Evidence map›Paper›PMID 39879987›Full record

ArticleAmerican journal of human genetics2025

Sequence variants in HECTD1 result in a variable neurodevelopmental disorder.

Gazelle Zerafati-Jahromi, Elias Oxman, Hieu D Hoang, Wu-Lin Charng, Tanvitha Kotla, Weimin Yuan, Keito Ishibashi, Sonia Sebaoui, Kathryn Luedtke, Bryce Winrow and 44 more

Abstract read
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In one paragraph

Article in American journal of human genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

54 authors.

Gazelle Zerafati-JahromiDepartment of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
Elias OxmanCenter for Genetic Medicine Research, Children's National Hospital, Washington, DC, USA.
Hieu D HoangDepartment of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA.
Wu-Lin CharngDepartment of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
Tanvitha KotlaDepartment of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA.
Weimin YuanDepartment of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA.
Keito IshibashiCenter for Genetic Medicine Research, Children's National Hospital, Washington, DC, USA.
Sonia SebaouiCenter for Neuroscience Research, Children's National Hospital, Washington, DC, USA.
Kathryn LuedtkeCenter for Genetic Medicine Research, Children's National Hospital, Washington, DC, USA.
Bryce WinrowCenter for Genetic Medicine Research, Children's National Hospital, Washington, DC, USA.
Rebecca D GanetzkyMitochondrial Medicine Frontier Program, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Center for Computational Genomics Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Anna RuizCenter for Genomic Medicine, Parc Taulí Hospital University, Parc Taulí Institute of Research and Innovation (I3PT-CERCA), Autonomous University of Barcelona, Sabadell, Spain.
Carmen Manso-BasúzCenter for Genomic Medicine, Parc Taulí Hospital University, Parc Taulí Institute of Research and Innovation (I3PT-CERCA), Autonomous University of Barcelona, Sabadell, Spain.
Nino SpataroCenter for Genomic Medicine, Parc Taulí Hospital University, Parc Taulí Institute of Research and Innovation (I3PT-CERCA), Autonomous University of Barcelona, Sabadell, Spain.
Peter KannuDepartment of Medical Genetics, Alberta Health Services, Edmonton, AB, Canada.
Taryn AtheyDepartment of Medical Genetics, Alberta Health Services, Edmonton, AB, Canada.
Christina PeroutkaDepartment of Pediatrics, University of Virginia, Charlottesville, VA, USA.
Caitlin BarnesDepartment of Pediatrics, University of Virginia, Charlottesville, VA, USA.
Richard SidlowDepartment of Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA, USA.
George AnadiotisDepartment of Genetics and Metabolism, Randall Children's Hospital at Legacy Emanuel, Portland, OR, USA.
Kari MagnussenDepartment of Genetics and Metabolism, Randall Children's Hospital at Legacy Emanuel, Portland, OR, USA.
Irene ValenzuelaDepartment of Clinical and Molecular Genetics, University Hospital Vall d'Hebron and Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain.
Alejandro Moles-FernandezDepartment of Clinical and Molecular Genetics, University Hospital Vall d'Hebron and Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain.
Seth BergerRare Disease Institute, Children's National Hospital, Washington, DC, USA.
Christina L GrantRare Disease Institute, Children's National Hospital, Washington, DC, USA.
Eric VilainInstitute for Clinical and Translational Science, University of California, Irvine, Irvine, CA, USA.
Gudny A ArnadottirdeCODE Genetics/Amgen Inc., Reykjavik, Iceland.
Patrick SulemdeCODE Genetics/Amgen Inc., Reykjavik, Iceland.
Telma S SulemdeCODE Genetics/Amgen Inc., Reykjavik, Iceland.
Kari StefanssondeCODE Genetics/Amgen Inc., Reykjavik, Iceland.
Shavonne MasseyDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Natalie GinnDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Annapurna PoduriDepartment of Neurology, Boston Children's Hospital, Boston, MA, USA; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
Alissa M D'GamaDivision of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Rozalia ValentineEpilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
Sara K TrowbridgeDepartment of Neurology, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA.
Chaya N MuraliDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Rachel FranciskovichDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Yen TranDepartment of Neurology, Baylor College of Medicine, Houston, TX, USA.
Bryn D WebbDepartment of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Kim M Keppler-NoreuilDepartment of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
April L HallDepartment of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Bobbi McGivernGeneDx, Gaithersburg, MD, USA.
Kristin G MonaghanGeneDx, Gaithersburg, MD, USA.
Maria J Guillen SacotoGeneDx, Gaithersburg, MD, USA.
Dustin BaldridgeDepartment of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA.
Gary A SilvermanDepartment of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA.
Sonika DahiyaDepartment of Pathology, Washington University in St. Louis, St. Louis, MO, USA.
Tychele N TurnerDepartment of Genetics, Washington University in St. Louis, St. Louis, MO, USA.
Tim SchedlDepartment of Genetics, Washington University in St. Louis, St. Louis, MO, USA.
Joshua G CorbinCenter for Neuroscience Research, Children's National Hospital, Washington, DC, USA.
Stephen C PakDepartment of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA.
Irene E ZohnCenter for Genetic Medicine Research, Children's National Hospital, Washington, DC, USA. Electronic address: izohn@childrensnational.org.
Christina A GurnettDepartment of Neurology, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: gurnettc@wustl.edu.

