ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000013.10) (NC_000013.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
26751395 Isidor et al. (2016) report 6 novel de novo truncating mutations identified by whole exome sequencing in patients with a similar clinical phenotype to that reported by Hempel (severe or moderate ID, hypotonia, absent or very poor speech, microcephaly and dysmorphic features). Functional studies show, "...that truncating protein variants of CHAMP1 are likely delocalized from chromatin and unable to bind to two of its direct partners, POGZ and HP1." The authors note that it is not clear if haploinsufficiency is the mechanism of pathogenicity since there is only one coding exon and mutants may escape nonsense mediated decay: "While CHAMP1 may be haploinsufficient... dominant-negative or gain-of-function effects... cannot be ruled out."
26340335 Hempel et al. (2015) report five unrelated individuals, three males and two females, with ID/GDD, severe speech impairment, and similar (though subtle) facial dysmorphisms. Trio whole exome sequencing found de novo frameshift or nonsense mutations in these individuals. The authors propose that in individuals with terminal deletions of 13q, CHAMP1 may be the cause of intellectual disability.
27148580 Tanaka et al. (2016) report 5 unrelated individuals with de novo predicted LOF CHAMP1 mutations identified via whole exome sequencing (3 nonsense mutations, 2 frameshift mutations). Clinical features are similar to Hempel and Isidor, including developmental delay, intellectual disability, microcephaly and dysmorphic features.

Haploinsufficiency phenotype comments:

CHAMP1 encodes chromosome alignment-maintaining phosphoprotein 1, an 812 amino acid zinc-finger containing protein, which functions in microtubule-kinetochore dynamics during chromosome segregation in cell division. The CHAMP1 gene contains two untranslated exons and one translated exon; this gene localizes to the distal region of chromosome 13q and is the last subtelomeric gene in the region. Multiple de novo sequence-level mutations, predicted to result in a loss-of-function for CHAMP1 have been identified in association with an intellectual disability phenotype that typically includes neonatal hypotonia, motor delay, severe speech impairment, facial anomalies (round face, facial hypotonia, hypertelorism) and microcephaly. CHAMP1 has also been proposed as a candidate gene for features observed in individuals with nonfocal 13q deletions involving additional genes. Functional studies performed by Isidor et al (2016) provide some question as to whether haploinsufficiency is the mechanism of pathogenicity for CHAMP1 mutation and as yet, focal CHAMP1 deletion has not been reported. Therefore the haploinsufficiency score is 2. Additional literature is summarized below: Rauch et al., 2012 (PMID 230209370) performed WES on a cohort of children with ID and identified a de novo nonsense mutation in CHAMP1 in two individuals.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

As yet, focal duplication of CHAMP1 has not been reported in association with clinical phenotypes; therefore the triplosensitivity score is 0.