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Cited by 14Genetics and Neurodevelopmental DisordersGenomics and Rare DiseasesGenomic variations and chromosomal abnormalities

Expansion of the Genotypic and Phenotypic Spectrum of WASF1-Related Neurodevelopmental Disorder

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Srivastava, Siddharth, Macke, Erica L., Swanson, Lindsay C., Coulter, David, Klee, Eric W., Mullegama, Sureni V., Xie, Yili, Lanpher, Brendan C. +6 more·2021·Brain Sciences
DOI 10.3390/brainsci11070931PMC PMC8307306
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Abstract

In humans, de novo truncating variants in WASF1 (Wiskott–Aldrich syndrome protein family member 1) have been linked to presentations of moderate-to-profound intellectual disability (ID), autistic features, and epilepsy. Apart from one case series, there is limited information on the phenotypic spectrum and genetic landscape of WASF1-related neurodevelopmental disorder (NDD). In this report, we describe detailed clinical characteristics of six individuals with WASF1-related NDD. We demonstrate a broader spectrum of neurodevelopmental impairment including more mildly affected individuals. Further, we report new variant types, including a copy number variant (CNV), resulting in the partial deletion of WASF1 in monozygotic twins, and three missense variants, two of which alter the same residue, p.W161. This report adds further evidence that de novo variants in WASF1 cause an autosomal dominant NDD.

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  • Trp161 and Lys172 of WASF1 reside within the WHD and basic region, respectively, whereas Leu535 is located within the WH2 domain.

    “Trp161 and Lys172 reside within the WHD (also called WH1, WASP homology 1, domain) and basic region, respectively95, whereas Leu535 is located within the WH2 domain.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [95]

    Results §3.1 identifies variants at Trp161 and Lys172 and says they cluster “at or near the end” of the WH1 domain. This supports the WH1 placement of Trp161 but does not establish that Lys172 is in the basic region. The citation appears before the separate Leu535 clause, so that clause is not attributed to this source. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Microcephaly, which is not observed in WASF1 KO mice, manifested in two monozygotic twins with a deletion spanning GPR6 and exons 8-10 of WASF1, and in two independent patients harboring the p.Trp161Arg variant.

    “Interestingly, microcephaly, which is not observed in KO mice, manifested in two monozygotic twins with a deletion spanning the entire GPR6 gene and exons 8–10 of WASF195, as well as in two independent patients harboring the identical missense variant p.Trp161Arg95,102.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [95]

    Results §3.1 identifies monozygotic twins with a deletion of all of GPR6 and WASF1 exons 8–10. It reports only one patient with p.W161R (p.Trp161Arg); the other variant at residue 161 is p.W161C. The passages found do not establish microcephaly in these patients or its absence in knockout mice (no page numbers available in our copy). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The WASF1 variant p.Lys172Glu was found in a patient with developmental delay, hypotonia, and autism.

    “Additionally, the variant p.Trp161Cys was reported in a patient with ID, autism, hypotonia, and epilepsy, whereas p.Lys172Glu was found in a patient with DD, hypotonia, and autism95.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [95]

    Results §3.1 identifies p.K172E (p.Lys172Glu) in patient P4. Results §3.2 says P4 had global developmental delay and that all six patients had hypotonia. It describes autism as nearly universal in the cohort but does not establish whether P4 had autism. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • A heterozygous deletion due to a CNV spanning exons 8-10 of WASF1 and encompassing the entire GPR6 gene was identified in monozygotic twins with ID, autism, and epilepsy.

    “A heterozygous deletion due to a CNV spanning exons 8–10 of WASF1 and encompassing the entire GPR6 gene was identified in monozygotic twins with ID, autism, and epilepsy95 (Table 2b).”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [95]

    Results §3.1 identifies a deletion of WASF1 exons 8–10 and the entire GPR6 gene in monozygotic twin sisters; the reported single copy supports its description as heterozygous. Results §§3.2–3.3 support ID and epilepsy in the twins, but §3.2 describes autism as nearly universal in the cohort without identifying whether both twins had it. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The p.Trp161Arg variant in WASF1, resulting from either c.481T > A or c.481T > C, causes similar phenotypes in two independent patients: intellectual disability, developmental delay, epilepsy, and microcephaly.

    “The phenotypes of two independent patients, each carrying the p.Trp161Arg variant in WASF1 resulting from distinct genomic alterations—either c.481T > A95 or c.481T > C102—are similar, displaying ID, DD, epilepsy, and microcephaly.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [95]

    Results §3.1 identifies one patient (P6) with WASF1 c.481T>A (p.W161R); §§3.2–3.3 report developmental impairment in the cohort and infantile spasms in P6. The paper does not report a second p.W161R patient with c.481T>C or compare two such patients, and the retrieved clinical passages do not establish microcephaly. Page numbers were not supplied in our copy. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 16

