Retinal disorders

Gene: PAK2

Green List (high evidence)

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 4 unrelated individuals reported in literature with retinal detachment associated with PAK2‐related Knobloch syndrome.

Created: 27 Jan 2026, 3:33 p.m. | Last Modified: 27 Jan 2026, 3:33 p.m.

Panel Version: 8.82

Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.


Other PAK2 cases not reporting ocular abnormalities:

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.

Created: 27 Jan 2026, 3:27 p.m. | Last Modified: 27 Jan 2026, 3:36 p.m.

Panel Version: 8.82

Antonarakis et al., 2021 (PMID: 33693784) reported two affected siblings from a non-consanguineous New Zealand family. Both had retinal detachment and interstitial parenchymal pulmonary changes on chest X-rays, but only one child had additional significant features such as cataract, posterior encephalocele, severe DD/ID with ASD, and epilepsy. WES revealed a heterozygous PAK2 variant (c.1303 G>A, p.Glu435Lys) in both individuals that apparently occurred de novo indicating parental germ-line mosaicism; however, mosaicism could not be detected by deep sequencing of blood parental DNA. Functional studies showed that the variant, located in the kinase domain, results in a partial loss of the kinase activity.
Sources: Literature

Created: 6 Jan 2022, 10:30 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Knobloch 2 syndrome, OMIM:618458

Publications

• 33693784
• 38894571
• 39876536
• 39994693
• 40262506
• 40247748