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.

Background: Neurodevelopmental disorder with absent language and variable seizures (NEDALVS, OMIM # 618707) is a newly described autosomal dominant condition caused by heterozygous de novo mutation in WASF1 gene. WASF1 is a key component of the WAVE regulatory complex (WRC) required for actin polymerization. So far, only 3 distinct truncating variants clustering at the WCA domain, 3 missense variants localized to the meander region and a copy number variant (CNV) of WASF1 have been identified among 11 NEDALVS cases previously reported.

Case Report: We report a pediatric patient carrying novel de novo heterozygous missense variant (NM_003931.2: c.481T > C, p.Trp161Arg) in WASF1 gene. During the first hospitalization at age of 5.5 months, the patient was initially diagnosed with infantile spasms, developmental delay (DD) and microcephaly due to nodding-like epileptic spasms in clusters and hypsarrhythmia on video-electroencephalography, lacking head control and body rollover, and abnormal head circumference 39 cm (<-2SD). The genetic diagnosis with a causal WASF1 variant detected by trio exome sequencing indicated the rare NEDALVS.

Literature Review: All the reported NEDALVS cases published in the PubMed English literature were reviewed to summarize the genetic and phenotypic spectrum of this novel disorder.

Conclusion: We describe the third patient with a recurrently mutated amino acid site at p.Trp161 in WASF1, currently the 12th patient with NEDALVS. This hotspot missense variant and the truncating variants in WASF1 lead to similar phenotypic patterns with core features of severe DD/ID, and seizures, hypotonia, and microcephaly frequently observed. Our finding expands the WASF1 mutation spectrum and confirms the de novo hotspot missense variant at p.Trp161, further supporting the association of the novel NEDALVS with WASF1 gene and the actin regulatory pathway.