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

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 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 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 also substantiate the candidacy of PAK2 variants in KNO2 and expand the KNO2 clinical spectrum.

Figure 1.. Monoallelic variants in PAK2.

(A) Pedigree of the family in the present study with the genotypes for NM_002577.4:c.1273G>A (NC_000003.12:g.196820490G>A) of sequenced individuals. Squares represent assigned male at birth; circles represent assigned female at birth; clear shapes indicate unaffected status; solid shapes indicate affected status. (B) Cranial MRI demonstrating prominence of ventricles and sulci with asymmetric fullness of the body of the left ventricle as well as abnormal bilateral signal within the ocular globes. (C) Top: linear PAK2 protein map with missense variants (represented as a triangle) identified in the present study (black) and previously published (grey) in individuals with KNO2. PRBD, p21-Rho-binding domain (green) and protein kinase domain (blue). Bottom: predicted tolerance landscape of PAK2 (ENST00000327134.3) by MetaDome analysis. Tolerance scores are based on dN/dS. (D) PAK2 protein alignment showing cross-species conservation at affected residues, as well as protein alignment with the homologous kinase region in paralogs PAK3 and PAK1 (bottom) with homologous PAK3/PAK1 kinase variants. (E) PyMOL visualization of PAK2 protein kinase domain structure (PDB: 6FD3_A) showing the p.(D425N) variant.