PHF21A – Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures

Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (IDDBCS; MONDO:0032883) is characterized by global neurodevelopmental delay, distinctive craniofacial features, overgrowth, and variable epilepsy. PHF21A encodes BHC80, a chromatin‐binding protein that reads unmethylated H3K4 and is critical for neurodevelopmental gene regulation.

To date, 13 unrelated patients have been reported with de novo heterozygous PHF21A variants in IDDBCS, including 12 in a multi‐patient cohort (PMID:37633153) and one additional case report (PMID:36843358).

The variant spectrum comprises frameshift (7/12), nonsense (4/12), and missense (1/12) mutations, with a recurrent p.Arg580Ter observed in three patients, and all events arise de novo (PMID:37633153).

PHF21A‐related IDDBCS follows an autosomal dominant de novo inheritance pattern with no evidence of transmission to additional affected relatives in pedigrees.

Functional studies demonstrate that PHF21A is highly expressed in the human fetal brain, and truncating mutations disrupt both the AT-hook and intrinsically disordered C-terminal domains, consistent with haploinsufficiency as the pathogenic mechanism (PMID:31649809).

RNA analysis of a novel splice donor variant confirms that skipping of exon 6 (p.Asn30_Gln51del) disrupts a leucine zipper domain essential for BHC80 function in neurodevelopmental disorders (PMID:38264805).

The combined genetic and experimental evidence supports a Strong gene–disease association for PHF21A in IDDBCS. Key take-home: PHF21A de novo loss-of-function variants reliably diagnose IDDBCS, guiding early genetic testing and tailored clinical management.

References

• Clinical genetics • 2023 • A novel de novo variant in the PHF21A causes craniofacial abnormalities, intellectual disability and skeletal manifestations. PMID:36843358
• Seizure • 2023 • De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review. PMID:37633153
• Molecular autism • 2019 • Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism. PMID:31649809
• American journal of medical genetics. Part A • 2024 • Naturally occurring splice variants dissect the functional domains of BHC80 and emphasize the need for RNA analysis. PMID:38264805

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