Ade novovariant inPAK2detected in an individual with Knobloch type 2 syndrome

Abstract

SUMMARYP21-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 monoallelicPAK2variants cause Knobloch syndrome type 2 (KNO2)—a developmental disorder primarily characterized by ocular anomalies. Here, we identified a novelde novoheterozygous missense variant inPAK2, NM_002577.4:c.1273G>A, p.(D425N), by whole genome sequencing in an individual with features consistent with KNO2. Notable clinical phenotypes include global developmental delay, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, FTT, 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 byin silicoanalysis. Previous clinical genetic testing did not report this variant due to unknown relevance ofPAK2variants at the time of testing, highlighting the importance of reanalysis. Our findings also substantiate the candidacy ofPAK2variants in KNO2 and expand the KNO2 clinical spectrum.