ClinGen Dosage Sensitivity Curation Page

CD40LG

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
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.
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.
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.

Haploinsufficiency phenotype 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.

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 score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
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.

Triplosensitivity phenotype comment:

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.

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.