  1. [1]Padrick S.B. Doolittle L.K. Brautigam C.A. King D.S. Rosen M.K. Arp2/3 complex is bound and activated by two WASP proteins Proc. Natl. Acad. Sci. USA 2011 108 E472 E479 10.1073/pnas.1100236108 21676863 PMC3158169 · DOI
  2. [2]Chen B. Chou H.-T. Brautigam C.A. Xing W. Yang S. Henry L. Doolittle L.K. Walz T. Rosen M.K. Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites eLife 2017 6 e29795 10.7554/eLife.29795 28949297 PMC5614565 · DOI · Paper page
  3. [3]Soderling S.H. Guire E.S. Kaech S. White J. Zhang F. Schutz K. Langeberg L.K. Banker G. Raber J. Scott J.D. A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory J. Neurosci. Off. J. Soc. Neurosci. 2007 27 355 365 10.1523/JNEUROSCI.3209-06.2006 17215396 PMC3740594 · DOI · Paper page
  4. [4]Pilpel Y. Segal M. Rapid WAVE dynamics in dendritic spines of cultured hippocampal neurons is mediated by actin polymerization J. Neurochem. 2005 95 1401 1410 10.1111/j.1471-4159.2005.03467.x 16190876 · DOI
  5. [5]Jaworski J. Kapitein L.C. Gouveia S.M. Dortland B.R. Wulf P.S. Grigoriev I. Camera P. Spangler S.A. Di Stefano P. Demmers J. Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity Neuron 2009 61 85 100 10.1016/j.neuron.2008.11.013 19146815 · DOI · Paper page
  6. [6]Ito Y. Carss K.J. Duarte S.T. Hartley T. Keren B. Kurian M.A. Marey I. Charles P. Mendonça C. Nava C. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures Am. J. Hum. Genet. 2018 103 144 153 10.1016/j.ajhg.2018.06.001 29961568 PMC6037130 · DOI · Paper page
  7. [7]Guillen Sacoto M.J. Tchasovnikarova I.A. Torti E. Forster C. Andrew E.H. Anselm I. Baranano K.W. Briere L.C. Cohen J.S. Craigen W.J. De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism Am. J. Hum. Genet. 2020 107 352 363 10.1016/j.ajhg.2020.06.013 32693025 PMC7413887 · DOI
  8. [8]Desvignes J.-P. Bartoli M. Delague V. Krahn M. Miltgen M. Béroud C. Salgado D. VarAFT: A variant annotation and filtration system for human next generation sequencing data Nucleic Acids Res. 2018 46 W545 W553 10.1093/nar/gky471 29860484 PMC6030844 · DOI
  9. [9]Sobreira N. Schiettecatte F. Valle D. Hamosh A. GeneMatcher: A matching tool for connecting investigators with an interest in the same gene Hum. Mutat. 2015 36 928 930 10.1002/humu.22844 26220891 PMC4833888 · DOI · Paper page
  10. [10]Visintainer P.F. Leppert M. Bennett A. Accardo P.J. Standardization of the Capute Scales: Methods and results J. Child Neurol. 2004 19 967 972 10.1177/08830738040190121101 15704872 · DOI
  11. [11]Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. O’Donnell-Luria A.H. Ware J.S. Hill A.J. Cummings B.B. Analysis of protein-coding genetic variation in 60,706 humans Nature 2016 536 285 291 10.1038/nature19057 27535533 PMC5018207 · DOI · Paper page
  12. [12]Srivastava S. Desai S. Cohen J. Smith-Hicks C. Barañano K. Fatemi A. Naidu S. Monogenic disorders that mimic the phenotype of Rett syndrome Neurogenetics 2018 19 41 47 10.1007/s10048-017-0535-3 29322350 PMC6156085 · DOI
  13. [13]Levy J.P. Oskoui M. Ng P. Andersen J. Buckley D. Fehlings D. Kirton A. Koclas L. Pigeon N. van Rensburg E. Ataxic-hypotonic cerebral palsy in a cerebral palsy registry Neurol. Clin. Pract. 2020 10 131 139 10.1212/CPJ.0000000000000713 32309031 PMC7156190 · DOI
  14. [14]Rosenbaum P. Paneth N. Leviton A. Goldstein M. Bax M. Damiano D. Dan B. Jacobsson B. A report: The definition and classification of cerebral palsy April 2006 Dev. Med. Child Neurol. Suppl. 2007 109 8 14 17370477
  15. [15]MacLennan A.H. Lewis S. Moreno-De-Luca A. Fahey M. Leventer R.J. McIntyre S. Ben-Pazi H. Corbett M. Wang X. Baynam G. Genetic or Other Causation Should Not Change the Clinical Diagnosis of Cerebral Palsy J. Child Neurol. 2019 34 472 476 10.1177/0883073819840449 30963790 PMC6582263 · DOI
  16. [16]Lee R.W. Poretti A. Cohen J.S. Levey E. Gwynn H. Johnston M.V. Hoon A.H. Fatemi A. A Diagnostic Approach for Cerebral Palsy in the Genomic Era Neuromol. Med. 2014 16 821 844 10.1007/s12017-014-8331-9 25280894 PMC4229412 · DOI

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Authors
Srivastava, S., Macke, E. L., Swanson, L. C., Coulter, D., Klee, E. W., Mullegama, S. V., Xie, Y., Lanpher, B. C., Bedoukian, E. C., Skraban, C. M., Villard, L., Milh, M., Leppert, M. L. O., & Cohen, J. S.
Affiliations
  • Boston Children's Hospital (US)
  • Mayo Clinic (US)
  • GeneDx Inc., Gaithersburg, MD 20877, USA
  • Children's Hospital of Philadelphia (US)
  • Inserm (FR)
  • Kennedy Krieger Institute (US)
Corresponding author
Cohen, Julie S.
ORCID
Venue
Brain Sciences
Publisher
MDPI AG
Published
2021-07-14
Volume
11
Issue
7
Pages
931
ISSN
2076-3425 (ISSN-L)
DOI
10.3390/brainsci11070931
PMC
PMC8307306
OpenAlex
W3186380715
Cited by
14
References
0
Citations by year
2026: 2 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 2
FWCI
1.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Neurological Disorders and Stroke (1K23NS119666-01A1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
neurodevelopmental disorders, de novo mutations, truncating mutations, copy number variation, missense mutations, intellectual disability, autism spectrum disorder, epilepsy, phenotypic spectrum, autosomal dominant inheritance, monozygotic twins, partial gene deletion

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