Barnard, R. A. | Search bioRxiv

bioRxiv2022

Shared and distinct functional effects of patient-specific Tbr1 mutations on cortical development

Predicted loss-of-function and missense heterozygous de novo mutations of TBR1 are strongly associated with intellectual disability and autism. The functional effects of these heterogeneous mutations on cortical development and genotype-phenotype relationships have yet to be explored. We characterized mouse models carrying patient mutations A136PfsX80 and K228E, finding convergent and discordant phenotypes. The A136PfsX80 mutation is loss-of-function and allelic to the Tbr1 knockout. In contrast, K228E causes significant upregulation of TBR1. Heterozygosity of either mutation produces axon defects, including reduction of the anterior commissure, and CTIP2 downregulation in adult cortex. While mice lacking TBR1 show extensive cortical apoptosis and inverted layering, K228E homozygotes show normal apoptosis levels and a complex layering phenotype--suggesting partial, yet abnormal, function of the allele. The construct and face validity of these Tbr1 patient mutation mice suggests they will be valuable translational models for studying the function of this essential brain transcription factor.

neuroscience↗

bioRxiv2016

Exonic somatic mutations contribute risk for autism spectrum disorder

Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Somatic mosaic mutations (SMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. Here, we systematically evaluate SMMs by leveraging whole-exome sequencing (WES) data on a large family-based ASD cohort, the Simons Simplex Collection (SSC). We find evidence that ~10% of previously published de novo mutations are potentially SMMs. When using a custom somatic calling pipeline, we recalled all SSC WES data. We validated high and low confidence mutation predictions for a subset of families with single molecule molecular inversion probes. With these validation data, we iteratively developed a high confidence calling approach integrating logistic regression modeling and additional heuristics and applied it to the full cohort. Surprisingly, we found evidence of significant synonymous SMM burden in probands, with mutations more likely to be close to splicing sites. Overall, we observe no strong evidence of missense SMM burden. However, we do observe nominally significant signal for missense SMMs in those families without germline mutations, which strengthens specifically in genes intolerant to mutations. In contrast to missense germline mutations, missense SMMs show potential enrichment for chromatin modifiers. We observe 7-10% of parental mosaics are transmitted germline to a child as occult de novo mutations, which has important implications for recurrence risk for families and potential subclinical ASD features. Finally, we find SMMs in previously implicated high-confidence ASD risk genes, including CHD2, CTNNB1, KMT2C, SYNGAP1, and RELN, further suggesting that this class of mutations contribute to population risk.

genetics↗