A de novo variant in PAK2 detected in an individual with Knobloch type 2 syndrome

• Published in: bioRxiv : the preprint server for biology
• Main Authors: Werren, Elizabeth A, Kalsner, Louisa, Ewald, Jessica, Peracchio, Michael, King, Cameron, Vats, Purva, Audano, Peter A, Robinson, Peter N, Adams, Mark D, Kelly, Melissa A, Matson, Adam P
• Format: Journal Article
• Language: English
• Published: United States 22.04.2024
• DOI: 10.1101/2024.04.18.590108

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 variants cause Knobloch syndrome type 2 (KNO2)-a developmental disorder primarily characterized by ocular anomalies. Here, we identified a novel heterozygous missense variant in 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 by analysis. Previous clinical genetic testing did not report this variant due to unknown relevance of variants at the time of testing, highlighting the importance of reanalysis. Our findings also substantiate the candidacy of variants in KNO2 and expand the KNO2 clinical spectrum.