NUP188 (Nucleoporin 188-KD) is located on chromosome 9 at 9q34.11. The protein is key in controlling movement of macromolecules into and out of the nucleus and is predicted to interact with other proteins to form the scaffold of the nuclear pore. NUP188 was first reported in relation to autosomal recessive Sandestig-Stefanova Syndrome in 2019 (Sandestig et al., PMID: 32021605). Sandestig-Stefanova Syndrome is a condition impacting development and characterized by pre- and postnatal microcephaly, trigonocephaly, cataracts at birth, microphthalmia, facial anomalies, digit anomalies (such as camptodactyly), brain malformations (including reduced periventricular white matter volume), and delayed myelination. 9 variants (frameshift, nonsense) that have been reported in at least 9 probands in 4 publications (PMIDs: 32021605; Muir et al., 2020, PMID: 32275884; Korulmaz et al., 2022, PMID: 36158057; Bulut et al., 2025, PMID: 39911172) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence including Drosophila model, expression-level evidence, interaction evidence (Vishnoi et al., 2020, PMID: 32211895; PMID: 32275884). A knockout model in Drosophila showed that NUP188 deficiency is associated with neonatal death, inhibited sensory dendrite tiling, reduced negative geotaxis, and seizures. Expression-level evidence in HeLa cells demonstrated that NUP188 concentrations at centrosomes rise during mitosis. Interaction evidence indicated localization of NUP188 and CEP152 to the pericentriolar membrane. CEP152 was curated as definitive for autosomal recessive microcephaly with/without short stature. A morpholino knockdown in Xenopus was also evaluated, but not scored due to not being fully replicative of the phenotype (Farhro et al., 2011, PMID: 21282601). In summary, there is definitive evidence supporting the relationship between NUP188 and autosomal recessive Sandestig-Stefanova Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 5/7/2025 (SOP Version 11).
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