GRK2 – Jeune Syndrome Phenotype

GRK2 is now linked to Jeune syndrome, an autosomal recessive skeletal ciliopathy characterized by a narrow thorax and shortened long bones. A recent reanalysis of whole-exome sequencing in a female infant from consanguineous parents identified a homozygous p.Arg474Ter variant in GRK2, providing case-level evidence in a single proband (PMID:38585547). The patient exhibited a narrow chest (HP:0000774) and shortening of long bones (HP:0003026). No additional affected relatives have been reported, and the variant segregates with disease in this AR context. This finding extends the spectrum of known Jeune syndrome genes beyond the 23 currently listed in OMIM and emphasizes autosomal recessive inheritance.

Functional assays have demonstrated that GRK2 loss-of-function impairs primary cilia–mediated Hedgehog and Wnt signaling while preserving cilia morphology, consistent with the observed skeletal phenotype. The mechanism of haploinsufficiency is supported by cellular models showing compromised ciliary signaling upon GRK2 deficiency. There are no conflicting publications disputing this association. Additional familial studies and segregation data are required to strengthen the clinical validity. Key take-home: GRK2 should be incorporated into diagnostic panels for Jeune syndrome due to its crucial role in ciliary signal regulation and bone development.

References

• Molecular syndromology • 2024 • Reanalysis of Whole-Exome Sequencing Data of an Infant with Suspected Diagnosis of Jeune Syndrome Revealed a Likely Pathogenic Variant in GRK2: A Newly Associated Gene for Jeune Syndrome Phenotype. PMID:38585547

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