Document Type

Article

Publication Date

6-1-2025

Keywords

JGM, Humans, Developmental Disabilities, Eye Abnormalities, Genetic Association Studies, Heterozygote, Mutation, Missense, p21-Activated Kinases, Phenotype, Retinal Detachment

JAX Source

Am J Med Genet A. 2025;197(6):e64006.

ISSN

1552-4833

PMID

39876536

DOI

https://doi.org/10.1002/ajmg.a.64006

Grant

P.A.A. was supported by NIH NIGMS R35GM133600 and NIH NCI P30CA034196.

Abstract

P21-activated kinase 2 (PAK2) is a serine/threonine kinase essential for a variety of cellular processes including signal transduction, cellular survival, proliferation, and migration. A recent report proposed monoallelic PAK2 variants cause Knobloch syndrome type 2 (KNO2)-a developmental disorder primarily characterized by ocular anomalies. Here, we identified a novel de novo heterozygous missense variant in PAK2, NM_002577.4:c.1273G>A, p.(D425N), by genome sequencing in an individual with features consistent with KNO2. Notable clinical phenotypes observed in this individual were global developmental delay, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(D425N) variant lies within the protein kinase domain and is predicted to be functionally damaging by in silico analysis. Previous clinical genetic testing did not report this variant due to unknown relevance of PAK2 variants at the time of testing, highlighting the importance of reanalysis. Our findings substantiate the candidacy of PAK2 variants in KNO2 and expand the KNO2 clinical phenotypic spectrum.

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