Further Evidence for Dlgap2 as Strong Autism Spectrum Disorders/Intellectual Disability Candidate Gene

Abstract

Autism spectrum disorders are classified as neurodevelopmental disorders characterised by diminished social communication and interaction. The core symptoms typically coexist with other medical conditions such as intellectual disability. The involvement of rare copy number variations of varying expressivity and penetrance as risk factors in autism spectrum disorders/intellectual disability phenotypes has been highlighted in large series. The DLGAP2 gene, whose glutamatergic postsynaptic density product may play a role in synaptogenesis and plasticity, has been identified as a novel candidate on the basis of 2 de novo duplications in sporadic non-syndromic autism spectrum disorders/intellectual disability males. It has also been suggested that increased DLGAP2 gene expression may contribute to the pathogenesis of schizophrenia spectrum disorders. Based on these results and after fine phenotyping of another patient with a de novo duplication involving DLGAP2 and presenting with autism spectrum disorder intersecting early-onset schizophrenia spectrum disorder, we gathered an international series of 9 cases (6 families) via international data sharing. Four sporadic males presented with autism spectrum disorders and one had other neurodevelopmental disorders. A family with 4 females displayed intellectual disability (2/4) and specific learning disorder (2/4). This study supports the hypothesis that rare copy number variations encompassing DLGAP2 with incomplete penetrance and variable expressivity could predispose to a broad range of early-onset neurodevelopmental disorders trajectories including autism spectrum disorders/intellectual disability, highlighting the existence of common predisposing factors to these overlapping phenotypic spectrums.

Epigenetic Symmetry of DLGAP2: Pre-Implantation Maternal Methylation Switches to a Random Monoallelic Profile in Somatic Tissues

“…Unfortunately, DLGAP2 is not expressed in either the placenta or kidney; therefore, investigation of allelic expression with reproducible parent-of-origin methylation in these tissues was not possible. Biallelic DLGAP2 expression was observed in brain, which is consistent with the inheritance of cytogenetically defined deletions and duplications of 8q23.3 from either parent in patients with ASD and intellectual disabilities [28,29]; Decipher database]. Single cell RNA-seq or RNA-FISH analyses are required to confirm random monoallelic expression in brain since single cell clonal expansion is not currently feasible; however, it must be noted that the results from these techniques may not reflect mitotically stable random allelic expression because gene expression within single cells is associated with allelic bursts, which increases the risk of misinterpretation of monoallelic expression at a single time-point [30].…”

De novo 8p21.3→ p23.3 Duplication With t(4;8)(q35;p21.3) Translocation Associated With Mental Retardation, Autism Spectrum Disorder, and Congenital Heart Defects: Case Report With Literature Review

“…Pinto et al (26) suggested that the DLGAP2 gene, located on chromosome 8p23.3, could be a novel candidate gene for ASD. Further evidence for the DLGAP2 gene as a strong candidate gene has been provided by Poquet et al (27) based on several cases with de novo duplications involving the DLGAP2 gene and presenting with ASD. Our patient also had a de novo duplication that included 8p23.3, DLGAP2 gene, respectively.…”

“…Thus, 8p12 region was associated with MR (6), 8p23.1 region was associated with MR, ASD (16,19), facial dysmorphism, especially prominent forehead (15,18,20), and CHD (18). 8p21.3→ p23.1 region was associated with MR (5,13,14,17), ADHD (5,17), ASD (27) and CHD (5,13,21). This study shows only one case that has a large duplication involving the entire 8p21.3→ p23.1 region, associated with mild facial dysmorphism with a prominent forehead, MR, ADHD, ASD, and CHD.…”

Segregating patterns of copy number variations in extended autism spectrum disorder (ASD) pedigrees

“…The potential role of DLGAP2 in ASD is unclear, however, as one study failed to identify statistically significant difference in frequency of rare missense and nonsense mutations in ASD cases versus controls, although the sample size was small: all cases were Asian, having been recruited in Taiwan (Chien et al, 2013). However, one other study has identified ASD and other neurodevelopmental phenotypes in nine nonoverlapping families with DLGAP2 duplications (Poquet et al, 2017).…”