WDR26 – Skraban-Deardorff Syndrome

Heterozygous de novo variants in WDR26 (HGNC:21208) have been implicated in Skraban-Deardorff syndrome (MONDO:0054636), an ultra-rare autosomal dominant neurodevelopmental disorder. Affected individuals typically present with intellectual disability, global developmental delay, seizures, feeding difficulties, and characteristic facial dysmorphism.

Genetic evidence comprises eight unrelated probands harboring de novo truncating WDR26 variants (n=6 frameshift, n=2 nonsense), including c.1498del (p.His500fs) (PMID:33506510) and other LoF alleles (PMID:33675273). All variants are consistent with autosomal dominant inheritance and predicted to result in haploinsufficiency. No segregation beyond de novo occurrence has been reported.

Patients exhibit a core phenotype of intellectual disability (HP:0001249) and global developmental delay (HP:0001263), often accompanied by seizures (HP:0001250) and feeding difficulties (HP:0011968) during infancy (PMID:33675273; PMID:33506510). Additional features such as ataxic gait, hypotonia, and speech impairment further delineate the clinical spectrum.

Functional studies support a haploinsufficiency mechanism. Structural mapping and complementation assays in engineered human cells demonstrate that 15 of 16 SKDEAS-associated WDR26 mutants impair CTLH E3 complex assembly and substrate binding (PMID:38575527). Moreover, WDR26 knockout in mammalian cells alters chromatin accessibility and dysregulates over 2000 genes, implicating the CTLH complex in transcriptional regulation (PMID:39837355).

No studies have disputed the association between WDR26 LoF variants and Skraban-Deardorff syndrome. The cumulative genetic and functional evidence meets ClinGen criteria for a strong gene–disease relationship.

Key Take-home: De novo truncating variants in WDR26 cause autosomal dominant Skraban-Deardorff syndrome via haploinsufficiency, warranting inclusion of WDR26 in diagnostic gene panels for early-onset intellectual disability and developmental delay.

References

• American journal of medical genetics. Part A | 2021 | Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review. PMID:33675273
• Clinical genetics | 2021 | Skraban-Deardorff syndrome: Six new cases of WDR26-related disease and expansion of the clinical phenotype. PMID:33506510
• FEBS letters | 2024 | Skraban-Deardorff intellectual disability syndrome-associated mutations in WDR26 impair CTLH E3 complex assembly. PMID:38575527
• Genomics | 2025 | WDR26 depletion alters chromatin accessibility and gene expression profiles in mammalian cells. PMID:39837355

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