PHF21A variants were first reported in relation to complex neurodevelopmental disorder in 2019 (PMID:30487643). The PHF21A gene encodes BHC80, a component of the BRAF35/HDAC complex that mediates repression of neuron-specific genes. At least 10 variants in PHF21A, including nonsense, frameshift and missense variants have been reported in the literature, with most variants occurring de novo. Patients with variants in this gene have been reported to have developmental delay, intellectual disability, and facial dysmorphism.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 2 publications (PMID: 30487643 and 31649809), including 6 frameshift, 3 nonsense (recurrent - c.1738C>T) and 1 missense (AT Hook region) (12 pts). Three of the frameshift variants are located at the last exons and are predicted to elongate the transcription product (PMID: 31649809). Due to limitations of the scoring interface, variants in two probands are not able to be formally entered. Patient 5 carries NM_001101802.1:c.1471_1472insT(p.Cys491LeufsTer?) and patient 7 carries NM_001101802.1:c.2024del(p.Gln675ArgfsTer?)) (PMID: 31649809).
This gene-disease relationship is also supported by a zebrafish model that recapitulates some of the human disease phenotype (PMID:22770980) and a protein interaction study (PMID:12032298).
In summary, there is definitive evidence to support the gene-disease relationship between PHF21A and complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 6, 2022 (SOP Version 8).
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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