ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
25363768 Iossifov et al (Nature 2014) performed a large whole exome sequencing study of over 2000 families from the Simons Simplex Collection. Found 1 family member with ASD, with a nonsense de novo change in PHF2 (supplemental table 2). The nonsense mutation is in exon 20/22 on the HGMD transcript and is predicted to result in non-sense mediated decay.
27824329 A 2016 study in Nature Communications sequenced the coding regions of 189 autism risk genes across 1,543 probands from the Autism Clinical and Genetic Resources in China using single-molecule molecular inversion probes. This study reported a patient with ASD and a splice site variant in the acceptor region (not maternally inherited, paternal status unknown).

Haploinsufficiency phenotype comments:

1) Of note in PMID 25363768, found a frameshift mutation is in the last exon 22/22 of the HGMD transcript resulting in a stop gain but may not undergo NMD. Please also note that PMID 22542183 are the same authors describing the same frame mutation/patient mentioned in their 2014 study and then the same frameshift/patient is again described in a 2017 article -- PMID: 28191890 supp Table 1 as the original Iossifov et al study). 2) Also of note in PMID 2782439, there were an additional 2 patients, reported as ASD with no other phenotype info provided, in supplemental data (Table 4). Both were missense variants (both variants also reported in gnomAD, one of these variants was maternally inherited with no phenotype info provided on mom and inheritance was not determined for the second variant as parents? DNA not available). Counting likely gene disrupting events, to date 2 families (PMID: 25363768) have been reported with de novo changes in PHF2. And in one of the 2 ASD families, the reported frameshift change is not predicted to lead to NMD due to its location in the last exon and therefore not counted (so based on individual case evidence for de novo occurrences and given lack of details/non-specific ASD phenotype, 0.15 points given for the 1 family with the nonsense change from category C ). With respect to the study (PMID: 27824329), the authors did not put PHF2 high on the list of autism risk genes and inheritance was unknown in 2 of the 3 cases reported (no points given in 'unknown inheritance' category since ASD phenotype for this gene is relatively non-specific) In terms of HI predictors, , PHF2 has a pLI score of 1 with a low observed/expected ratio of 0.08 (52 expected and 4 observed as of Feb 2019). But %HI is 54.82 from DECIPHER. The weight of these two predictive scores are not necessarily in agreement with each other -- no points given for these predictors.

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

Triplosensitivity phenotype comment:

Focal duplications of PHF2 not reported