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

Siddharth Srivastava; Erica L Macke; Lindsay C Swanson; David Coulter; Eric W Klee; Sureni V Mullegama; Yili Xie; Brendan C Lanpher; Emma C Bedoukian; Cara M Skraban; Laurent Villard; Mathieu Milh; Mary L O Leppert; Julie S Cohen

doi:10.3390/brainsci11070931

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

Brain Sci. 2021 Jul 14;11(7):931. doi: 10.3390/brainsci11070931.

Authors

Siddharth Srivastava¹, Erica L Macke^{2

3}, Lindsay C Swanson¹, David Coulter¹, Eric W Klee^{2

3}, Sureni V Mullegama⁴, Yili Xie⁴, Brendan C Lanpher^{2

5}, Emma C Bedoukian^{6

7}, Cara M Skraban^{6

7}, Laurent Villard^{8

9}, Mathieu Milh^{9

10}, Mary L O Leppert^{11

12}, Julie S Cohen^{11

13}

Affiliations

¹ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
² Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55902, USA.
³ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55902, USA.
⁴ GeneDx Inc., Gaithersburg, MD 20877, USA.
⁵ Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55902, USA.
⁶ Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁷ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁸ Department of Medical Genetics, AP-HM, La Timone Children's Hospital, 13385 Marseille, France.
⁹ Inserm, Marseille Medical Genetics Center, Faculté de Médecine de Marseille, Aix Marseille University, 13385 Marseille, France.
¹⁰ Department of Pediatric Neurology, AP-HM, La Timone Children's Hospital, 13385 Marseille, France.
¹¹ Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
¹² Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

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.

Keywords: WASF1; autism; intellectual disability; neurodevelopmental disorder.

Abstract

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