Autism spectrum disorders: from genes to neurobiology

Abstract

Advances in genome-wide technology, coupled with the availability of large cohorts, are finally yielding a steady stream of autism spectrum disorder (ASD) genes carrying mutations of large effect. These findings represent important molecular clues, but at the same time present notable challenges to traditional strategies for moving from genes to neurobiology. A remarkable degree of genetic heterogeneity, the biological pleiotropy of ASD genes, and the tremendous complexity of the human brain are prompting the development of new approaches to translating genetic discoveries into therapeutic targets. Recent developments in systems biology approaches that ‘contextualize’ these genetic findings along spatial, temporal, and cellular axes of human brain development are beginning to bridge the gap between high-throughput gene discovery and testable pathophysiological hypotheses.

De Novo Coding Variants Are Strongly Associated with Tourette Disorder

“…Moreover, the integration of de novo CNV data should further increase the yield of risk genes (Sanders et al, 2015). The discovery of a large number of TD-associated genes will provide a critical substrate for model systems and systems-biological studies aimed at understanding the spatial, temporal, and cell-level dynamics of TD pathology (Parikshak et al, 2013; Willsey et al, 2013; Willsey and State, 2015; Xu et al, 2014) and, importantly, for the development of novel, more effective therapeutic targets.…”

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

“…The genetic landscape of ASD is extremely complex, involving some 400-1200 genes according to current best estimates (De Rubeis and Buxbaum, 2015a; Geschwind and State, 2015; Ronemus et al, 2014; Willsey and State, 2015). In a handful of rare syndromes, autistic features arise from dysfunction of only one gene, as exemplified by Rett ( MECP2 ), Angelman ( UBE3A ), Timothy ( CACNA1C ), Fragile X ( FMR1 ) and Tuberous sclerosis ( TSC1,2 ) syndromes.…”

Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis

“…MNB was originally identified in Drosophila , where hypomorph mutants produce a smaller brain and exhibit defects in visual and olfactory behavior (Fischbach and Heisenberg, 1981; Tejedor et al, 1995). Located on chromosome 21, DYRK1a in trisomy produces learning and memory defects associated with DS pathology (Altafaj et al, 2001; Guimera et al, 1996; Shindoh et al, 1996; Smith et al, 1997; Song et al, 1996), and is one of the genes most strongly associated with ASD (O’Roak et al, 2014; Willsey and State, 2015). However, its mode of action and downstream molecular pathways are not well defined.…”