Abstract
Rare post-zygotic mutations in the brain are now known to contribute to several neurodevelopmental disorders, including autism spectrum disorder (ASD). However, due to the limited availability of brain tissue, most studies rely on estimates of mosaicism from peripheral samples. In this study, we undertook whole exome sequencing on brain tissue from 26 ASD brain donors from the Harvard Brain Tissue Resource Center (HBTRC) and ascertained the presence of post-zygotic and germline mutations categorized as pathological, including those impacting known ASD-implicated genes. Although quantification did not reveal enrichment for post-zygotic mutations compared with the controls (n = 15), a small number of pathogenic, potentially ASD-implicated mutations were identified, notably in TRAK1 and CLSTN3. Furthermore, germline mutations were identified in the same tissue samples in several key ASD genes, including PTEN, SC1A, CDH13, and CACNA1C. The establishment of tissue resources that are available to the scientific community will facilitate the discovery of new mutations for ASD and other neurodevelopmental disorders.
Highlights
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of early childhood onset, characterized principally by socio-communicative impairments and certain restricted behavioural patterns, and associated with other neuropsychiatric and medical conditions
Brain specimens are a rare resource in neurodevelopmental disorders but can uniquely provide insight into the genetic mechanisms of disease through the ability to directly study the very tissues that underlie the manifestations of these disorders [9–13,15]
This includes the ability to identify the tissue of specific post-zygotic mutations
Summary
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of early childhood onset, characterized principally by socio-communicative impairments and certain restricted behavioural patterns, and associated with other neuropsychiatric and medical conditions. The genetic underpinning of this disorder is rapidly evolving, and the exact genetic mechanisms are complex and not fully understood, despite many ASDimplicated genes having been identified [1–4]. Rare, de novo, single nucleotide variants (SNV) and copy number variants (CNV) of variable size are implicated. These variants, whether SNVs or CNVs, are often variable in their penetrance and almost certainly act in concert with each other and with other epigenetic and non-genetic factors. Genetic variants that are more commonly observed in the population (‘common variants’, minor allele frequency [MAF] ~1% or more) play a role, but their discovery for ASD has lagged behind other neurodevelopmental and neuropsychiatric disorders [5]. The relative contribution of these different genetic factors and other non-genetic factors in any one individual is unclear, cases have been described of Mendelian, or otherwise highly penetrant, single-gene/locus mutations [6,7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
