ArticleAmerican journal of human genetics2020
Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.
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Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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37citing papers in PubMed
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Who cites it
37 citing papers in PubMed, 52 citations in OpenAlex.
- Sensory Reactivity Symptoms Are a Core Feature of ADNP Syndrome Irrespective of Autism Diagnosis.Genes · 2021Trial
- Article
- Clinical and Genetic Characterization of Patients with ADNP Related Helsmoortel-Van der Aa Syndrome.Indian journal of pediatrics · 2026Article
- ADNP Functions During Early Brain Development and Their Relevance to ASD and ADNP Syndrome.International journal of molecular sciences · 2026Review
- An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice.EBioMedicine · 2026Article
- A Systematic Review Illustrates the Expanding Clinical and Molecular Landscape of Helsmoortel-Van der Aa Syndrome.Brain sciences · 2025Review
- Analysis Methods for Diagnosing Rare Neurodevelopmental Diseases with Episignatures: A Systematic Review of the Literature.Biomedicines · 2025Review
- A frameshift variant in activity-dependent neuroprotective protein (ADNP) causes nucleocytoskeletal alterations in a dizygotic male twin: a case study.Clinical epigenetics · 2025Article
- Axonal motor polyneuropathy in a 13 years old Girl with a de Novo variant in ADNP.Neurogenetics · 2025Article
- Discovery of a DNA methylation profile in individuals with Sifrim-Hitz-Weiss syndrome.American journal of human genetics · 2025Article
- Transcriptomic Analysis Uncovers an Unfolded Protein Response in ADNP Syndrome.Molecular and cellular biology · 2025Article
- Expanding GABAergic Neuronal Diversity in iPSC-Derived Disease Models.bioRxiv : the preprint server for biology · 2024Article
- Anorectal malformations.Nature reviews. Disease primers · 2024Review
- Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome.Translational psychiatry · 2024Article
- Tracing the invisible mutant ADNP protein in Helsmoortel-Van der Aa syndrome patients.Scientific reports · 2024Article
- Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome.European journal of human genetics : EJHG · 2024Article
- ADNP dysregulates methylation and mitochondrial gene expression in the cerebellum of a Helsmoortel-Van der Aa syndrome autopsy case.Acta neuropathologica communications · 2024Article
- Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males.Journal of molecular neuroscience : MN · 2024Article
- Article
- PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework.Nature genetics · 2023Article
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Authors and funding
29 authors at 11 institutions in 4 countries.
Michael S BreenSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Paras GargDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Lara TangSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Danielle MendoncaSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Tess LevySeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Mafalda BarbosaSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Anne B ArnettDepartment of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
Evangeline Kurtz-NelsonDepartment of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
Emanuele AgoliniLaboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital, 00145 Rome, Italy.
Agatino BattagliaDepartment of Developmental Neuroscience, IRCCS "Stella Maris Foundation," 56128 Pisa, Italy.
Andreas G ChiocchettiDepartment of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence, University Hospital Frankfurt Goethe University, Deutschordenstr. 50, 60528 Frankfurt am Main, Germany.
Christine M FreitagDepartment of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence, University Hospital Frankfurt Goethe University, Deutschordenstr. 50, 60528 Frankfurt am Main, Germany.
Alicia Garcia-AlconChild and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid 28007, Spain.
Paola GrammaticoMedical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, 00152 Rome, Italy.
Irva Hertz-PicciottoMIND Institute, School of Medicine, University of California, Davis, Davis, CA 95817, USA; Department of Public Health Sciences, School of Medicine, University of California, Davis, Davis, CA 95616, USA.
Yunin Ludena-RodriguezDepartment of Public Health Sciences, School of Medicine, University of California, Davis, Davis, CA 95616, USA.
Carmen MorenoChild and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid 28007, Spain.
Antonio NovelliLaboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital, 00145 Rome, Italy.
Mara ParelladaChild and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid 28007, Spain.
Giulia PascoliniMedical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, 00152 Rome, Italy.
