Common and Distinct Disruptions of Cortical Surface Morphology Between Autism Spectrum Disorder Children With and Without SHANK3 Deficiency

Abstract

SH3 and Multiple Ankyrin Repeat Domains 3 (SHANK3)-caused autism spectrum disorder (ASD) may present a unique opportunity to clarify the heterogeneous neuropathological mechanisms of ASD. However, the specificity and commonality of disrupted large-scale brain organization in SHANK3-deficient children remain largely unknown. The present study combined genetic tests, neurobehavioral evaluations, and magnetic resonance imaging, aiming to explore the disruptions of both local and networked cortical structural organization in ASD children with and without SHANK3 deficiency. Multiple surface morphological parameters such as cortical thickness (CT) and sulcus depth were estimated, and the graph theory was adopted to characterize the topological properties of structural covariance networks (SCNs). Finally, a correlation analysis between the alterations in brain morphological features and the neurobehavioral evaluations was performed. Compared with typically developed children, increased CT and reduced nodal degree were found in both ASD children with and without SHANK3 defects mainly in the lateral temporal cortex, prefrontal cortex (PFC), temporo-parietal junction (TPJ), superior temporal gyrus (STG), and limbic/paralimbic regions. Besides commonality, our findings showed some distinct abnormalities in ASD children with SHANK3 defects compared to those without. Locally, more changes in the STG and orbitofrontal cortex were exhibited in ASD children with SHANK3 defects, while more changes in the TPJ and inferior parietal lobe (IPL) in those without SHANK3 defects were observed. For the SCNs, a trend toward regular network topology was observed in ASD children with SHANK3 defects, but not in those without. In addition, ASD children with SHANK3 defects showed more alterations of nodal degrees in the anterior and posterior cingulate cortices and right insular, while there were more disruptions in the sensorimotor areas and the left insular and dorsomedial PFC in ASD without SHANK3 defects. Our findings indicate dissociable disruptions of local and networked brain morphological features in ASD children with and without SHANK3 deficiency. Moreover, this monogenic study may provide a valuable path for parsing the heterogeneity of brain disturbances in ASD.

Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-causing mutations

“…In this study, iPSC technology was used in order to investigate the physiological features of cortical neurons derived from human patients with different ASD-related mutations: Dup7, GRIN2B, SHANK3, and UBTF. For that purpose, we differentiated patient-derived iPSCs into cortical neurons 55 since cortical alterations and malformations within the brain were identi ed in these mentioned mutations 16,32,44,50 .…”

“…The individuals affected by the 22q13 deletion syndrome 27,28 , also known as Phelan-McDermid syndrome (PMS), suffer from developmental delays, a low muscular tone, a weakened perception of pain, delayed speech, seizures, ASD and autistic-like behaviors with a prevalence of 84% [29][30][31] . The patients also exhibit cortical alterations 32 .…”

Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations

“…In this study, iPSC technology was used in order to investigate the physiological features of cortical neurons derived from human patients with different ASD-related mutations: Dup7 , GRIN2B , SHANK3, and UBTF . For that purpose, we differentiated patient-derived iPSCs into cortical neurons 53 since cortical alterations and malformations within the brain were identified in these mentioned mutations 16,32,44,50 .…”

“…In this study, iPSC technology was used in order to investigate the physiological features of cortical neurons derived from human patients with different ASD-related mutations: Dup7, GRIN2B, SHANK3, and UBTF. For that purpose, we differentiated patient-derived iPSCs into cortical neurons 53 since cortical alterations and malformations within the brain were identified in these mentioned mutations 16,32,44,50 . A broad range of mutations has been associated with ASD, sharing autistic-like behaviors such as difficulties in social communication and interaction and restricted or repetitive behaviors or interests.…”

“…The individuals affected by the 22q13 deletion syndrome 27,28 , also known as Phelan-McDermid syndrome (PMS), suffer from developmental delays, a low muscular tone, a weakened perception of pain, delayed speech, seizures, ASD and autistic-like behaviors with a prevalence of 84% [29][30][31] . The patients also exhibit cortical alterations 32 .…”