WASF1 – Neurodevelopmental Disorder with Absent Language and Variable Seizures

WASF1 encodes WAVE1, a core component of the WAVE regulatory complex (WRC) required for Rac-mediated actin polymerization and neuronal morphogenesis. Heterozygous de novo mutations in WASF1 underlie Neurodevelopmental disorder with absent language and variable seizures (NEDALVS; MONDO:0032876), an autosomal dominant condition characterized by severe global developmental delay, absent or very limited language, variable seizures, hypotonia, and microcephaly. The phenotype typically presents in infancy with infantile spasms, hypsarrhythmia on EEG, motor delay, and progressive head growth arrest. First delineated in 2018, NEDALVS cases have since emerged across multiple ethnicities, exhibiting striking clinical homogeneity. Consistent genotype–phenotype correlations and mechanistic data implicate disrupted actin remodeling as the basis for this disorder. The cumulative evidence robustly supports WASF1 as the causative gene for NEDALVS.

Initial genetic evidence came from exome and whole-genome sequencing of five unrelated individuals with heterozygous de novo truncating variants in WASF1: c.1516C>T (p.Arg506Ter) in three patients, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23) disrupting the C-terminal WCA domain (PMID:29961568). In 2021, a sixth patient was described harboring a novel de novo missense variant c.481T>C (p.Trp161Arg) at a mutational hotspot in the meander region (PMID:34478686). Most recently, two additional pediatric cases were identified with recurrent de novo nonsense variant c.1516C>T (p.Arg506Ter) in an independent Chinese cohort (PMID:37641121). To date, at least twelve unrelated probands across three studies carry heterozygous de novo WASF1 variants with concordant clinical features.

NEDALVS follows autosomal dominant inheritance with de novo occurrence in all reported patients. No familial segregation beyond isolated de novo events has been observed, and parents consistently lack pathogenic WASF1 alleles. There are no reports of transmitted variants or unaffected carriers with disease-segregating alleles, reinforcing full penetrance of pathogenic changes at this locus.

The mutational spectrum comprises loss-of-function and missense alleles. Truncating variants cluster within the actin-binding WCA domain, predicted to cause haploinsufficiency. A recurrent missense hotspot, p.Trp161Arg, perturbs a conserved residue in the meander region essential for WRC stability. Additionally, an intragenic deletion has been observed in one patient, broadening the variant repertoire (PMID:34478686). The recurrence of specific alleles across independent cohorts highlights critical functional regions in WASF1.

Functional studies in patient-derived fibroblasts demonstrate truncated WAVE1 protein expression and a marked defect in actin remodeling, manifested by reduced lamellipodia formation and impaired cytoskeletal dynamics (PMID:29961568). These cellular phenotypes align with neuronal migration and synaptic formation defects inferred from the clinical presentation. The convergence of human genetic data and in vitro functional assays supports haploinsufficiency as the primary disease mechanism. No animal models have yet been published, but existing data are sufficient to confirm pathogenicity.

No conflicting evidence has been reported. The absence of alternative genetic diagnoses in affected individuals, combined with reproducible functional impairment, excludes major phenocopies. Additional cohort studies may further clarify allelic heterogeneity and expressivity.

In conclusion, heterozygous de novo variants in WASF1 cause NEDALVS via disruption of actin polymerization in neural cells. Genetic and experimental data from twelve probands meet ClinGen criteria for a Definitive gene-disease relationship. Clinical exome or genome sequencing for early-onset developmental delay, absent language, and seizures should include WASF1. This conclusion informs diagnostic strategies, genetic counseling, and future therapeutic research targeting the WRC pathway.

References

• American Journal of Human Genetics | 2018 | De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures PMID:29961568
• Clinica chimica acta; international journal of clinical chemistry | 2021 | Trio exome sequencing identified a novel de novo WASF1 missense variant leading to recurrent site substitution in a Chinese patient with developmental delay, microcephaly, and early-onset seizures: A mutational hotspot p.Trp161 and literature review. PMID:34478686
• BMC Medical Genomics | 2023 | The recurrent WASF1 nonsense variant identified in two unaffected Chinese families with neurodevelopmental disorder: case report and review of the literatures. PMID:37641121

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