WWOX – WWOX-related Epileptic Encephalopathy (WOREE syndrome)

Biallelic pathogenic variants in the WWOX gene cause a severe early-onset neurodevelopmental disorder, developmental and epileptic encephalopathy, 28 (WOREE syndrome). This autosomal recessive condition is typified by drug-resistant epilepsy, global developmental delay, and a high risk of premature death in infancy or early childhood.

Inheritance is autosomal recessive with robust segregation of compound heterozygous or homozygous variants in unaffected carrier parents. A cohort study of 20 additional patients from 18 unrelated families and a comprehensive literature review identified 37 probands from 27 unrelated families (PMID:30356099). Four isolated case reports further describe single affected individuals harboring biallelic WWOX variants (PMID:35573960; PMID:37974179; PMID:38407561; PMID:39416860).

The variant spectrum encompasses loss-of-function alleles—nonsense, frameshift, splice-site, and multi-exon deletions—and missense changes. Notable examples include c.790C>T (p.Arg264Ter) and splice-site c.516+1G>A, as well as exon deletions confirmed by array-CGH and qPCR. Both homozygous and compound heterozygous configurations have been reported; no recurrent founder variants have been described to date.

Functional studies support a loss-of-function mechanism. Patient fibroblasts homozygous for c.689A>C (p.Gln230Pro) exhibit normal transcript levels but complete absence of WWOX protein, pointing to impaired translation or protein instability (PMID:29808465). Minigene assays for the c.172+1G>C splice variant confirm exon skipping and premature truncation (PMID:39101447).

Neuroimaging data from 30 patients reveal cerebellar and cerebral hypoplasia, white matter abnormalities, and ventriculomegaly, correlating with the more severe null/null genotypes (PMID:38161429). These concordant clinical, genetic, and radiological findings underscore WWOX’s critical role in neuronal development and CNS homeostasis.

No conflicting evidence disputes the WWOX–WOREE association. The aggregation of 37 probands from 27 families with consistent segregation and functional data justifies a Definitive clinical validity classification. Key take-home: targeted genetic testing for biallelic WWOX variants is essential for accurate diagnosis, genetic counseling, and management of WOREE syndrome.

References

• Frontiers in pediatrics • 2022 • A Phenotypic-Driven Approach for the Diagnosis of WOREE Syndrome. PMID:35573960
• BMC medical genomics • 2023 • Identification of compound heterozygous deletion of the WWOX gene in WOREE syndrome. PMID:37974179
• American journal of medical genetics. Part A • 2024 • Identification of a novel splice-site WWOX variant with paternal uniparental isodisomy in a patient with infantile epileptic encephalopathy. PMID:38407561
• Frontiers in pediatrics • 2024 • WWOX-related epileptic encephalopathy caused by a novel mutation in the WWOX gene: a case report. PMID:39416860
• Genetics in medicine : official journal of the American College of Medical Genetics • 2019 • The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature. PMID:30356099
• Neurogenetics • 2018 • A novel missense variant in the SDR domain of the WWOX gene leads to complete loss of WWOX protein with early-onset epileptic encephalopathy and severe developmental delay. PMID:29808465
• Molecular genetics & genomic medicine • 2024 • Developmental epileptic encephalopathy caused by homozygosity of a c.172+1G>C variant in the WWOX gene. PMID:39101447
• Frontiers in pediatrics • 2023 • Neuroimaging features of WOREE syndrome: a mini-review of the literature. PMID:38161429

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