White matter impairment in the speech network of individuals with autism spectrum disorder

AbstractImpairments in language and communication are core features of Autism Spectrum Disorder (ASD), and a substantial percentage of children with ASD do not develop speech. ASD is often characterized as a disorder of brain connectivity, and a number of studies have identified white matter impairments in affected individuals. The current study investigated white matter integrity in the speech network of high-functioning adults with ASD. Diffusion tensor imaging (DTI) scans were collected from 18 participants with ASD and 18 neurotypical participants. Probabilistic tractography was used to estimate the connection strength between ventral premotor cortex (vPMC), a cortical region responsible for speech motor planning, and five other cortical regions in the network of areas involved in speech production. We found a weaker connection between the left vPMC and the supplementary motor area in the ASD group. This pathway has been hypothesized to underlie the initiation of speech motor programs. Our results indicate that a key pathway in the speech production network is impaired in ASD, and that this impairment can occur even in the presence of normal language abilities. Therapies that result in normalization of this pathway may hold particular promise for improving speech output in ASD

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders.

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB