TY - JOUR
T1 - Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype
AU - Breen, Michael S.
AU - Garg, Paras
AU - Tang, Lara
AU - Mendonca, Danielle
AU - Levy, Tess
AU - Barbosa, Mafalda
AU - Arnett, Anne B.
AU - Kurtz-Nelson, Evangeline
AU - Agolini, Emanuele
AU - Battaglia, Agatino
AU - Chiocchetti, Andreas G.
AU - Freitag, Christine M.
AU - Garcia-Alcon, Alicia
AU - Grammatico, Paola
AU - Hertz-Picciotto, Irva
AU - Ludena-Rodriguez, Yunin
AU - Moreno, Carmen
AU - Novelli, Antonio
AU - Parellada, Mara
AU - Pascolini, Giulia
AU - Tassone, Flora
AU - Grice, Dorothy E.
AU - Di Marino, Daniele
AU - Bernier, Raphael A.
AU - Kolevzon, Alexander
AU - Sharp, Andrew J.
AU - Buxbaum, Joseph D.
AU - Siper, Paige M.
AU - De Rubeis, Silvia
N1 - Publisher Copyright:
© 2020 American Society of Human Genetics
PY - 2020/9/3
Y1 - 2020/9/3
N2 - 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.
AB - 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.
KW - ADNP
KW - DNA methylation
KW - Helsmoortel-Van der Aa syndrome
KW - autism spectrum disorder
KW - biomarkers
KW - epigenetic signature
KW - episignature
KW - genotype-phenotype correlations
KW - intellectual disability
KW - neurodevelopmental disorders
UR - http://www.scopus.com/inward/record.url?scp=85089978747&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2020.07.003
DO - 10.1016/j.ajhg.2020.07.003
M3 - Article
C2 - 32758449
AN - SCOPUS:85089978747
SN - 0002-9297
VL - 107
SP - 555
EP - 563
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -