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Abstracts

Sequence Variants in HECTD1 Result in a Variable Neurodevelopmental Disorder

Abstract number : 3.125
Submission category : 12. Genetics / 12A. Human Studies
Year : 2024
Submission ID : 495
Source : www.aesnet.org
Presentation date : 12/9/2024 12:00:00 AM
Published date :

Authors :
Presenting Author: Gazelle Zerafati-Jahromi, MD – Children's Hospital of Philadelphia

Elias Oxman, MS – Children's National Hospital
Hieu Hoang, PhD – Washington University in St. Louis
Wu-lin Charng, PhD – Washington University in St. Louis
Tanvitha Kotla, BS – Washington University in St. Louis
Weimin Yuan, PhD – Washington University in St. Louis
Keito Ishibashi, BS – Children's National Hospital
Kathryn Luedtke, BS – Children's National Hospital
Bryce Winrow, BS – Children's National Hospital
Rebecca Ganetzky, MD – Children's Hospital of Philadelphia
Anna Ruiz, PhD – University of Barcelona
Peter Kannu, MB ChB, DCH, PhD, FRACP, FRCPC – Alberta Health Services
Taryn Athey, MSc, CCGC – Alberta Health Services
Christina Peroutka, MD, FAAP, FACMG – University of Virginia
Caitlin Barnes, MS, CGC – University of Virginia
Richard Sidlow, MD – Valley Children's Healthcare
George Anadiotis, DO – Randall Children's Hospital
Kari Magnussen, MS LCGC – Randall Children's Hospital
Irene Valenzuela, MD – Valle Hebron Research Institute
Alejandro Moles-Fernandez, PhD – Valle Hebron Research Institute
Seth Berger, MD, PhD – Children's National Hospital
Christina Grant, MD, PhD – Children's National Hospital
Gudny Arnadottir, PhD – deCODE genetics/Amgen Inc.
Patrick Sulem, MD – deCODE genetics/Amgen Inc.
Telma Sulem, MD – deCODE genetics/Amgen Inc.
Kari Stefansson, MD – deCODE genetics/Amgen Inc.
Annapurna Poduri, MD, MPH – Boston Children's Hospital
Chaya Murali, MD, FACMG – Baylor College of Medicine
Rachel Franciskovich, MS, CGC – Baylor College of Medicine
Yen Tran, MD – Baylor College of Medicine
Bryn Webb, MD, FACMG – University of Wisconsin
Kim Keppler-Noreuil, MD – University of Wisconsin
April Hall, PhD, MS, CGC – University of Wisconsin
Dustin Baldridge, MD, PhD – Washington University in St. Louis
Gary Silverman, MD, PhD – Washington University in St. Louis
Sonika Dahiya, MD – Washington University in St. Louis
Tychele Turner, PhD – Washington University in St. Louis
Tim Schedl, PhD – Washington University in St. Louis
Joshua Corbin, PhD – Children's National Hospital
Stephen Pak, PhD – Washington University in St. Louis
Irene Zohn, PhD – Children's National Hospital
Christina Gurnett, MD, PhD – Washington University in St. Louis
Carmen Manso-Bazus, MD – University of Barcelona
Eric Vilain, MD, PhD – University of California
Rozalia Valentine, MS CGC – Boston Children's Hospital
Sara Trowbridge, MD – Boston Children's Hospital
Kristin Monaghan, PhD, FACMG – GeneDx

Rationale: Many neurodevelopmental disorders (NDD) result from genetic differences in the Ubiquitin-Proteasome System. Dysregulation of genes encoding the homologs to E6AP C-terminus (HECT) E3 ubiquitin ligases has been linked to cancer and structural birth defects. One member of this family, the HECT domain E3 ubiquitin protein ligase 1 (HECTD1), mediates developmental pathways including cell signaling, gene expression, and embryogenesis, but has previously only been associated with human neural tube defects. The role of HECTD1 in brain development and human NDDs remains largely unknown. Here, we present clinical data from 14 patients with HECTD1 variants and molecular data from mouse and C. elegans models supporting a critical requirement of HECTD1 for human brain development. We furthermore propose that de novo missense and likely gene-disruptive variants in HECTD1 are associated with epilepsy, NDD and autism.


Methods: The index patient was identified through a research sequencing study at Washington University in St. Louis and confirmed by clinical sequencing at GeneDx. The other 13 participants were identified through GeneMatcher. Clinical data were gathered by means of retrospective chart review using a standardized survey completed by each clinician. Variants were analyzed in silico using multiple pathogenicity scores. Homozygous neural-specific conditional Hectd1 knockout mice were generated, whose brains were harvested for histological analysis of their morphology. C. elegans models of several patient variants were generated using CRISPR/Cas9 in order to analyze the functional consequences of these variants upon markers of development as well as ubiquitin-mediated protein degradation.


Results: Through GeneMatcher, we identified 14 unrelated individuals with 15 different variants in HECTD1 with NDD, including epilepsy, autism, attention-deficit/hyperactivity disorder. Homozygous neural-specific conditional knockout mice had microcephaly, severe hippocampal malformations, and complete agenesis of the corpus callosum, supporting a role for Hectd1 in embryonic brain development (Figure 1). Functional studies in a C. elegans model of several patient variants revealed a dominant effect of these variants (Figure 2).


Conclusions: We conclude that de novo missense and likely gene-disruptive variants in HECTD1 are associated with epilepsy, NDD and autism.


Funding: -Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences of the NIH
-Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the NIH under Award Number P50HD103525 to the Intellectual and Developmental Disabilities Research Center at Washington University
-R01HD110556 from NICHD
-Children’s Discovery Institute, St. Louis Children’s Hospital Foundation (GAS and SCP)
-National Institute of Mental Health of the NIH (T32-MH014677) (WC)
-R01HD098861 from NICHD (PI: IEZ)
-District of Columbia Intellectual Developmental Disabilities Research Center Award P50HD105328 from NICHD
-National Human Genome Research Institute of the National Institutes of Health, as part of GREGoR Consortium: 1U01HG011745


Genetics