PHF6

Gene Facts

• HGNC Symbol: PHF6 (HGNC:18145)
• HGNC Name: PHD finger protein 6
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: BFLS, BORJ
• Alias symbols: KIAA1823, MGC14797, CENP-31
• %HI: 8.85
• pLI: 1
• LOEUF: 0.17
• Cytoband: Xq26.2
• Genomic Coordinates:

  GRCh37/hg19:	chrX:133507342-133562820
  GRCh38/hg38:	chrX:134373312-134428790

• MANE Select Transcript: NM_001015877.2 ENST00000370803.8
• Function: Transcriptional regulator that associates with ribosomal RNA promoters and suppresses ribosomal RNA (rRNA) transcription. {ECO:0000269|PubMed:23229552}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-3118
• ClinGen Curation ID: CCID:007657
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 02/24/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Borjeson-Forssman-Lehmann syndrome (BFLS)

HI Evidence

• PUBMED: 12415272
  Lower et al (2002) reported two families with Borjeson-Forssman-Lehmann syndrome (BFLS), each with nonsense variants in PHF6, 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). In addition, missense variants were detected in affected males from seven unrelated families.
• PUBMED: 15994862
  Crawford et al (2006) reported PHF6 variants in five unrelated BFL patients, four males and one female. Two unrelated males had the recurrent p.R342X variant, which was previously published elsewhere. The c.940ARG/p.I314V and c.2TRC/p.M1T (previously reported) variants were detected in other two males, respectively. A de novo c.27_28insA (p.G10fsX21) variant was detected in a female patient with BFLS phenotype with highly (93%) skewed X-inactivation.
• PUBMED: 22190899
  Berland et al (2011) identified de novo 15-kb deletion of the terminal 3 exons of PHF6 by microarray study in a female with intellectual disability, irregular teeth, slight body asymmetry, and striated skin pigmentation. In retrospect, her phenotype resembled that of males with BFLS. Highly skewed X-inactivation increased the likelihood of an X-linked cause of her condition.
• PUBMED: 24092917
  Zweier et at (2013) detected de novo variants, including two truncating variants and two duplications of exons 4 and 5, in female patents with variable ID and a distinct appearance of sparse hair, remarkable facial features, hypoplastic nails, and teeth anomalies quantitative real-time PCR and multiplex ligation dependent probe amplification (MLPA). All the patients in this cohort displayed a recognizable phenotype that overlaps but was not identical with the phenotype observed in male patients with BFLS.
• PUBMED: 23906836
  Wieczorek et al (2013) identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs∗53) and a de novo missense variant (c.914G>T, p.Cys305Phe) in PHF6 in two female patients initially thought to have Coffin Siris syndrome using whole genome sequencing.
• PUBMED: 24380767
  Di Donato et al (2014) described a 100 kb deletion of Xq26.2, including last 5 exons of PHF6 and exons 1-7 of HPRT (excluded in the mother, paternal DNA was not available) in a female patient with intellectual disability and a phenotype resembling Coffin Siris syndrome (CSS) and distinct from BFLS. Another female patient had a mosaic 270 kb deletion of Xq26.2, including entire PHF6. This mosaic female presented with a very mild phenotype.

• HI Evidence Comments: The PHF6 gene consists of ten coding exons (NM_032458.3) and encodes a protein which contains four nuclear localization signals and two plant homeodomain (PHD)‐like zinc finger domains. PHF6 is thought to play a role in transcriptional regulation, cell growth, and proliferation. Pathogenic variants of PHF6 have been reported in patients with Borjeson-Forssman-Lehman syndrome (BFLS; OMIM 301900). The majority of variants identified have been missense variants in males, as well as a splice variant, and an in-frame 3 bp deletion (PMIDs: 12415272, 19161141, 12676923). It has been suggested that variants that result in complete loss of function maybe be lethal in males and fully penetrant in females, whereas missense or other types of variants that retain some function may cause BFLS in males and potentially mild features in some females depending on X-inactivation (PMID: 22190899). BFLS, first described in 1962, is a rare X-linked disease characterized by intellectual disability, obesity, short stature, hypogonadism, epilepsy, and a recognizable facial phenotype in males. Affected females have been reported (see above) with putative loss of function variants and/or skewed X-inactivation. However, many carrier females appear unaffected. Younger affected females with de novo pathogenic variants in PHF6 have been described as having some phenotypic overlap with individuals with Coffin Siris syndrome (CSS), which is characterized by intellectual disability, sparse hair and hypoplastic nails. In adolescent or older female patients, the observed phenotype overlaps but is not identical to BFLS in males. Additional evidence includes: Farwell et al (2015) identified a de novo nonsense variant of PHF6 in a patient with BFL syndrome (PMID: 25356970, Supplementary Table 3). Zweier et at (2014) reviewed de novo PHF6 variants phenotypes in females (PMID: 25099957). The GeneReviews for Coffin-Siris syndrome also references the phenotypic overlap between genes associated with that disorder and PHF6 (https://www.ncbi.nlm.nih.gov/books/NBK131811/).

NOTE

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 (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: At this time there is no evidence that supports the triplosensitivity of PHF6.

NOTE

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.