CCDC88A – PEHO-like syndrome

Biallelic loss-of-function variants in CCDC88A cause PEHO-like syndrome (MONDO:0020495) in an autosomal recessive pattern. In a consanguineous Saudi family, two siblings presented with profound global developmental delay, seizures, optic nerve and cerebellar atrophy, intellectual disability, and pedal edema. Whole exome sequencing and Sanger validation identified a novel homozygous nonsense variant c.1292G>A (p.Trp431Ter) in both probands, absent from 100 controls (PMID:30392057). No additional affected relatives were reported.

Functional characterization in patient-derived fibroblasts and CRISPR-Cas9 knockout models demonstrates that girdin deficiency disrupts actin remodeling, accelerates proliferation, and impairs migration, consistent with neurodevelopmental deficits (PMID:40401444). These data support a haploinsufficiency mechanism whereby complete loss of girdin function leads to the PEHO phenotype. No conflicting evidence has been reported. Key take-home: CCDC88A biallelic truncating variants should be considered in patients with PEHO-like features.

References

• Neurological sciences • 2019 • A novel homozygous nonsense mutation in CCDC88A gene cause PEHO-like syndrome in consanguineous Saudi family. PMID:30392057
• Human molecular genetics • 2025 • Genome sequencing reveals CCDC88A variants in malformations of cortical development and immune dysfunction. PMID:40401444

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