ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000004.11) (NC_000004.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
27824329 Wang et al (Nature Comm 2016) performed targeted sequencing using molecular inversion probe technology based on the frequency and severity of de novo variants in autism risk genes previously published from exome studies. A total 1,086 ASD proband?parent trios from the Autism Clinical and Genetic Resources in China were collected. Among this cohort, 1 proband was identified with a confirmed de novo frameshift 1bp deletion in exon 8/17 (from supp table 6). This was not reported in gnomAD.
24463507 Fromer et al (Nature 2014) performed exome sequencing on 623 schizophrenia trios. They found one confirmed de novo frameshift variant in exon 4/17 on the HGDM transcript in an individual with schizophrenia (supp data, details of the phenotype not provided). The authors note that severe gene disruptive variants have a relatively lesser role in schizophrenia as opposed to intellectual disability and/or ASD phenotypes demonstrating more highly conserved mutation hotspots.

Haploinsufficiency phenotype comments:

PMID 28135719 (Nature - 2017) McRae et al performed WES on 4,293 individuals among the DDD cohort and found a de novo missense variant in YTHDC1 in an individual with developmental delay (not reported in gnomAD, parental testing and detailed phenotype info not provided). Of note, this gene did not reach statistical significance based on their genome-wide analysis to be considered a developmental disorder gene. PMID: 25363768 Iossifov et al (Nature ? 2014) prioritized a list of targets of recurrent de novo variants in ASD, YTHDC1 ranked fairly low on this list as severe likely gene disrupting variants being very rare in this gene. In terms of HI predictors, YTHDC1 has a pLI score of 1 with an observed/expected ratio of 50 expected and 1 observed as of April 2019. %HI is 10 from DECIPHER (in the higher ranks). The weight of these two predictive scores are in agreement -- this could be considered as supporting evidence for HI. Overall, additional information is necessary to understand the relationship between haploinsufficiency of this gene and complex neurodevelopmental disorders.

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

Triplosensitivity phenotype comment:

To date, no gross duplications reported in literature or HGMD