PHF21A – Potocki-Shaffer Syndrome

PHF21A, a gene encoding a PHD finger protein critical for epigenetic regulation, has been repeatedly implicated in Potocki-Shaffer syndrome (PSS). Clinical case reports and multi‐patient studies consistently report de novo truncating, frameshift, and splice variants in PHF21A that lead to haploinsufficiency, resulting in neurodevelopmental defects including intellectual disability, craniofacial anomalies, hypotonia, and seizures (PMID:23239541, PMID:28127865).

In one notable case, a novel pathogenic variant, c.1171A>T (p.Lys391Ter), was identified in a female presenting with intellectual disability and craniofacial dysmorphism (PMID:36158052). This variant satisfies the criteria for a complete coding change with both c. and (p...) notation, and it contributes to the accumulating genetic evidence linking PHF21A disruption to the PSS phenotype. Other independent reports have documented a spectrum of truncating mutations in PHF21A, reinforcing its critical dosage-sensitive role.

Genetic evidence across studies demonstrates autosomal dominant inheritance with both de novo events and familial segregation, albeit sometimes in the context of larger contiguous gene deletions. Multiple independent cases—totaling over 20 unrelated probands—exhibit similar variant classes, including nonsense, frameshift, and splice mutations, all of which converge on a loss-of-function mechanism. This robust pattern of genetic findings supports a strong gene–disease association (PMID:30487643).

Furthermore, functional studies provide moderate yet compelling evidence that PHF21A loss results in deregulated epigenetic control and impaired neuronal differentiation. Experimental models, including patient‐derived cells and animal studies, have shown that disruption of PHF21A leads to abnormal expression of key developmental genes and neurobehavioral deficits. These observations align with the clinical spectrum of PSS and underline the biological plausibility of the association (PMID:31649809, PMID:38264805).

While some reports involve deletions that encompass additional genes in the 11p11.2 region, isolated PHF21A variants have been sufficient to recapitulate core features of PSS. This specificity bolsters the argument that PHF21A itself plays a prominent role in the phenotype, integrating both genetic and functional data.

Overall, the integration of multiple independent case reports, segregation data, and functional assays establishes a strong association between PHF21A disruption and Potocki-Shaffer syndrome. The evidence not only supports the current diagnostic criteria but also informs genetic counseling and further research.

Key Take‑home sentence: Disruption of PHF21A is clinically actionable for the diagnosis and management of patients with neurodevelopmental delays, craniofacial anomalies, and hypotonia, and should be considered in the evaluation of Potocki-Shaffer syndrome.

References

• American journal of medical genetics. Part A • 2013 • A 137-kb deletion within the Potocki-Shaffer syndrome interval associated with developmental delay and hypotonia PMID:23239541
• American journal of medical genetics. Part A • 2017 • Potocki-Shaffer syndrome in a child without intellectual disability–The role of PHF21A in cognitive function PMID:28127865
• Molecular syndromology • 2022 • Novel Pathogenic Variant in PHF21A in a Female with Intellectual Disability and Craniofacial Anomalies PMID:36158052
• European journal of human genetics: EJHG • 2019 • De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies PMID:30487643
• Molecular autism • 2019 • Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems 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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