ClinGen Dosage Sensitivity Curation Page

ABCD1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
8040304 Fanen et al. (1994) used denaturing gradient gel electrophoresis to analyze exons 6 and 8, which encode the ATP binding domain, in 50 affected ALD patients. Three patients were identified with single or two base pair deletions (1937delC, 2177delTA, 2204delG) that result in a frameshift and are predicted to result in premature termination. The study also identified a patient with a nonsense variant (R464X).
23835273 Hung et al. (2013) performed sequencing analysis on 4 families with X linked adrenoleukodystrophy. Proband ADL-1 was found to have c.1272g>a splice donor site variant that was predicted to result in the activation of a cryptic splice site in exon 4 and resultin in a truncated ABCD1 (p.Val425fs*92)
25835712 Kallabi et al. (2015) described a Tunisian male with X-ALD identified a de novo splice site variant c.1780+2T>G predicted to activate a new splice donor site leading to a frameshift and premature stop.
7825602 Ligtenberg et al. (1995) performed sequencing analysis on 28 independent kindreds with X-linked adrenoleukodystrophy. In the analysis 4 nonsense, 5 frameshifts and 2 splice variants were identified.

Haploinsufficiency phenotype comments:

Additional PMIDs: 7581394, 8566952, 11748843, 7825602 Pathogenic variants in ABCD1 cause X-linked adrenoleukodystrophy in males, which affects the nervous system and the adrenal cortex. Phenotypic variability in males and age of onset are variable from childhood to adult onset ( see PMID 11204280). The clinical presentation can vary within the same family. Although the variation in clinical phenotypes is great , neurologic manifestations are present in nearly all males by adulthood. Female carriers can develop mild to moderate spastic paraparesis in middle age or later. See Gene Reviews.

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

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.