PHF6 was first reported in relation to X-linked Börjeson-Forssman-Lehmann syndrome in 2002 (Lower et al., PMID: 12415272). PHF6 encodes a protein involved in transcriptional regulation. Börjeson-Forssman-Lehmann syndrome is characterized by intellectual disability, epilepsy, obesity, hypogonadism, characteristic facial features with narrow palpebral fissures, tapered fingers and short toes. Heterozygote females may exhibit a similar but milder clinical phenotype; however, many carrier females appear unaffected.
Nine variants (nonsense, frameshift, splice, missense, start loss) that have been reported in 13 probands in five publications (PMIDs: 12415272, 15241480, 15466013, 15994862, 23906836) are included in this curation. The p.Arg342* variant is recurrent and was reported in three unrelated families (PMID: 15241480). Variants in this gene segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence, including a mouse model showing that loss of PHF6 impairs neuronal migration in the brain, and protein interaction with the NuRD complex (PMIDs: 22720776, 23791194).
In summary, there is definitive evidence supporting the relationship between PHF6 and X-linked Börjeson-Forssman-Lehmann syndrome. 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 February 21, 2018 (SOP Version 5). As of July 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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