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Am J Med Genet A. 2018 Dec;176(12):2668-2676. doi: 10.1002/ajmg.a.40666. Epub 2018 Dec 9.

Genotype and phenotype correlations for SHANK3 de novo mutations in neurodevelopmental disorders.

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Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
Mental Health Center of Shandong Province, Jinan, Shandong, China.
Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Child Healthcare Department, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, Guangxi, China.
Child Healthcare Department, The Third affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
College of Life Science and Technology, Xinjiang University, Xinjiang, China.


SHANK3 has been identified as the causative gene of 22q13.3 microdeletion syndrome phenotype. De novo mutations (DNMs) of SHANK3 were subsequently identified in patients with several neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia (SCZ), a Rett syndrome-like phenotype, and intellectual disability (ID). Although broad developmental phenotypes of these patients have been described in single studies, few studies have reviewed the genotype and phenotype relationships using a relatively large cohort of patients with SHANK3 DNMs. In this study, we identified a de novo splice mutation (NM_033517.1: c.2265+1G>A) that functionally impairs mRNA splicing, produces multiple splice variants, and results in the reduction of the amounts of mRNA. To analyze the genotype and phenotype correlations for SHANK3 DNMs, we reviewed 37 previously published patients with 28 SHANK3 DNMs. Our results revealed that haploinsufficiency of SHANK3 causes a broad spectrum of neurodevelopmental phenotypes with impaired social interaction, repetitive behavior, speech impairment, ID, and regression as the most common observations. Seizures, hypotonia, global development delay, dysmorphic features, and several other features also occurred recurrently. Specific phenotypes are also observed in certain genotypes. Our study provides the frequency of the heterogeneous co-occurring conditions caused by SHANK3 DNMs, which will be beneficial for diagnosis and clinical management.


SHANK3; ASD; clinical phenotype; de novo mutation; splice mutation


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