ClinGen Dosage Sensitivity Curation Page

PHF6

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
12415272 Lower (2002): Two families with Borjeson-Forssman-Lehmann Syndrome (BFLS) are reported, each with nonsense mutations segregating with affected males. Carrier mothers were phenotypically normal and showed 100% skewed X-inactivation. Additional clinical follow up is reported by Turner et al. (PMID: 14756673).
15994862 Crawford (2006): Report of a female with BFLS who had a de novo frameshift mutation. She had clear clinical features of BFLS despite skewed X-inactivation.
22190899 Berland (2011): Report of a female with BFLS and a de novo 15.16 kb deletion involving the last 3 exons of PHF6. She also showed skewed X-inactivation but this did not prevent abnormal clinical features.

Haploinsufficiency phenotype comments:

Mutations in PHF6 result in Borjeson-Forssman-Lehmann syndrome. The majority of mutations identified have been missense mutations in males, as well as a splice mutation, and an in-frame 3 bp deletion (PMIDs: 12415272, 19161141, 12676923). It has been suggested that mutations that result in complete loss of function maybe be lethal in males and fully penetrant in females, whereas missense or other types of mutations that retain some function may cause BFLS in males and potentially mild features in some females depending on X-inactivation (PMID: 22190899).

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.