CTCF – intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome

CCCTC-binding factor (CTCF) haploinsufficiency causes an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, feeding difficulties, developmental delay, microcephaly, and short stature (intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome).

Genetic evidence supporting this association includes four unrelated individuals with de novo heterozygous CTCF variants, identified through trio exome sequencing and confirmed by Sanger sequencing. Three of these cases harbor diverse loss-of-function alleles, including frameshifts and a truncating variant, establishing a clear de novo mutational mechanism (4 unrelated probands)(PMID:28619046). No unaffected carrier relatives have been reported.

The variant spectrum comprises at least five distinct alleles: two missense (c.1169A>G (p.Asp390Gly), c.1468A>G (p.Lys490Glu)), one nonsense (c.1369C>T (p.Arg457Ter)), and two frameshifts (c.950_951dup (p.Gly318fs), c.1670_1674del (p.Val556_Cys557insTer)) all predicted or shown to induce loss of CTCF function (PMID:28619046).

Functional assays of the recurrent p.Arg567Trp variant demonstrate impaired CTCF binding to the IGF1 promoter in lymphocyte, HEK-293T, and LO2 cell lines, resulting in significantly reduced IGF1 transcription and secretion, which correlates with the short stature phenotype (PMID:36847142). These in vitro data concordantly support a haploinsufficiency mechanism for CTCF in growth and neurodevelopment.

No contradictory data have been reported that dispute the CTCF–MRD21 association. However, additional cohort studies and knock-in animal models could further solidify genotype-phenotype correlations and functional thresholds.

In summary, multiple de novo, loss-of-function CTCF variants in unrelated individuals, together with mechanistic cellular studies, provide strong evidence for an autosomal dominant haploinsufficiency disorder. This supports molecular diagnosis, genetic counseling, and potential therapeutic targeting of IGF1 pathways in affected patients.

References

• BMC medical genetics • 2017 • Identification of a novel CTCF mutation responsible for syndromic intellectual disability - a case report. PMID:28619046
• Journal of molecular endocrinology • 2023 • CTCF variant begets to short stature by down-regulation of IGF1. PMID:36847142

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