• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
CD40LG (HGNC:11935) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
CD40 ligand
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
HIGM1, IMD3, TNFSF5
Alias symbols
CD40L, TRAP, gp39, hCD40L, CD154, CD40-L, HIGM1, T-BAM
%HI
8.39(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.72(Read more about gnomAD pLI score)
LOEUF
0.56(Read more about gnomAD LOEUF score)
Cytoband
Xq26.3
Genomic Coordinates
GRCh37/hg19: chrX:135730317-135742549 NCBI Ensembl UCSC
GRCh38/hg38: chrX:136648158-136660390 NCBI Ensembl UCSC
MANE Select Transcript
NM_000074.3 ENST00000370629.7 (Read more about MANE Select)
Function
Cytokine that acts as a ligand to CD40/TNFRSF5 (PubMed:1280226, PubMed:31331973). Costimulates T-cell proliferation and cytokine production (PubMed:8617933). Its cross-linking on T-cells generates a costimulatory signal which enhances the production of IL4 and IL10 in conjunction with the TCR/CD3 ligation and CD28 costimulation (PubMed:8617933). Induces the activation of NF-kappa-B (PubMed:15067037, PubMed:31331973). Induces the activation of kinases MAPK8 and PAK2 in T-cells (PubMed:15067037). ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-36732
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
04/08/2020

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 22750225
    Martinez et al. (2012) reported a maternally inherited exons 1-3 deletion of CD40LG gene in two brothers with recurrent otitis, bronchitis, pneumonias and diarrhea together with neutropenia since the earliest years of life. Both patients presented very low levels of IgG and undetectable of IgA and IgE, and none of the patients expressed CD40L even after T cell stimulation. They were both diagnosed with Hyper-IgM syndromes (HIGM). The mother who also carried a poly (p.G219R) on her second allele was healthy.
  • PUBMED: 24768948
    Tang et al. (2014) identified 10 distinct loss-of-function variants in CD40LG, including nonsense, as well as insertion and deletions which resulted in frame shift in 11 males with HIGM. Among them was a exon 1 deletion. All these patients showed no expression of CD40L on activated T cells. 7 out of 11 males inherited the variants from carrier mother.
  • PUBMED: 16019685
    Schuster et al. (2005) identified a deletion involving only the entire CD40LG gene in a 13 yro boy with HIGM, who also showed autoimmune retinopathy with retinal pigment epithelium (RPE) hypersensitivity. The younger brother of the patient was also affected by HIGM, however without any ophthalmological symptoms and it was not specified if he also carry the deletion.
HI Evidence Comments:
Lee et al. 2005 (PMID:15358621) In an effort to determined the prevalence of variants in CD40LG and 4 other genes (NEMO, CD40, AICDA and UNG, that have also been associated with autosomal recessive HIGM syndromes) in 140 patients with HIGM (130 M and 10 F), 98 males from 77 families were found to carry a pathogenic loss-of-function variant in CD40LG gene, including exons 1-3 and whole gene deletions. These variants were throughout the gene. In addition, there are numerous loss-of-function variants in HGMD, including nonsense, splicing, small frame shift deletion/insertion, and gross deletions that have been identified in patients with HIGM.
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Published Evidence:
  • PUBMED: 29499223
    Le Coz et al. (2018) identified a 240 kb microduplication involving CD40LG, its regulatory elements and three other protein-coding genes in a 6-month old boy and his 25 yro mother. CD40L expression and CD40LG transcripts in the affected boy were twice that of unaffected relatives and he had coombs-positive hemolytic anemia that evolved into multi-lineage autoimmune cytopenias associated with massive splenomegaly. While his initial immunoglobulin A, G and M serum concentrations exceeded age-matched control ranges, IgM progressively declined until subject III.1 became selectively IgM deficient at five years old. His mother was diagnosed with mixed connective tissue disease and autoimmune thyroiditis, which resolved spontaneously during pregnancy 8 years later. Her CD40L level was indistinguishable from unaffected relatives, indicating random X-inactivation. The author speculated that the temporary reactivation of the CD40LG duplicated X-chromosome, with resultant functional trisomy, may have contributed to the development of her historical autoimmune disorders and the resumption of epigenetic control, to resolution of her disease.
TS Evidence Comments:
Trivellin et al. (2014) (PMID: 25470569) identified microduplications on chromosome Xq26.3 in 13 patients with childhood onset gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. Of note, CD40LG was involved in all these microduplications and also was within one of the region of overlap. However, GPR101 gene was the only gene shown to be overexpressed in patients’ pituitary lesions. The same authors (PMID: 30773288) also clarified that no autoimmune phenotypes have been observed to date in these patients. Due to the lack of report of focal duplication of CD40LG in the literature, the triplosensitivity score is 0.
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)