CITED2

Gene Facts

• HGNC Symbol: CITED2 (HGNC:1987)
• HGNC Name: Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: MRG1
• %HI: 3.47
• pLI: 0.9
• LOEUF: 0.59
• Cytoband: 6q24.1
• Genomic Coordinates:

  GRCh37/hg19:	chr6:139692944-139695785
  GRCh38/hg38:	chr6:139371807-139374648

• MANE Select Transcript: NM_006079.5 ENST00000367651.4
• Function: Transcriptional coactivator of the p300/CBP-mediated transcription complex. Acts as a bridge, linking TFAP2 transcription factors and the p300/CBP transcriptional coactivator complex in order to stimulate TFAP2-mediated transcriptional activation. Positively regulates TGF-beta signaling through its association with the SMAD/p300/CBP-mediated transcriptional coactivator complex. Stimulates the peroxisome proliferator-activated receptors PPARA transcriptional activity. Enhances estrogen-dependent ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-7814
• ClinGen Curation ID: CCID:006871
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: No Evidence for Haploinsufficiency (0)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 11/29/2023

Haploinsufficiency (HI) Score Details

• HI Score: 0
• HI Evidence Strength: No Evidence for Haploinsufficiency

HI Disease

• congenital heart defects, multiple types

HI Evidence

• PUBMED: 16287139
  Sperling et al. (2005) screened a cohort of 392 patients with CHD and 192 control individuals and identified three variants that alter the amino acid sequence (p.Ser170_Gly178del, p.Gly178_Ser179ins9, and p.Ser198_Gly199del) in the serine-glycine-rich junction of the protein, and showed that these changes reduced CITED2 function.
• PUBMED: 31515672
  Dianatpour et al. (2020) examined a cohort of 150 Iranian pediatric congenital heart disease (CHD) patients and 98 controls by direct sequencing. A homozygous 1-bp insertion within CITED2 (c.716insG), which creates an early stop codon and was predicted to alter the binding energy of the resulting protein, was identified in two individuals with VSD. Three heterozygous variants in the non-coding first exon, one in-frame deletion, and two missense variants were also identified in this cohort.
• PUBMED: 33439552
  Zheng et al (2021) studied 200 Han Chinese patients with isolated and sporadic ventral septal defect (VSD) and 200 controls, and identified five heterozygous variants in the promoter region of CITED2 in 7 patients. Functional analyses of the variants in HEK-293 cells showed that 4 of the 5 variants decreased transcriptional activity of CITED2; however, the authors noted that the “degree of decreased transcriptional activity is rather small”.
• PUBMED: 23082118
  Chen et al. (2012) reported five synonymous variants, four missense variants (p.N62S, p.R92G, p.T166N, p.A187T), and one in-frame deletion (p.Gly180_Ala187del) within CITED2 after screening 1126 sporadic CHD patients from the UK along with 1227 controls via Sanger sequencing. Variants p.N62S, p.T166N, and p.G180-A187del were determined to be inherited from unaffected parents. Two missense variants were unique to controls, while one missense variant and two in-frame deletions were found in both cases and controls. The authors concluded that “…mutations clustering in the SRJ region are unlikely to be the sole cause of the malformations observed in patients with sporadic CHD.”
• PUBMED: 28687891
  Liu et al. (2017) completed Sanger sequencing on 187 Tibetan CHD patients and 200 Tibetan controls, in which they identified a CITED2 missense variant (p.G143A) in a girl with patent ductus arteriosus. A dual-luciferase assay was performed to examine VEGF expression in response to HFI1A alone, HIF1A with wild type CITED2, and HIF1A with the CITED2 p.G143A variant. Results showed that the presence of this variant led to a significantly decreased inhibitory effect of CITED2 on VEGF.
• PUBMED: 24848765
  Liu et al. (2014) completed a Sanger sequencing study on 700 Chinese patients with CHD and 250 controls. Five heterozygous variants of CITED2 were identified in cases, including 3 missense (p.P140S, p.S183L, p.S196G) and two in-frame deletions (p.Ser161del, p. Ser192_Gly193del). All variants except p.P140S were located in the SRJ region. The authors explain that, “Wild-type CITED2 caused an approximately 32% decrease of activity [of VEGF] compared with the control (t test, p<0.01). P140S showed no difference with wild-type in luciferase activity. As for the other four mutants, Ser161delAGCAGC showed an observable promotion of VEGF-promoter resulting in higher luciferase activity than wild-type (t test, p<0.01) and the rest [of the] mutants showed few differences compared with wt-type (t test, p<0.05).”

• HI Evidence Comments: CITED2 (NM_006079.5) is a 2-exon gene, in which only the second exon is coding. The CITED2 protein is a transcriptional regulator and co-activator/inhibitor of multiple genes involved in cardiogenesis. The most common cardiac issues observed in individuals with CITED2 variants are ASD, VSD, TOF, and transposition of the great arteries (TGA). Braganca et al. (2019) explain, “Most of CITED2 variants identified in patients with CHD, only marginally affect its capacity to repress the transcriptional activity of HIF-1ɑ and/or to co-activate TFAP2 ex vivo. However, CITED2 mutations in patients may result in severe impairment of VEGF and PITX2C gene expression, which are necessary for normal development of the vasculature and left-right patterning, respectively”. Variants within the 3’ and 5’ UTRs may also decrease expression of CITED2 by inducing abnormal stability, processing, localization, or translation (PMID: 31378782). However, Xu et al. (2014) suggest that additional factors such as epigenetic modifications during fetal development could influence disease penetrance (PMID: 24456003), and inheritance from an unaffected parent has been reported (PMID: 23082118). The majority of variants identified in cases are missense or small insertions/deletions that do not result in a frame-shift. There are no deletions overlapping this gene in the Database of Genomic Variants, although there is one XX individual with a deletion overlapping CITED2 exon 2 in gnomAD CNVs v4.0. Additional CITED2 variants associated with cardiac defects: PMIDs: 22709740, 24456003, 28436679, 28991257, 29368431, 29536580, 33706167, 36286273, 37481008 CITED2 variants reported in individuals with other disorders: PMIDs: 22709740 (premature ovarian failure), 33574475 (myelomeningocele), 34758253 (mitochondrial disorders), 35982160 (autism)

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity