PI4KB – EAST syndrome

The association between PI4KB and EAST syndrome has been observed in a recent study that identified a novel homozygous variant in PI4KB in a consanguineous family diagnosed with EAST syndrome (PMID:31640787). The study reported that the variant co‑segregated in all four affected individuals, suggesting a possible contributory role for PI4KB in the disease phenotype, which notably includes intellectual disability.

EAST syndrome, inherited in an autosomal recessive manner, presents with a complex neurodevelopmental phenotype. In this context, the affected family demonstrated intellectual disability (HP:0001249) along with other clinical features that overlap with the established presentation of the syndrome. Segregation analysis revealed that the variant was present in the proband and three additional affected relatives (PMID:31640787).

The genetic evidence for PI4KB centers around the detection of a novel homozygous variant, reported as c.450C>T (p.Pro150Ser), in a family affected by EAST syndrome. This finding, albeit limited to a single family, provides primary support for a potential gene–disease association but awaits independent replication to strengthen its clinical validity.

Functional evidence specific to PI4KB in the context of EAST syndrome remains sparse. Although experimental studies have shed light on gene functions and related pathways in viral replication and other cellular contexts (PMID:34468191), no dedicated functional assays have been conducted to directly link PI4KB dysfunction with the clinical manifestations of EAST syndrome.

Some conflicting insights arise from studies of the PI4KB/OSBP pathway in alternate disease settings, which do not correlate with the neurodevelopmental impairment seen in EAST syndrome. This emphasizes the need for additional functional validation to clarify the mechanism by which PI4KB may contribute to the phenotype.

In summary, while the initial genetic finding in a four‐patient family raises the possibility of PI4KB involvement in EAST syndrome, the current evidence is limited. Key take‑home message: Although preliminary data links PI4KB to EAST syndrome, further studies are required to validate its diagnostic utility and clinical significance.

References

• Human genomics • 2019 • Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance PMID:31640787
• Microbiology spectrum • 2021 • High-Order Epistasis and Functional Coupling of Infection Steps Drive Virus Evolution toward Independence from a Host Pathway PMID:34468191

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