5. Further evidence of GABRA4 and TOP3B as autism susceptibility genes

      Copy number variants (CNVs) are a known contributor to neurodevelopmental conditions such as autism spectrum disorder (ASD). Both array comparative genomic hybridization and Next-Generation sequencing techniques have led to increased detection of small CNVs and the identification of many candidate susceptibility genes for ASD. We report familial inheritance of two CNVs that include genes with known involvement in neurodevelopment. These CNVs are found in various combinations among four siblings with autism spectrum disorder, as well as in their phenotypically normal parents. We describe a 2.4 Mb duplication of 4p12 to 4p11 that includes GABRA4 and other GABA receptor genes, as well as a 246 kb deletion at 22q11.22 involving the TOP3B gene. The maternally inherited 4p duplication was detected in three siblings, two of whom also had the paternally inherited 22q11.22 deletion. The fourth sibling only had the 22q11.22 deletion. These CNVs have rarely been reported in the literature. Upon review, a single publication was found describing a similar 4p duplication in three generations of a family with neurodevelopmental and neuropsychiatric disorders, as well as in an unrelated patient with autism. TOP3B falls within the distal 22q11.22 deletion syndrome and has been associated with schizophrenia, neurodevelopmental disorders including epilepsy, and cardiac defects. The identification of this family contributes to the understanding of specific genetic contributors to neurodevelopmental disorders and an emerging phenotype associated with proximal 4p duplication.
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