Prospective and detailed behavioral phenotyping in DDX3X syndrome

Molecular Autism

Puneet Belani¹  Ivy Giserman-Kiss²  Jessica Zweifach²  Sylvia Guillory²  Christina Layton²  Emanuel Frowner²  Bonnie Lerman²  Ana Kostic²  Yitzchak Frank²  Tess Levy²  Jennifer H. Foss-Feig²  Lara Tang²  Danielle Halpern²  Reymundo Lozano³  Michael S. Breen⁴  Joseph D. Buxbaum⁵  Alexander Kolevzon⁶  Paige M. Siper⁷  Silvia De Rubeis⁸  Dorothy E. Grice⁹ 

[1] Department of Radiology, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, Box 1230, 1425 Madison Avenue, 10029, New York, NY, USA;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, Box 1230, 1425 Madison Avenue, 10029, New York, NY, USA;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, Box 1230, 1425 Madison Avenue, 10029, New York, NY, USA;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, Box 1230, 1425 Madison Avenue, 10029, New York, NY, USA;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, Box 1230, 1425 Madison Avenue, 10029, New York, NY, USA;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, Box 1230, 1425 Madison Avenue, 10029, New York, NY, USA;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, Box 1230, 1425 Madison Avenue, 10029, New York, NY, USA;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, Box 1230, 1425 Madison Avenue, 10029, New York, NY, USA;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Division of Tics, OCD, and Related Disorders, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;

关键词: Autism;    Developmental delay;    Genotype–phenotype correlation;    Intellectual disability;    DDX3X syndrome;   

DOI  :  10.1186/s13229-021-00431-z

来源: Springer

【 摘 要 】

BackgroundDDX3X syndrome is a recently identified genetic disorder that accounts for 1–3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored.MethodsWe carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions.ResultsEighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype–phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants.LimitationsSample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder.ConclusionThis study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype–phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes.

【 授权许可】

CC BY