Maternally inherited genetic variants ofCADPS2are present in Autism Spectrum Disorders and Intellectual Disability patients

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Abstract

Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic deletion of maternal origin in two siblings with mild ID and epilepsy in theCADPS2gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction.CADPS2allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin.Cadps2gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting thatCADPS2is subjected to tissue- and temporal-specific regulation in human and mice. We suggest thatCADPS2variants may contribute to ID/ASD development, possibly through a parent-of-origin effect.

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