Alternative titles; symbols
HGNC Approved Gene Symbol: PHF21A
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38) : 11:45,929,319-46,121,454 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p11.2 | Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures | 618725 | Autosomal dominant | 3 |
The PHF21A gene encodes BHC80, a component of a BRAF35 (605535)/histone deacetylase (HDAC; see 601241) complex (BHC) that mediates repression of neuron-specific genes through the cis-regulatory element known as repressor element-1 (RE1) or neural restrictive silencer (NRS) (Hakimi et al., 2002).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned BHC80, which they designated KIAA1696. The deduced 635-amino acid protein contains a PHD-type zinc finger. RT-PCR ELISA detected intermediate expression in all tissues and specific brain regions examined.
Hakimi et al. (2002) identified BHC80 as a component of a BHC purified from HeLa cell nuclear extracts. They sequenced tryptic peptides and determined that the 634-amino acid BHC80 protein contains an N-terminal leucine zipper, a PHD zinc-finger domain most similar to that of the MI2 protein (see 602120), and a C-terminal leucine zipper. RT-PCR detected tissue-specific expression, with the highest level in brain.
The PHF21A gene maps to the critical interval on chromosome 11p11.2 for the contiguous gene disorder Potocki-Shaffer syndrome (PSS; 601224), and within the refined interval associated with impaired intellectual development and craniofacial anomalies (Kim et al., 2012).
Kim et al. (2012) identified 3 patients with balanced translocations disrupting the PHF21A gene on chromosome 11p11.2. All 3 patients had impaired intellectual development, and 1 had no speech. Craniofacial anomalies included microcephaly, brachycephaly, narrow nose, and downturned mouth. Hypotonia and myopia were also present. None of the 3 patients had exostoses or parietal foramina, which are caused by mutations in genes other than PHF21A within the PSS critical region.
Hakimi et al. (2002) determined that, in contrast to BRAF35, overexpression of transfected BHC80 in human embryonic kidney cells completely abrogated RE1-dependent transcriptional repression.
Kim et al. (2012) showed that injection of zebrafish embryos with morpholinos against the phf21a gene resulted in both craniofacial abnormalities and neuronal apoptosis. Along with lysine-specific demethylase-1 (LSD1; 609132), PHF21A is a component of the BRAF-HDAC complex that represses target gene transcription. In lymphoblastoid cell lines from 2 translocation subjects in whom PHF21A was directly disrupted by the respective breakpoints, Kim et al. (2012) observed derepression of the neuronal gene SCN3A (182391) and reduced LSD1 occupancy at the SCN3A promoter, supporting a direct functional consequence of PHF21A haploinsufficiency on transcriptional regulation.
In 3 children with intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (IDDBCS; 618725), Hamanaka et al. (2019) identified heterozygous de novo truncating variants in the PHF21A1 gene (608325.0001-608325.0003).
Kim et al. (2019) identified 7 heterozygous coding mutations (e.g., 608325.0002, 608325.0004), 6 of which were shown to be de novo, in 7 patients with IDDBCS. Six of the 7 mutations were nonsense or frameshift, but 1 was a missense variant at a highly conserved position (G429S; 608325.0004). A C-terminal intrinsically disordered region (IDR) was truncated in 6 of the patients, suggesting that this domain may play an important role in PHF21A1 function.
In a 3-year-old Japanese boy (patient 1) with intellectual developmental disorder with behavioral abnormalities, craniofacial dysmorphism, and seizures (IDDBCS; 618725), Hamanaka et al. (2019) identified a heterozygous de novo duplication (c.1220dupC, NM_001101802.1) of a single nucleotide in exon 12 of the PHF21A gene that resulted in frameshift and premature termination (Glu408ArgfsTer3). This variant was not found in public human genome variation databases.
In a 5-year-old Japanese boy (patient 2) with intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism (IDDBCS; 618725), Hamanaka et al. (2019) identified a heterozygous de novo c.1738C-T transition (c.1738C-T, NM_001101802.1) in exon 17 of the PHF21A gene that was predicted to result in an arg580-to-ter (R580X) substitution that truncated the C-terminal coiled-coil domain. Because the variant was located in the penultimate exon, the authors stated that the mutant protein might escape nonsense-mediated mRNA decay. This variant was not found in public human genome variation databases. Hamanaka et al. (2019) stated that the presence of seizures in this individual was not determined.
In 2 boys (patients 4 and 6) with IDDBCS, the former with and the latter without seizures, Kim et al. (2019) identified a heterozygous R580X mutation in PHF21A and showed it to have occurred de novo in both cases.
In a 9.5-year-old Norwegian boy (patient 3) with intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism without seizures (IDDBCS; 618725), Hamanaka et al. (2019) identified a heterozygous de novo insertion of 2 basepairs (c.657_658insAA, NM_001101802.1) in exon 8 of the PHF21A gene, resulting in a frameshift and premature termination (Pro220AsnfsTer48). This variant was not found in public human genome variation databases.
In a 3-year-old male (patient 2) with intellectual developmental disorder with behavioral abnormalities, craniofacial dysmorphism, and seizures (IDDBCS; 618725), Kim et al. (2019) identified a heterozygous de novo c.1285G-to-A transition (c.1285G-A, NM_001101802.1) at the last nucleotide of exon 13 of the PHF21A gene, resulting in a glycine-to-serine substitution at codon 429 (G429S). The glycine at this position is fully evolutionarily conserved through Xenopus. Kim et al. (2019) modeled the effect of this variant in the AT-hook region of PHF21A, which binds AT-rich DNA, and found that the presence of the hydroxyl group in the side chain of serine relative to glycine creates a repulsive charge due to its proximity to the negatively charged phosphate backbone of DNA.
Hakimi, M.-A., Bochar, D. A., Chenoweth, J., Lane, W. S., Mandel, G., Shiekhattar, R. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Nat. Acad. Sci. 99: 7420-7425, 2002. [PubMed: 12032298] [Full Text: https://doi.org/10.1073/pnas.112008599]
Hamanaka, K., Sugawara, Y., Shimoji, T., Nordtveit, T. I., Kato, M., Nakashima, M., Saitsu, H., Suzuki, T., Yamakawa, K., Aukrust, I., Houge, G., Mitsuhashi, S., and 9 others. De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies. Europ. J. Hum. Genet. 27: 378-383, 2019. [PubMed: 30487643] [Full Text: https://doi.org/10.1038/s41431-018-0289-x]
Kim, H.-G., Kim, H.-T., Leach, N. T., Lan, F., Ullmann, R., Silahtaroglu, A., Kurth, I., Nowka, A., Seong, I. S., Shen, Y., Talkowski, M. E., Ruderfer, D, and 23 others. Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies. Am. J. Hum. Genet. 91: 56-72, 2012. [PubMed: 22770980] [Full Text: https://doi.org/10.1016/j.ajhg.2012.05.005]
Kim, H.-G., Rosenfeld, J. A., Scott, D. A., Benedicte, G., Labonne, J. D., Brown, J., McGuire, M., Mahida, S., Naidu, S., Gutierrez, J., Lesca, G., des Portes, V., and 16 others. Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism. Molec. Autism 10: 35, 2019. Note: Electronic Article. [PubMed: 31649809] [Full Text: https://doi.org/10.1186/s13229-019-0286-0]
Nagase, T., Kikuno, R., Hattori, A., Kondo, Y., Okumura, K., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 347-355, 2000. [PubMed: 11214970] [Full Text: https://doi.org/10.1093/dnares/7.6.347]