Funding

Pediatric Mendelian Genomics Research CenterU01HG011745 · NHGRI · UNIVERSITY OF CALIFORNIA-IRVINE · PI Eric J. Vilain · 2021 to 2026
$13.3M
Neurobehavioral Evaluation CoreP50HD105328 · NICHD · CHILDREN'S RESEARCH INSTITUTE · PI KENWORTHY, LAUREN · 2021 to 2025
$6.9M
Research_ProjectU54HD090257 · NICHD · CHILDREN'S RESEARCH INSTITUTE · PI GUAY-WOODFORD, LISA MARIE · 2016 to 2020
$5.9M
Gene x Environment Interactions and Congenital Heart Defects – Illuminating the MechanismsR01HD113214 · NICHD · CHILDREN'S RESEARCH INSTITUTE · PI Irene E Zohn · 2023 to 2026
$2.3M
Regulation of Cranial Mesenchyme Expansion Driving Neural Fold ElevationR01HD098861 · NICHD · CHILDREN'S RESEARCH INSTITUTE · PI ZOHN, IRENE E · 2020 to 2024
$1.9M
NHGRI NIH HHS U01 HG011745NICHD NIH HHS P50 HD105328NICHD NIH HHS R01 HD098861NICHD NIH HHS R01 HD113214NICHD NIH HHS U54 HD090257
6 · The paper itself

Abstract

Dysregulation of genes encoding the homologous 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-containing protein 1 (HECTD1), mediates developmental pathways, including cell signaling, gene expression, and embryogenesis. Through GeneMatcher, we identified 14 unrelated individuals with 15 different variants in HECTD1 (10 missense, 3 frameshift, 1 nonsense, and 1 splicing variant) with neurodevelopmental disorders (NDDs), including autism, attention-deficit/hyperactivity disorder, and epilepsy. Of these 15 HECTD1 variants, 10 occurred de novo, 3 had unknown inheritance, and 2 were compound heterozygous. While all individuals in this cohort displayed NDDs, no genotype-phenotype correlation was apparent. Conditional knockout of Hectd1 in the neural lineage in mice resulted in microcephaly, severe hippocampal malformations, and complete agenesis of the corpus callosum, supporting a role for Hectd1 in embryonic brain development. Functional studies of select variants in C. elegans revealed dominant effects, including either change-of-function or loss-of-function/haploinsufficient mechanisms, which may explain phenotypic heterogeneity. Significant enrichment of de novo variants in HECTD1 was also shown in an independent cohort of 53,305 published trios with NDDs or congenital heart disease. Thus, our clinical and functional data support a critical requirement of HECTD1 for human brain development.

Indexed as

Neurodevelopmental DisordersUbiquitin-Protein LigasesAdolescentAnimalsAttention Deficit Disorder with HyperactivityAutistic DisorderCaenorhabditis elegansChildChild, PreschoolEpilepsyFemaleHumansMaleMiceMice, KnockoutMutationUbiquitin-Protein LigasesautismepilepsyHECTD1neurodevelopmental disordersubiquitin-proteasome system

Identifiers

PMID39879987
PMCPMC11947180

What Socratic holds

Textmetadata
LicenceCC BY
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.