PHACTR1 – Developmental and Epileptic Encephalopathy 70

Developmental and epileptic encephalopathy 70 (DEE70) is a severe neurodevelopmental disorder characterized by refractory seizures, global developmental delay, and other neurological deficits. The MONDO:0032663 disease entity is defined as Developmental and epileptic encephalopathy 70, and pathogenic variants in PHACTR1 have been identified as a primary cause.

Five unrelated probands have been described ([PMID:36535243]) with de novo heterozygous missense variants in PHACTR1 presenting with DEE70. All cases arose sporadically, and no familial segregation beyond the index cases has been reported.

Reported variants localize to the RPEL3 domain critical for G-actin and PPP1CA binding; for instance, c.1555C>G (p.Leu519Val) ([PMID:33463715]) impairs actin-binding affinity in vitro. The missense spectrum suggests a dominant‐negative or gain‐of‐function mechanism targeting cytoskeletal regulation in neurons.

Inheritance is autosomal dominant with de novo occurrence in all five probands; no multi-generational segregation has been observed. Functional characterization specific to DEE70 remains limited, although analogous PHACTR1 variants disrupt neuronal migration and synaptic regulation in other epileptic contexts ([PMID:30256902], [PMID:33463715]).

No conflicting evidence has been reported. Overall, the genetic data—five de novo cases with consistent phenotypes—and mechanistic concordance support a moderate level of clinical validity for PHACTR1 in DEE70 (ClinGen–Moderate). This association enables molecular diagnosis, informs genetic counseling, and provides a foundation for targeted functional assays and therapeutic development.

References

• Cytogenetic and genome research • 2022 • Epileptic Encephalopathy with Variants in the PHACTR1 and AFF2 Genes: A Case Report. PMID:36535243
• Clinical genetics • 2021 • Mutation in PHACTR1 associated with multifocal epilepsy with infantile spasms and hypsarrhythmia. PMID:33463715
• Brain : a journal of neurology • 2018 • De novo PHACTR1 mutations in West syndrome and their pathophysiological effects. PMID:30256902

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