutation in the CTCF gene. Patient 1 was a 9.5-year-old boy with mild intellectual disability, short stature, microcephaly, cleft palate, and congenital heart defects. Patient 2 was a 9-year-old boy with borderline intelligence but developmental delay, pronounced learning difficulties, and behavioral problems, as well as microcephaly. Patient 3 was a 4-year-old boy with microcephaly, severe intellectual disability with autistic features, and severe feeding difficulties that necessitated tube feeding.

Konrad et al. (2019) described 39 individuals with MRD21 and noted a widely variable phenotype. All individuals had developmental delay and a variable degree of learning or cognitive difficulties, ranging from low normal IQ to severely impaired intellectual development. Feeding anomalies, failure to thrive, and behavioral anomalies were the most frequently observed associated findings. Other findings included postnatal short stature, microcephaly, and a range of different anomalies including vision anomalies (15 patients), recurrent infections of the urinary tract, airway, or middle ear (14 patients), palatal anomalies (12 patients), heart defects (11 patients), and hearing loss (10 patients). Dysmorphic facial features included prominent forehead, bulbous nasal tip, and long palpebral fissures. The authors did not consider the phenotype to be clinically recognizable.

By trio exome sequencing in a 9.5-year-old boy with intellectual developmental disorder-21, Gregor et al. (2013) identified a de novo frameshift mutation in the CTCF gene (604167.0001). Screening of the CTCF gene in 399 individuals with intellectual disability revealed 2 more de novo mutations in 2 boys: another frameshift mutation (604167.0002) and a missense mutation (R567W; 604167.0003). A search of the Decipher database yielded a 15-year-old girl with intellectual disability and a de novo deletion on chromosome 16 involving 8 genes, including CTCF.

In 39 individuals with MRD21, Konrad et al. (2019) identified mutations involving the CTCF gene, including 2 large deletions encompassing CTCF and neighboring genes, and 8 likely gene disruptive (2 frameshift and 6 nonsense), 2 splice site, and 20 missense mutations in CTCF. There were 2 familial cases and 6 cases in which one or both parents were unavailable for testing; the remaining cases were shown to be de novo. All missense variants involved highly conserved residues located in exons encoding one of the 11 zinc fingers. Among the missense variants, 7 amino acid residues were recurrently affected (R342, R368, H373, R377, P378, R448, R567). No genotype/phenotype correlations were identified. RNA sequencing on blood cells of 2 individuals with likely gene disruptive variants showed similarly decreased CTCF expression, and at least 2 of 3 individuals with missense variants had only mildly decreased CTCF levels, compared to healthy controls. The authors showed differential gene expression (sometimes upregulation and more often downregulation) for over 3,800 genes in affected persons, with enrichment for genes involved with neurodevelopmental disorders, compared to controls. There was significant overlap in the differentially expressed genes between individuals with likely gene disruptive variants and missense variants.

Konrad et al. (2019) created a Drosophila model showing that Ctcf dosage alteration resulted in impaired gross neurologic functioning and learning and memory deficits.