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| Retinal disorders v8.82 | PAK2 |
Arina Puzriakova changed review comment from: 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. 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. 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. 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.; to: 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. |
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| Retinal disorders v8.82 | PAK2 | Arina Puzriakova Classified gene: PAK2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v8.82 | PAK2 | Arina Puzriakova Added comment: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v8.82 | PAK2 | Arina Puzriakova Gene: pak2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v8.81 | PAK2 | Arina Puzriakova Publications for gene: PAK2 were set to 33693784 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v8.80 | PAK2 | Arina Puzriakova Tag Q1_26_promote_green tag was added to gene: PAK2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v8.80 | PAK2 |
Arina Puzriakova edited their review of gene: PAK2: Added comment: 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. 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. 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. 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.; Changed rating: GREEN; Changed publications to: 33693784, 38894571, 39876536, 39994693, 40262506, 40247748; Changed phenotypes to: Knobloch 2 syndrome, OMIM:618458 |
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| Retinal disorders v8.80 | PAK2 | Arina Puzriakova Phenotypes for gene: PAK2 were changed from Knobloch 2 syndrome to Knobloch 2 syndrome, OMIM:618458 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v2.241 | PAK2 |
Arina Puzriakova gene: PAK2 was added gene: PAK2 was added to Retinal disorders. Sources: Literature Mode of inheritance for gene: PAK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PAK2 were set to 33693784 Phenotypes for gene: PAK2 were set to Knobloch 2 syndrome Review for gene: PAK2 was set to RED Added comment: 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 |
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