WDR45 – West syndrome

WDR45, located on Xp11.23, encodes a WD repeat protein essential in macroautophagy. West syndrome is an early-onset epileptic encephalopathy defined by clustered spasms and hypsarrhythmia. Genetic heterogeneity is well established, yet WDR45 has only recently been implicated in this phenotype. The identification of WDR45 variants explains severe West syndrome in males and highlights a role for disrupted autophagy in early epileptic encephalopathies.

In a 2016 study, exome sequencing of three independent male probands with West syndrome uncovered hemizygous WDR45 mutations: two de novo and one maternally inherited mosaic transmitted to a brother and sister (total probands = 3) (PMID:27030146). Affected individuals presented with intractable spasms, profound intellectual disability, global developmental delay, and cerebral atrophy on MRI. Segregation in a single sib pair supports pathogenicity of WDR45 disruption in West syndrome.

A targeted epilepsy panel in 45 West syndrome patients identified one additional case harboring a WDR45 variant among 11 genetic diagnoses, raising the overall diagnostic yield to 29% (PMID:31791873). This expands the allelic series to four unrelated probands, three arising de novo and one familial, underscoring WDR45’s contribution to West syndrome.

The reported variant spectrum in West syndrome comprises loss-of-function mutations. A representative allele is c.34del (p.Leu12fs) in exon 1, predicted to truncate WDR45 and abolish autophagy function. All variants disrupt critical WD repeats, consistent with a loss-of-function mechanism.

While functional studies in β-propeller protein–associated neurodegeneration (BPAN) demonstrate that WDR45 deficiency impairs autophagy, disease-specific models for West syndrome are lacking. No direct functional assays in neuronal models of epileptic spasms have been reported, limiting confirmation of mechanistic links.

Integration of genetic findings reveals that hemizygous WDR45 mutations cause a severe, early-onset West syndrome phenotype in males. Additional research into neuronal autophagy in seizure networks may elucidate pathogenesis. Key take-home: WDR45 should be included in genetic testing panels for West syndrome to improve diagnosis and guide counseling.

References

• Journal of human genetics • 2016 • WDR45 mutations in three male patients with West syndrome. PMID:27030146
• European journal of paediatric neurology • 2020 • Genotype-phenotype correlation on 45 individuals with West syndrome. PMID:31791873

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