Abstract
Intellectual disability (ID) is a heterogeneous disorder caused by chromosomal abnormalities, monogenic factors and environmental factors. 22q13 deletion syndrome is a genetic disorder characterized by severe ID. Although the frequency of 22q13 deletions in ID is unclear, it is believed to be largely underestimated. To address this issue, we used Affymetrix Human SNP 6.0 array to detect the 22q13 deletions in 234 Chinese unexplained ID patients and 103 controls. After the Quality Control (QC) test of raw data, 22q13 deletions were found in four out of 230 cases (1.7%), while absent in parents of the cases and 101 controls. A review of genome-wide microarray studies in ID was performed and the frequency of 22q13 deletions from the literatures was 0.24%, much lower than our report. The overlapping region shared by all 4 cases encompasses the gene SHANK3. A heterozygous de novo nonsense mutation Y1015X of SHANK3 was identified in one ID patient. Cortical neurons were prepared from embryonic mice and were transfected with a control plasmid, shank3 wild-type (WT) or mutant plasmids. Overexpression of the Y1015 mutant in neurons significantly affected neurite outgrowth compared with shank3 WT. These findings suggest that 22q13 deletions may be a more frequent cause for Chinese ID patients than previously thought, and the SHANK3 gene is involved in the neurite development.
Highlights
Intellectual disability (ID), commonly referred to as developmental delay (DD), mental retardation (MR) or learning disability, is a developmental disorder characterized by significant impairment of intellectual function and deficiency in two or more adaptive behaviors, with onset before the age of 18 years
Genotype-phenotype correlation studies have been undertaken to examine the clinical significance of copy number variants (CNVs) in ID
All 4 cases shared a refined 113 Kb deletion that encompassed the gene SHANK3 (Figure 1). These CNVs were identified by all four CNVcalling algorithms, and we designed a MLPA assay as an independent method to verify that all 22q13 deletions were heterozygous
Summary
Intellectual disability (ID), commonly referred to as developmental delay (DD), mental retardation (MR) or learning disability, is a developmental disorder characterized by significant impairment of intellectual function and deficiency in two or more adaptive behaviors, with onset before the age of 18 years. Fragile X syndrome and fetal alcohol syndrome are the most common syndromes associated with ID [1]. Chromosomal abnormalities, such as aneuploidies, rearrangements, and subtelomeric deletions, play an important role in the etiology of ID, accounting for nearly 40% of cases of moderate to severe ID and approximately 10% of mild ID [2]. Koolen et al reviewed 16 genome-wide microarray studies in 1,364 patients with ID, 11.2% had detectable CNVs related to ID [4]. Cooper et al performed a whole genome-wide array CGH study in 15,767 children with ID and 8,329 unaffected adult controls and estimated that 14.2% of ID was caused by CNVs.400 kb [7]
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