Autism spectrum disorders (ASDs) affect 1% or more of American children. ASDs are characterized by defects in social behavior, including language delay, abnormal social interactions, and repetitive or stereotyped interests or behaviors. ASDs show a large genetic component, with estimates of heritability as high as 60- 90%. However, the extreme heterogeneity of ASD is a persistent hurdle to gene discovery, and known genetic causes account for less than 15% of diagnoses. Although high throughput sequencing (HTS) methods allow systematic analysis of genetic variation across the entire exome, or even the entire genome, the interpretation of this data faces analytical challenges that have by no means been solved. The use of consanguineous pedigrees, in which parents share ancestry, allows the identification of candidate genes that can then be analyzed more broadly in nonconsanguineous families. Consanguineous families 1] reduce the heterogeneity of ASD, 2] simplify HTS analysis and validation, and 3] provide genetic linkage evidence to support the validity of specific mutations in a single family. Preliminary data confirms that HTS in such pedigrees can efficiently identify, in an unbiased fashion, recessive genetic causes of ASD relevant to both consanguineous and nonconsanguineous cohorts of patients. This study will seek to enroll consanguineous families diagnosed with ASD, perform homozygosity mapping to locate regions of the genome likely to harbor the mutation that causes their ASD, and perform whole genome sequencing (WGS) on the affected individuals to identify candidate variants. Further, linkage and whole exome sequencing data that was generated on consanguineous families from previous studies will continue to be analyzed. This study will expand on the previous work by 1] Generating WGS data on normal controls to identify common alleles within Middle Eastern populations thus allowing swifter, more sensitive and ultimately cheaper analysis in this and many other Middle Eastern WGS studies;2] Generating relatively high throughput methods of functionally validating strong candidate genes discovered through WGS using yeast models, transformed somatic cell lines, and other model systems;and 3] Using RNAi to generate mouse models of candidate genes discovered in this study, and an ongoing neuronal activity-dependent gene study, to examine the effects of removing the genes on dendrite and dendritic spine morphology and synaptic activity. Recent studies suggest that, despite the high level of heterogeneity, there are common biochemical pathways associated with ASD. The findings from this study will be instrumental in the identification of the genes that make up these pathways, and provide potential pharmaceutical targets for the treatment of ASD.

Public Health Relevance

Autism and autism spectrum disorders (ASD) are a group of neurological conditions that affect 1% or more of American children and are characterized by impairment in the ability to communicate, form relationships, and respond appropriately to the environment. With 60-70% of autistic individuals having some degree of intellectual disability, and most requiring lifelong assistance, the financial costs to society are very high, while the emotional and psychological costs to family members cannot even be estimated. This study seeks to identify the genetic causes of ASD as well as to enhance our understanding of how the disease affects the developing brain, in order to develop better treatments.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Addington, Anjene M
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Children's Hospital Boston
United States
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Walsh, Christopher A (2018) Rainer W. Guillery and the genetic analysis of brain development. Eur J Neurosci :
Doan, Ryan N; Shin, Taehwan; Walsh, Christopher A (2018) Evolutionary Changes in Transcriptional Regulation: Insights into Human Behavior and Neurological Conditions. Annu Rev Neurosci 41:185-206
Khalil, Raida; Kenny, Connor; Hill, R Sean et al. (2018) PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features. Am J Med Genet B Neuropsychiatr Genet 177:736-745
Lakhani, Shenela; Doan, Ryan; Almureikhi, Mariam et al. (2017) Identification of a novel CNTNAP1 mutation causing arthrogryposis multiplex congenita with cerebral and cerebellar atrophy. Eur J Med Genet 60:245-249
Jamuar, Saumya S; Schmitz-Abe, Klaus; D'Gama, Alissa M et al. (2017) Biallelic mutations in human DCC cause developmental split-brain syndrome. Nat Genet 49:606-612
Lim, Elaine T; Uddin, Mohammed; De Rubeis, Silvia et al. (2017) Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat Neurosci 20:1217-1224
Wang, Xuefeng; Zhang, Zhenyu; Morris, Nathan et al. (2017) Rare variant association test in family-based sequencing studies. Brief Bioinform 18:954-961
Oaks, Adam W; Zamarbide, Marta; Tambunan, Dimira E et al. (2017) Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits. Cereb Cortex 27:1670-1685
Doan, Ryan N; Bae, Byoung-Il; Cubelos, Beatriz et al. (2016) Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Cell 167:341-354.e12
Chaste, Pauline; Klei, Lambertus; Sanders, Stephan J et al. (2015) A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity? Biol Psychiatry 77:775-84

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