ClinGen Dosage Sensitivity Curation Page

CHRDL1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
22284829 CHRDL1 (Chordin-like 1) gene is composed of 12 exons and maps to Xq23. CHRDL1 encodes ventropin, a bone morphorphogenic protein antagonist which is known to play a crucial role anteroposterior and dorsoventral axes in the retina and tectum during development. Loss of function variants in CHRDL1 are associated with X-linked megalocornea (MGC1, OMIM 309300) which is characterized by an increased corneal diameter and deep anterior chamber evident at birth with later onset of mosaic corneal degeneration (shagreen), arcus juvenilis, and presenile cataracts. Webb et al. 2012: Discusses 7 different variants in CHRDL1 in families with X-linked megalocornea (MGC1), including two microdeletions, one of which contained only CHRDL1, as well as one nonsense mutation (p.Arg218X) and two frameshifts (c.872delG [p.Cys291LeufsX25] and c.101delAG [p.Glu34AspfsX14]). The microdeletion segregating with the phenotype in that family and the frameshift and nonsense mutations were found in the patients' unaffected mothers.
25093588 Davidson et al (2014) performed whole exome sequencing, Sanger sequencing, and PCR to identify mutations in 10 new families with a diagnosis of MGC1. In all families, mutations of CHRDL1 segregated with affected males and carrier females were unaffected. Structural variants were identified which included whole gene deletions (2 families), nonsense mutations (4 families), and missense mutations (4 families).
26020825 Mangialavori et al (2015) studied 2 families with MGC1 from the same region of Italy. These families apparently are unrelated despite attempts to identify a common ancestor. Between the two families, 5 affected males were identified. All affected individuals in both families family had the same 11-base pair deletion that leads to a stop codon in the second coding exon of the CHRDL1 gene. The mothers of the probands were found to be heterozygous carriers and this mutation was not detected in unaffected male family members.

Haploinsufficiency phenotype comments:

From Webb et al. (2012): No neurological or systemic abnormalities were detected for any affected individuals and carrier females had no clinical signs of MGC1. Han et al (2015, PMID 24073597) described a frameshift mutation in a mother and her four sons affected with MGC1. All these family members had a novel frameshift mutation c.167delC (p.(Pro56Leu*8)) in exon 3. The unaffected brother did not have this variant.

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.