De Novo Gene Disruptions in Children on the Autistic Spectrum

By I. Iossifov, M. Ronemus, D. Levy, Zi-Hua Wang, I. Hakker, J. Rosenbaum, B. Yamrom, Yoon-ha Lee, G. Narzisi, A. Leotta and 25 more. Neuron, 2012

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SUMMARY Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.

Subfields: Cognitive Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/10b97062bbe2df60830c23c655198206caa53de7

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Citations in the corpus

Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015, methodology): “…regulation level, ChIP–seq in induced pluripotent stem cell-derived neurons has been used to define the network of genes regulated by chro-modomain helicase DNA-binding protein 8 ( CHD8 ) 118 , which is the gene most frequently affected by ASD-associated rare de novo variation 72,119–121 .”
Most genetic risk for autism resides with common variation (2014, neutral): “(1) Californian twins for strictly defined”
A SPECTRAL APPROACH INTEGRATING FUNCTIONAL GENOMIC ANNOTATIONS FOR CODING AND NONCODING VARIANTS (2016, positive): “In total for ASD, we have n = 2,027 such mutations among which 1, 753 are missense [22, 23, 24, 25, 26].”
Regional missense constraint improves variant deleteriousness prediction (2017, background): “…focused on neurodevelopmental disorders, such as intellectual disability 1-3 , developmental delay 4,5 , epileptic encephalopathy 6 , and autism spectrum disorders 7-12 —to evaluate the role of de novo variation in the hope of identifying genes and pathways relevant to disease etiology.”
Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019, neutral): “Among these is the fragile X mental retardation 1 gene ( FMR1 ), required for normal cognitive development (Iossifov et al., 2012; Parikshak et al., 2013; Sittler et al., 1996). oASD mice show decreased inclusion rates of a skipped exon in FMR1 (Figure 3F).”
De novo mutations in human genetic disease (2012, background): “Healthy siblings, Iossifov et al.(16) 343 288 0.”