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.

Arman Zhao, Rui Zhou, Qin Gu, Min Liu, Bingbing Zhang, Jing Huang, Bin Yang, Ruen Yao, Jian Wang, Haitao Lv, Jian Wang, Yiping Shen, Hongying Wang, Xuqin Chen

Journal: Clinica chimica acta; international journal of clinical chemistry 2021;523():10-18

PMID: 34478686

Full Text on Elsevier Science View on PubMed

Abstract

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.

Address: Department of Clinical Laboratory, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected].; Department of Neurology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China.; Department of Rehabilitation Medicine, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China.; Department of Clinical Laboratory, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China.; Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Pudong New District, Shanghai 200127, China.; Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Pudong New District, Shanghai 200127, China. Electronic address: [email protected].; Department of Cardiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China.; Department of Pediatric Surgery, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China.; Department of Genetics and Metabolism, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, Guangxi, China; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States. Electronic address: [email protected].; Department of Clinical Laboratory, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China; Department of Clinical Laboratory, Children's Hospital of Wujiang District, Suzhou, 169 Park Road, Wujiang District, Suzhou 215234, Jiangsu, China. Electronic address: [email protected].; Department of Neurology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected].

DOI: 10.1016/j.cca.2021.08.030

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MeSH Terms: Child, China, Exome, Humans, Infant, Intellectual Disability, Language, Microcephaly, Mutation, Seizures, Wiskott-Aldrich Syndrome Protein Family