Flora TassoneMIND Institute, School of Medicine, University of California, Davis, Davis, CA 95817, USA; Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA 95817, USA.
Dorothy E GriceSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Daniele Di MarinoDepartment of Life and Environmental Sciences, New York-Marche Structural Biology Center (NY-MaSBiC), Polytechnic University of Marche, 60131 Ancona, Italy.
Raphael A BernierDepartment of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
Alexander KolevzonSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Andrew J SharpDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Joseph D BuxbaumSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Paige M SiperSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: paige.siper@mssm.edu.
Silvia De RubeisSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: silvia.derubeis@mssm.edu.
Child Health and Development Institute · USAllen Institute for Brain Science · USHospital General Universitario Gregorio Marañón · ESIcahn School of Medicine at Mount Sinai · USUniversity of California, Davis · USUniversity of Washington · USBambino Gesù Children's Hospital · ITCarlo Forlanini Hospital · ITGoethe University Frankfurt · DEFondazione Stella Maris · ITMarche Polytechnic University · IT
Funding
UC Davis Environmental Health Sciences Core CenterP30ES023513 · NIEHS · UNIVERSITY OF CALIFORNIA AT DAVIS · PI Nicholas J. KENYON · 2015 to 2026
$26.0MRevisiting ReCHARGE: ECHO Follow up on Middle Childhood and AdolescenceUH3OD023365 · OD · UNIVERSITY OF CALIFORNIA AT DAVIS · PI Deborah Hall Bennett, Irva Hertz-Picciotto · 2018 to 2026
$21.9MTHE CHARGE STUDY: CHILDHOOD AUTISM RISKS FROM GENETICS AND THE ENVIRONMENT - ADMINISTRATIVE SUPPLEMENTR01ES015359 · NIEHS · UNIVERSITY OF CALIFORNIA AT DAVIS · PI HERTZ-PICCIOTTO, IRVA · 2007 to 2019
$13.8MUC Davis Center for Children's Environmental Health (CCEH)P01ES011269 · NIEHS · UNIVERSITY OF CALIFORNIA DAVIS · PI VAN DE WATER, JUDY A. · 2001 to 2018
$12.5MMechanisms of Brain Dysmorphology in MN1 C-Terminal Truncation Syndrome, a Novel Intellectual Developmental Disability Disorder P50HD103524 · NICHD · UNIVERSITY OF WASHINGTON · PI DANIEL DOHERTY · 2020 to 2026
$9.9M1/4 - The Autism Sequencing Consortium: Autism Gene Discovery in >50,000 ExomesU01MH111661 · NIMH · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI BUXBAUM, JOSEPH D. · 2017 to 2021
$2.6MBig Omics Data Engine 2 SupercomputerS10OD026880 · OD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI KOVATCH, PATRICIA · 2019 to 2019
$2.0MTransforming Genomics with 5 PB Big Omics Data Engine Cray CS300-AC SupercomputerS10OD018522 · OD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI KOVATCH, PATRICIA · 2014 to 2014
$1.9MNICHD NIH HHS P50 HD103524NIEHS NIH HHS P01 ES011269NIEHS NIH HHS P30 ES023513NIEHS NIH HHS R01 ES015359NIH HHS S10 OD018522NIH HHS S10 OD026880NIH HHS UH3 OD023365NIMH NIH HHS U01 MH111661
Abstract
Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.
Indexed as
Autism Spectrum DisorderChildDevelopmental DisabilitiesDNA MethylationEpigenesis, GeneticFemaleHomeodomain ProteinsHumansIntellectual DisabilityMaleMutationNerve Tissue ProteinsNeurodevelopmental DisordersPhenotypeTranscriptomeADNP protein, humanHomeodomain ProteinsNerve Tissue ProteinsADNPautism spectrum disorderbiomarkersDNA methylationepigenetic signatureepisignaturegenotype-phenotype correlationsHelsmoortel-Van der Aa syndromeintellectual disabilityneurodevelopmental disorders
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