Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype: American Journal of Human Genetics

M.S. Breen, P. Garg, L. Tang, D. Mendonca, T. Levy, M. Barbosa, A.B. Arnett, E. Kurtz-Nelson, E. Agolini, A. Battaglia, A.G. Chiocchetti, C.M. Freitag, A. Garcia-Alcon, P. Grammatico, I. Hertz-Picciotto, Y. Ludena-Rodriguez, C. Moreno, A. Novelli, M. Parellada, G. PascoliniF. Tassone, D.E. Grice, D. Di Marino, R.A. Bernier, A. Kolevzon, A.J. Sharp, J.D. Buxbaum, P.M. Siper, S. De Rubeis

Research output: Contribution to journalArticlepeer-review


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. © 2020 American Society of Human Genetics
Original languageEnglish
Pages (from-to)555-563
Number of pages9
JournalAm. J. Hum. Genet.
Issue number3
Publication statusPublished - 2020


  • ADNP
  • autism spectrum disorder
  • biomarkers
  • DNA methylation
  • epigenetic signature
  • episignature
  • genotype-phenotype correlations
  • Helsmoortel-Van der Aa syndrome
  • intellectual disability
  • neurodevelopmental disorders
  • transcriptome
  • ADNP protein, human
  • homeodomain protein
  • nerve protein
  • Article
  • child
  • clinical article
  • clinical outcome
  • cohort analysis
  • controlled study
  • correlational study
  • developmental disorder
  • disease severity
  • female
  • gene mutation
  • genetic association
  • genetic disorder
  • genetic screening
  • Helsmoortel Van der Aa syndrome
  • human
  • male
  • molecular probe
  • neurobiology
  • phenotype
  • priority journal
  • prospective study
  • RNA analysis
  • RNA blood level
  • syndrome
  • transcriptome blood level
  • autism
  • genetic epigenesis
  • genetics
  • intellectual impairment
  • mental disease
  • mutation
  • pathology
  • Autism Spectrum Disorder
  • Child
  • Developmental Disabilities
  • DNA Methylation
  • Epigenesis, Genetic
  • Female
  • Homeodomain Proteins
  • Humans
  • Intellectual Disability
  • Male
  • Mutation
  • Nerve Tissue Proteins
  • Neurodevelopmental Disorders
  • Phenotype
  • Transcriptome


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