Autosomal dominant mental retardation 21 (MRD21) is a very rare condition, characterized by short stature, microcephaly, mild facial dysmorphisms and intellectual disability that ranged from mild to severe. MRD21 is caused by mutations in CCCTC-binding factor (CTCF) and this was established through only four unrelated cases, two of which had frameshift mutations. CTCF is a master transcriptional regulator that controls chromatin structure and may serve as insulator and transcriptional activator and repressor.
This study presents, clinically and molecularly, an Emirati patient with de novo frameshift mutation in CTCF. This novel mutation was uncovered using whole exome sequencing and was confirmed by Sanger sequencing in the trio. In silico analysis, using SIFT Indel, indicates that this frameshift; p.Lys206Profs*13 is functionally damaging with the likely involvement of nonsense-mediated mRNA decay.
Upon comparing the clinical picture of the herewith-reported individual with previously reported cases of MRD21, there seems to be many common symptoms, and few new ones that were not observed before. This helps to further define this rare condition and its molecular underpinnings.

Aberrant methylation of seven potential binding sites of the CTCF factor in the differentially methylated region upstream of the H19 gene (H19-DMR) has been suggested as critical for the regulation of IGF2 and H19 imprinted genes. In this study, we analyzed the allele-specific methylation pattern of CTCF binding sites 5 and 6 using methylation-sensitive restriction enzyme PCR followed by RFLP analysis in matched tumoral and lymphocyte DNA from head-and-neck squamous cell carcinoma (HNSCC) patients, as well as in lymphocyte DNA from control individuals who were cancer-free. The monoallelic methylation pattern was maintained in CTCF binding site 5 in 22 heterozygous out of 91 samples analyzed. Nevertheless, a biallelic methylation pattern was detected in CTCF binding site 6 in a subgroup of HNSCC patients as a somatic acquired feature of tumor cells. An atypical biallelic methylation was also observed in both tumor and lymphocyte DNA from two patients, and at a high frequency in the control group (29 out of 64 informative controls). Additionally, we found that the C/T transition detected by HhaI RFLP suppressed one dinucleotide CpG in critical CTCF binding site 6, of a mutation showing polymorphic frequencies. Although a heterogeneous methylation pattern was observed after DNA sequencing modified by sodium bisulfite, the biallelic methylation pattern was confirmed in 9 out of 10 HNSCCs. These findings are likely to be relevant in the epigenetic regulation of the DMR, especially in pathological conditions in which the imprinting of IGF2 and H19 genes is disrupted.