Submission Details

Truncating variants in PHF12 have been reported in large cohort studies of individuals with neurodevelopmental disorders, including autism spectrum disorder, intellectual disability and developmental delay; the first report was published in 2016 (PMID: 27479843). Thus, this curation concerns the relationship between PHF12 and autosomal dominant complex neurodevelopmental disorder.

Twelve de novo predicted loss-of-function variants (5 nonsense, 5 frameshift, 2 splicing) reported in 13 probands in 8 publications (PMIDs: 27479843, 28135719, 28263302, 31981491, 33004838, 33057194, 34740920, 35982160) are included in this curation. The variants were identified in large-scale sequencing studies with no phenotype information besides the main neurodevelopmental diagnosis in the cohort. We therefore decided to downgrade the score of the variants by half. The maximum score for genetic evidence has been reached focusing solely on de novo loss-of-function variants. Additional loss-of-function variants beyond those documented here have been reported, but inheritance information is unknown (PMIDs: 31981491, 33004838, 35982160). PHF12 is significantly constrained for loss-of-function variants (pLI = 1, LOEUF = 0.12, gnomAD v4.1.1). The fact that the majority of the reported variants are either nonsense, frameshift or splicing variants is consistent with a loss-of-function effect, but no functional studies have been performed.

PHF12 is a SIN3A binding protein essential for preventing premature cell cycle exit and entry into cellular senescence. It is involved in recruitment of functional SIN3A complexes to DNA, and represses transcription at least in part through the activity of an associated histone deacetylase (PMIDs: 11390640, 27956701). PHF12 can also repress transcription in a SIN3A-independent manner through recruitment of functional TLE5 complexes to DNA (PMIDs: 11390640).

This gene-disease relationship is also supported by experimental evidence, including protein interactions with the SIN3A complex, specifically the SIN3A gene, which is implicated in autosomal dominant SIN3A-related intellectual disability syndrome.

In summary, there is definitive evidence supporting the relationship between PHF12 and autosomal dominant complex neurodevelopmental disorder. However, as detailed phenotypic information in patients is lacking, additional case reports are needed to understand the spectrum of the phenotype. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 19, 2025 (SOP Version 11).

Truncating variants in PHF12 have been reported in large cohort studies of individuals with neurodevelopmental disorders, including autism spectrum disorder, intellectual disability and developmental delay; the first report was published in 2016 (PMID: 27479843). Thus, this curation concerns the relationship between PHF12 and autosomal dominant complex neurodevelopmental disorder.

Twelve de novo predicted loss-of-function variants (5 nonsense, 5 frameshift, 2 splicing) reported in 13 probands in 8 publications (PMIDs: 27479843, 28135719, 28263302, 31981491, 33004838, 33057194, 34740920, 35982160) are included in this curation. The variants were identified in large-scale sequencing studies with no phenotype information besides the main neurodevelopmental diagnosis in the cohort. We therefore decided to downgrade the score of the variants by half. The maximum score for genetic evidence has been reached focusing solely on de novo loss-of-function variants. Additional loss-of-function variants beyond those documented here have been reported, but inheritance information is unknown (PMIDs: 31981491, 33004838, 35982160). PHF12 is significantly constrained for loss-of-function variants (pLI = 1, LOEUF = 0.12, gnomAD v4.1.0). The fact that the majority of the reported variants are either nonsense, frameshift or splicing variants is consistent with a loss-of-function effect, but no functional studies have been performed.

PHF12 is a SIN3A binding protein essential for preventing premature cell cycle exit and entry into cellular senescence. It is involved in recruitment of functional SIN3A complexes to DNA, and represses transcription at least in part through the activity of an associated histone deacetylase (PMIDs: 11390640, 27956701). PHF12 can also repress transcription in a SIN3A-independent manner through recruitment of functional TLE5 complexes to DNA (PMIDs: 11390640).

This gene-disease relationship is also supported by experimental evidence, including protein interactions with the SIN3A complex, specifically the SIN3A gene, which is implicated in autosomal dominant SIN3A-related intellectual disability syndrome.

In summary, there is definitive evidence supporting the relationship between PHF12 and autosomal dominant complex neurodevelopmental disorder. However, as detailed phenotypic information in patients is lacking, additional case reports are needed to understand the spectrum of the phenotype. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 19, 2025 (SOP Version 11).