title: Neurogenetic analysis of childhood disintegrative disorder.
abstract: Childhood disintegrative disorder (CDD) is a rare form of autism spectrum disorder (ASD) of unknown etiology. It is characterized by late-onset regression leading to significant intellectual disability (ID) and severe autism. Although there are phenotypic differences between CDD and other forms of ASD, it is unclear if there are neurobiological differences.
  
  
  
  We pursued a multidisciplinary study of CDD (n= 17) and three comparison groups: low-functioning ASD (n= 12), high-functioning ASD (n= 50), and typically developing (n= 26) individuals. We performed whole-exome sequencing (WES), copy number variant (CNV), and gene expression analyses of CDD and, on subsets of each cohort, non-sedated functional magnetic resonance imaging (fMRI) while viewing socioemotional (faces) and non-socioemotional (houses) stimuli and eye tracking while viewing emotional faces.
  
  
  
  We observed potential differences between CDD and other forms of ASD. WES and CNV analyses identified one or more rare de novo, homozygous, and/or hemizygous (mother-to-son transmission on chrX) variants for most probands that were not shared by unaffected sibling controls. There were no clearly deleterious variants or highly recurrent candidate genes. Candidate genes that were found to be most conserved at variant position and most intolerant of variation, such asTRRAP,ZNF236, andKIAA2018, play a role or may be involved in transcription. Using the human BrainSpan transcriptome dataset, CDD candidate genes were found to be more highly expressed in non-neocortical regions than neocortical regions. This expression profile was similar to that of an independent cohort of ASD probands with regression. The non-neocortical regions overlapped with those identified by fMRI as abnormally hyperactive in response to viewing faces, such as the thalamus, cerebellum, caudate, and hippocampus. Eye-tracking analysis showed that, among individuals with ASD, subjects with CDD focused on eyes the most when shown pictures of faces.
  
  
  
  Given that cohort sizes were limited by the rarity of CDD, and the challenges of conducting non-sedated fMRI and eye tracking in subjects with ASD and significant ID, this is an exploratory study designed to investigate the neurobiological features of CDD. In addition to reporting the first multimodal analysis of CDD, a combination of fMRI and eye-tracking analyses are being presented for the first time for low-functioning individuals with ASD. Our results suggest differences between CDD and other forms of ASD on the neurobiological as well as clinical level.
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut USA.|Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Abha R
authors.initials: AR
authors.lastname: Gupta
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.|Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Westphal
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Daniel Y J
authors.initials: DYJ
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Catherine A W
authors.initials: CAW
authors.lastname: Sullivan
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eilbott
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Avery
authors.initials: A
authors.lastname: Voos
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Brent C
authors.initials: BC
authors.lastname: Vander Wyk
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Pam
authors.initials: P
authors.lastname: Ventola
authors.affiliation: Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Zainulabedin
authors.initials: Z
authors.lastname: Waqar
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.|Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Fernandez
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: A Gulhan
authors.initials: AG
authors.lastname: Ercan-Sencicek
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Walker
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Evelina London Children's Hospital, Guy's and St. Thomas' Trust, Kings Health Partners AHSC, London, UK.
authors.forename: Tammy
authors.initials: T
authors.lastname: Hedderly
authors.affiliation: Evelina London Children's Hospital, Guy's and St. Thomas' Trust, Kings Health Partners AHSC, London, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Baird
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Friedman
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Cara
authors.initials: C
authors.lastname: Cordeaux
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ristow
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Shic
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Volkmar
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Pelphrey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000067877:Autism Spectrum Disorder / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D001931:Brain Mapping; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000737:chemistry*; D056915:DNA Copy Number Variations; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D008607:Intellectual Disability / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D000072741:Maternal Inheritance; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index; D035781:Siblings; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome; D000073359:Exome Sequencing
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C000622661:USF3 protein, human; C121390:ZNF236 protein, human; C113829:transformation-transcription domain-associated protein
keywords: Autism spectrum disorder (ASD); Childhood disintegrative disorder (CDD); Eye tracking; Functional magnetic resonance imaging (fMRI); Genetics; Intellectual disability (ID); Regression