Genetic and Neurobehavioral Profile of the SHANK3 Gene Deficiency Children in China

Background:  SHANK3 is a scaffolding protein of excitatory glutamatergic synapses. Genetic studies suggested that molecular variations in the SHANK3 gene had a strong causal relationship with ASD and/or 22q13.3 deletion syndrome, and different defects in this gene potentially resulting in clinical heterogeneity.

Objectives:  To determine the data of Chinese ASD patients with SHANK3 deletion.

Methods:  MLPA and Sanger sequencing were carried out to confirm the SHANK3 deficiency of nine Chinese children. Moreover, systematic and comprehensive evaluations were performed to Chinese-specific features. ADOS scale was applied to examine the severity of autism and Griffith scale was used to assess the development level.

Results:   Six participants lacked the whole gene of SHANK3 with 22q13.3 deletions ranging in size from 55 kb to 4.8 Mb and three participants with de novo SHANK3 mutation were included. The samples were characterized by high rates (100%) of ASD, developmental delay, hypotonia, several dysmorphologies and perception abreaction. New and rare features were also viewed in this study: ectropion of nostril sparse hair, ankle deformity, whole-body hairy, hanked-3-lap arms, snaggletoothed or extra teeth and unusual-dehydrated skin, and extreme hyperactivity/self-sitimulation. There was no significant statistical difference between SHANK3 defect group and ASD group. However, SHANK3 defect children displayed severer developmental delay in language, social, gross motor, fine motor, adaptability and other items comparing with ASD group. In addition, separating numerous phenotypes into inherent phenotypes and ameliorable phenotypes may contribute to better analyze genotype-phenotype correlations. Ameliorable phenotypes may be independent of gene deficiency and improvable. Epilepsy and degeneration could aggravate symptoms and deteriorate prognosis of diseases.

Conclusions:  This study supports findings from previous research on the severity of intellectual, hypotonia, and speech impairments seen in SHANK3 deficiency, and highlights the prominence of SHANK3 in the syndrome. Early diagnosis and early intervention, as well as consciousness and training of caregivers were very critical in the improvement of these children.