Modeling Motor Neuron Deficits in a Family with Phelan-Mcdermid Syndrome and Autism Spectrum Disorder
Several studies have found copy number variation (CNV) plays a role in autism spectrum disorder (ASD), especially rare CNV which has been found to carry larger effects than common variations.
This work aims to identify the pathological impact of ASD-related CNVs found only in the cases especially in a family with Phelan-Mcdermid Syndrome (PMS) and ASD harboring SHANK3 deletion.
First, we conducted a case-control association study in a sample of 335 individuals with a clinical diagnosis of ASD, confirmed by the Chinese version of the Autism Diagnostic Interview-Revised, and 1093 healthy controls after quality control checked. All the genetic samples of all the subjects were analyzed with Affymetrix SNP 6.0 for the CNVs. Second, after CNV discovery we conducted a gene expression analysis of lymphoblastoid cell lines (LCLs). Also, human motor neuron derived from induced pluripotent stem cells (hiPSCs) from patients with PMS and ASD are used as a cellular model of ASD.
Among the genes found only in the cases, 32 genes were reported to have the association with neuropsychiatric disorders. CNVs both duplication and deletion of genes may influence gene expression level in LCLs. The mRNA expression levels of 7 genes, HDAC4, SND1, ABAT, SLC38A10, GNB1L, RPL10, and RAB39B, were changed by CNVs in LCLs. Additionally, the oxygen consumption rate (OCR) is reduced in motor neurons derived from PMS-1 and PMS-2 patient (P<0.001 and P<0.01, respectively).
Combining our recent publication (Yin et al., 2016) and this work, we suggest that case-only CNVs may play an essential role underlying the pathogenesis of ASD. Mitochondrial dysfunction may contribute to motor deficits in PMS and ASD.