An updated catalog of CTCF variants associated with neurodevelopmental disorder phenotypes

Abstract

IntroductionCTCF-related disorder (CRD) is a neurodevelopmental disorder (NDD) caused by monoallelic pathogenic variants in CTCF. The first CTCF variants in CRD cases were documented in 2013. To date, 76 CTCF variants have been further described in the literature. In recent years, due to the increased application of next-generation sequencing (NGS), growing numbers of CTCF variants are being identified, and multiple genotype-phenotype databases cataloging such variants are emerging.MethodsIn this study, we aimed to expand the genotypic spectrum of CRD, by cataloging NDD phenotypes associated with reported CTCF variants. Here, we systematically reviewed all known CTCF variants reported in case studies and large-scale exome sequencing cohorts. We also conducted a meta-analysis using public variant data from genotype-phenotype databases to identify additional CTCF variants, which we then curated and annotated.ResultsFrom this combined approach, we report an additional 86 CTCF variants associated with NDD phenotypes that have not yet been described in the literature. Furthermore, we describe and explain inconsistencies in the quality of reported variants, which impairs the reuse of data for research of NDDs and other pathologies.DiscussionFrom this integrated analysis, we provide a comprehensive and annotated catalog of all currently known CTCF mutations associated with NDD phenotypes, to aid diagnostic applications, as well as translational and basic research.

Enhancer–promoter specificity in gene transcription: molecular mechanisms and disease associations

“…3 changes in CTCF protein levels; altered CpG methylation patterns; modified CTCF DNA-binding profile 131 , 134 , 135 , 171 , 172 , 197 , 198 neurodevelopmental disorders; cardiac defects numerous DBD and non-DBD frameshifts, including p.Gly111fs*29, pVal126Cysfs*14, p.Lys206Profs*13/15, pArg396Lysfs*13; missense mutations in DBD ZnF (e.g., D390N, R567W); also see Fig. 3 altered CTCF binding or not determined 130 , 132 , 169 , 170 , 197 , 199 multiple cancer types; neurodegenerative disease; severe influenza; hearing loss; osteoporosis CTCF binding site mutations loss of CTCF binding 118 , 130 , 136 , 137 Cohesin Cornelia de Lange syndrome NIPBL, SMC1A, SMC3, RAD21 Indel, frameshift, missense mutations multiple, including defective DNA repair, chromosome instability, and disruption of TADs/E-P interactions 140 , 141 peripheral sclerocornea RAD21 A622T dysregulated cohesin binding 200 chronic intestinal pseudo-obstruction/Mungan syndrome RAD21 R450C separase cleavage site in RAD21 201 Condensin neurodevelopmental disorders NCAPH, NCAPD2 missense and splice site mutations; NCAPD3 frameshift, intronic mutation creating a de novo splice site impaired chromosome segregation and chromosome structural integrity 148 neurological disorders, nervous system tumors NCAPH2, NCAPG2, NCAPD2, NCAPH deletion and haploinsufficiency; SMC2, SMC4, NCAPG2 overexpression multiple, including defective DNA repair and TGFβ pathway activation 147 MeCP2 ...…”

Brain and cancer associated binding domain mutations provide insight into CTCF’s relationship with chromatin and its contribution to gene regulation

“…In total, we analyzed mutations in eight amino acid residues and for R377, the most highly mutated residue in cancer, we included two distinct mutations (R377H and R377C) that are equally represented in patients ( Figure 1E and Figure S1 ). It should be noted, that a subset of the selected mutations (R339Q, R342C, R448Q, R377H and R377C) have also been shown to be implicated in neurodevelopmental disorders ( Figure S1 ) (Price, Fedida et al 2023, Valverde de Morales, Wang et al 2023). To analyze the impact of each CTCF mutation, individual clones with comparable levels of transgene expression (mutant and WT) were selected based on FACS and Western blot analysis ( Figure 1F, G and Figure S2 ).…”