ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000011.9) (NC_000011.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
30487643 Hamanaka et al. (2019) identified three de novo truncating variants within the PHF21A gene resulting in PHF21A haploinsufficiency using trio-based exome sequencing. The common features in the three cases included intellectual disability, motor development delay, speech delay and craniofacial anomalies. The variants in case 1 [c.1220dupC, p.(Glu408Argfs*3)] and case 3[c.657_658insAA, p.(Pro220Asnfs*48)] are likely to be functionally null. The variant in case 2 [c.1738C>T, p.(Arg580*)] is located in the penultimate exon and could form a truncating protein without the C terminal coiled-coiled domain. Given the PHF21A functions as a subunit of a protein complex, the truncating PHF21A protein in case 3 may not be incorporated into the protein complex leading to functional impairment. A subsequent publication (Kim et al. 2019, see below) reports this variant (de novo) in 2 additional probands with neurodevelopmental disorders. Kim et al. note that this particular variant is predicted to remove the LZD2 functional domain.
25262651 The collaboration of two consortia (EuroEPINOMICS and Epi4K/EPGP) reported exome-sequencing data of 356 trios with "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut sydrome. One patient (isnd38199aic1) with infantile spasms was found with a de novo splice acceptor in the PHF21A gene (at genomic position chr11:45958122). There was no further clinical detail available.
25363768 Iossifov et al. (2014) reported exome sequencing data for more than 2,500 families from the Simons Simplex Collections (SSC), each having a child with autism spectrum disorder (ASD). One female patient (Family ID 11339) from this study was found to have a de novo frameshift mutation (11:45971023:CT:C) within the PHF21A gene. There was no further clinical detail available.

Haploinsufficiency phenotype comments:

PHF21A is often included in larger genomic deletions resulting in Potocki-Shaffer syndrome (PSS). PSS is a contiguous gene deletion syndrome characterized by developmental delay, intellectual disability, multiple exostoses, and parietal foramina. Loss of the gene EXT2 causes the multiple exostoses phenotype, while loss of ALX4 causes the parietal foramina phenotype. PHF21A has been proposed as a cause for the neurodevelopmental phenotype. In addition to the cases reported above, Kim et al. (2019) (PMID:31649809) report 7 additional probands with variants in PHF21A and variable neurodevelopmental phenotypes, including intellectual disability, developmental delay, autism spectrum disorders, and seizures. Three of these variants were de novo frameshift variants that were predicted to result in elongated protein; the authors noted that these were not expected to result in nonsense-mediated decay (NMD), but where expected to truncate the intrinsically disordered region of the protein. There were two de novo observations of the p.Arg580Ter variant observed in Hamaka et al. (above); this variant is not expected to result in NMD due to its location, but is expected to result in loss of the LZD2 functional domain. The sixth variant was a frameshift expected to result in NMD, but full inheritance information was not available (father not available for testing, variant not found in mother). The seventh variant was a de novo missense variant. Additional supportive information includes: As of April 2020, the DECIPHER database includes two putative LOF de novo variants interpreted as "likely pathogenic," as well as one additional frameshift de novo variant (also interpreted as likely pathogenic) in the last exon of the gene: - Patient 384482 with abnormality of the nervous system: c.959_967?delinsTTACA (p.Gln320Leufs*53). - Patient 301795 with intellectual delay, joint hypermobility and tall stature: c.703C?>T (p.Arg235*). - Patient 292807 with broad forehead, moderate global developmental delay, narrow nose, overgrowth, seizures, short nose, and umbilical hernia: c.1855A?>T ( p.Lys619*). Kim et al. (2012) [PMID: 22770980] identified two patients and characterized a third previously reported patient with de novo balanced translocations with breakpoints that disrupt the PHF21A gene and clinical features overlapping PSS. They also provided a comparative deletion mapping of PSS subjects that localized PHF21A within the critical region for intellectual disability and craniofacial anomalies. The study also performed supportive functional studies showing a role for this gene in neurodevelopment. Montgomery et al. (2012) [PMID: 23239541] reported a de novo 137 kb deletion involving PHF21A and five additional genes in a boy with developmental delays, hypotonia, subtle dysmorphic features, and neurobehavioral deficits; features that overlap with those observed in PSS. Labonne et al. (2015) [PMID: 26333423] described a de novo 234 kb deletion that include PHF21A and four additional genes in a male with global developmental delay, craniofacial anomalies, minor limb anomalies and micropenis. By comparing this deletion with the deletion described by Montgomery et al. (2013), the minimal critical region was narrowed down to include PEX16, GYLTL1B and PHF21A genes. Reduced PHF21A expression level in the patient further confirmed the deletion pathological role in PSS. Expression studies conducted by Porter et al. (2018) [PMID: 28571721] using RNA sequencing showed a reduction in expression of the PHF21A gene when compare to controls. When assessing the impact of PHF21A haploinsufficiency, the study showed reduction in expression for genes that mediate cAMP signalling, which is a relevant pathway for brain development and learning.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity