De novo genic mutations among a Chinese autism spectrum disorder cohort

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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A de novo mosaic mutation in SPAST with two novel alternative alleles and chromosomal copy number variant in a boy with spastic paraplegia and autism spectrum disorder

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2017.07.015 ◽

2017 ◽

Vol 60 (10) ◽

pp. 548-552 ◽

Cited By ~ 3

Author(s):

A.M. Matthews ◽

M. Tarailo-Graovac ◽

E.M. Price ◽

I. Blydt-Hansen ◽

A. Ghani ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Copy Number ◽

De Novo ◽

Copy Number Variant ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Spastic Paraplegia ◽

Chromosomal Copy Number ◽

Chromosomal Copy

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Increased burden of deleterious variants in essential genes in autism spectrum disorder

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1613195113 ◽

2016 ◽

Vol 113 (52) ◽

pp. 15054-15059 ◽

Cited By ~ 30

Author(s):

Xiao Ji ◽

Rachel L. Kember ◽

Christopher D. Brown ◽

Maja Bućan

Keyword(s):

Autism Spectrum Disorder ◽

Large Scale ◽

De Novo ◽

Autism Spectrum ◽

Essential Genes ◽

Spectrum Disorder ◽

Model Organisms ◽

Disease Genes ◽

Priority List ◽

Human Orthologs

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.

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