ClinGen Dosage Sensitivity Curation Page

PHF8

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
16199551 Laumonnier et al. (2005) describes a family (referred to as family N42) with 3 affected males in 2 generations, with X-linked intellectual disability (XLID) and clefting, plus other features, and linkage to the Xp11 region. This family has also been described by Siderius et al. (1999). Laumonnier et al. identified a 12bp deletion in PHF8 resulting in loss of the intron 8 splice donor site. RT-PCR of lymphoblastoid cell lines detected a transcript that retained intron 8, resulting in a premature stop codon. There was an additional very weakly expressed transcript that was also abnormal, with some intron 8 retention. There are 4 segregations in this family between the three affected males and 2 intervening, obligate carrier females. The finding in family N42 prompted sequencing of PHF8 in additional XLID + clefting families including one with 4 affected males in 2 generations discovered a c.621C>T nonsense variant in exon 7 (Family 2). Though there were reportedly 4 affected males in the family (including the proband), only the proband was able to be tested for the variant, as the other affected individuals (three maternal uncles of the proband) were deceased. The proband's mother and maternal grandmother were found to carry the variant. Note that not all affected males have clefting (1 affected male from Family 2 had ID without clefting). Obligate carrier females were confirmed to be heterozygous.
17594395 Abidi et al (2007) performed PHF8 Sanger sequencing of 26 ID + clefting cases. A de novo c.529A>T (p.K177X) nonsense variant in exon 6 was detected in an individual with cleft lip, cleft palate, intellectual disability, and microcephaly; the authors did confirm maternity.
28135719 The DDD paper (2017) reports 1 de novo variant in PHF8, predicted to be LOF, detected by WES, plus one additional since publication: a) Patient 274085 - de novo c.704+1G?>A splice, ID - https://decipher.sanger.ac.uk/patient/274085 b) Patient 389584 - de novo c.1627-1G?>A splice, ID - https://decipher.sanger.ac.uk/patient/389584 3 additional maternally inherited LOF in Decipher c) Patient 260452 - mat c.738_739?insT fs, ID (affected maternal uncle pers comm) - https://decipher.sanger.ac.uk/patient/260452 d) Patient 274463 - mat c.753G?>A nonsense, ID - https://decipher.sanger.ac.uk/patient/274463 e) Patient 322628 - mat c.1839-2A?>G splice, ID - https://decipher.sanger.ac.uk/patient/322628 Additional information (though not counted for scoring purposes due to additional variants): Patient 274736 - de novo c.2065C?>T nonsense, ID + clefting, two other potentially pathogenic variants detected (both de novo) - https://decipher.sanger.ac.uk/patient/274736 Patient 359780 - mat c.1839-2A?>G splice, neuro, two other potentially pathogenic variants detected (one de novo and one X-linked) - https://decipher.sanger.ac.uk/patient/359780

Haploinsufficiency phenotype comments:

Additional information includes: PMID 17661819 - Koivisto et al (2007) 2 Finnish brothers with XLID + clefting had a maternally inherited c.836C>T missense. Several affected deceased male family members reportedly. PMID 23092983 - Nava et al (2012) - sequencing X chr in autism cases - mat c.2904_2906del inframe del, also in affected brother. PMID 18498374 - Qiao et al. (2008) 2 brothers with ID + clefting had a maternally inherited 470 kb deletion that encompasses PHF8 and two other genes. The mother had completely skewed X-inactivation and the deletion was de novo in her. PMID 31906484 - Ibarluzea et al (2020) - targeted sequencing of 82 X-linked intellectual disability genes - mat. c.252C>A nonsense, ID/autism, mother with skewed X-inactivation There are a number of further publications with cases, usually mat inheritance but no other cases in these families. Note that while PHF8 haploinsufficiency is associated with MR in all cases reviewed, the association with clefting is not completely conclusive.

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.