NUP188 – Sandestig-Stefanova Syndrome

Sandestig-Stefanova syndrome is an autosomal recessive developmental disorder caused by biallelic loss-of-function variants in the nuclear pore complex gene NUP188 and characterized by microcephaly, trigonocephaly, congenital cataracts, microphthalmia, craniofacial dysmorphism, neurologic deficits, and multiorgan anomalies. The gene–disease relationship has been defined through multiple independent case reports identifying homozygous truncating mutations in affected individuals.

Two unrelated probands with homozygous loss-of-function variants in NUP188 have been reported: c.1087C>T (p.Gln363Ter) and c.124C>T (p.Arg42Ter) (PMID:36158057, PMID:39911172). Both variants occur in exon regions and are predicted to undergo nonsense-mediated decay, abolishing NUP188 function. Parental segregation confirmed carrier status in consanguineous families, and one additional affected sibling was noted (PMID:39911172).

Affected individuals present with a consistent phenotype including bilateral congenital cataracts (HP:0000519), hypotonia (HP:0001252), ambiguous genitalia (HP:0000062), cryptorchidism (HP:0000028), hypospadias (HP:0000047), bifid uvula (HP:0000193), hydrocephalus (HP:0000238), tetralogy of Fallot (HP:0001636), and hepatomegaly (HP:0002240) alongside core neurologic and craniofacial features, expanding the known phenotypic spectrum of this syndrome.

Functional studies in yeast demonstrate that loss of Nup188p perturbs nuclear pore complex (NPC) structure and impairs nucleocytoplasmic transport pathways, including defects in protein import and mRNA export (PMID:16361228, PMID:30021831). Additionally, human cell assays reveal that TDP-43 regulates NUP188 mRNA splicing, implicating NUP188 in NPC homeostasis (PMID:31527135). These concordant experimental data support a loss-of-function mechanism underlying disease.

No conflicting evidence has been reported to date. The combination of two independent homozygous truncating variants with segregation data and mechanistic studies warrants a Moderate clinical validity classification according to ClinGen criteria, with Moderate genetic evidence and Limited functional evidence.

Key Take-home: Biallelic truncating variants in NUP188 cause autosomal recessive Sandestig-Stefanova syndrome, supporting molecular diagnosis and enabling early multidisciplinary management of multisystem involvement.

References

• Molecular syndromology • 2022 • A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities. PMID:36158057
• Molecular syndromology • 2025 • A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus. PMID:39911172
• Genetics • 2006 • The integral membrane protein Pom34p functionally links nucleoporin subcomplexes. PMID:16361228
• G3 (Bethesda, Md.) • 2018 • Identification of the Novel Nup188-brr7 Allele in a Screen for Cold-Sensitive mRNA Export Mutants in Saccharomyces cerevisiae. PMID:30021831
• Life science alliance • 2019 • Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis. PMID:31527135

Evidence Based Scoring (AI generated)