Submission Details

The PHF8 gene has been associated with syndromic X-linked intellectual disability, Siderius type. Variants in PHF8 have been reported in humans as early as 1999 (10398231, 10470851). The affected males typically have mild to moderate intellectual disability. They often have delayed speech and motor development, and cleft lip/palate. Some of the them also manifest distinctive facial features, including a long face, a sloping forehead, a broad nasal bridge, a prominent bone in the lower forehead (supraorbital ridge), upslanting palpebral fissures, low-set ears, and large hands. This disease association was made using case-level data and experimental data. At least 7 variants (missense, nonsense, frameshift, and splice site variant) were curated from five publications (17594395, 29276005, 17661819, 16199551, 25167861). To date, 8 unique variants with PHF8 have been classified as Pathogenic in ClinVar. The gene-disease association is supported by mouse model, zebrafish model, cell culture model, and their respective rescue experiments. In summary, PHF8 is definitively associated with syndromic X-linked intellectual disability, Siderius type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/7/18 (SOP Version 6).

PHF8 was first reported in relation to syndromic X-linked intellectual disability, Siderius type in 2005 (Laumonnier et al., PMID: 16199551). Affected males typically have mild to moderate intellectual disability. They often have delayed speech and motor development, and cleft lip/palate. Some also have distinctive facial features, including long face, sloping forehead, broad nasal bridge, prominent supraorbital ridge, upslanting palpebral fissures, low-set ears, and large hands.

Seven variants (missense, nonsense, frameshift, and splice site) that have been reported in seven probands in five publications (PMIDs: 16199551, 17594395, 17661819, 25167861, 29276005) are included in this curation. The mechanism of pathogenicity is loss of function. The gene-disease relationship is also supported by mouse, zebrafish and cell culture models, and rescue experiments.

In summary, there is definitive evidence supporting the relationship between PHF8 and syndromic X-linked intellectual disability, Siderius type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 7, 2018 (SOP Version 6).