| Background:Intellectual disability (ID) or mental retardation (MR) is defined as a significant impairment of both cognitive (IQ<70) and social adaptive functions, with onset before18years of age. For children younger than5years, the term "Developmental delay (DD)" is usually used. The incidence of ID/DD in general population approaches1-3%, among them the incidence of moderate-severe ID/DD in0.3-0.4%, male to female ratio is about1.4-1.6:1. The syndromic mental retardation often occurs with multiple congenital anomalies (MCA) and facial abnormalities. The etiologies of ID/DD are complex, including environmental factors, perinatal hypoxia and genetic factors. It is estimated that two-thirds of ID/DD is resulted from genetic etiology. Children with ID/DD in our country are the main group of patients in neurology, and at least2/3of them with uncertain etiology. In recent years, with the widelyspread and applications of microarray comparative genomic hybridization (array CGH) and single nucleotide polymorphism microarrays (SNP array) in analysis of genome-wide copy number variations (CNVs), making subchromosome submicroscopic abrretions to be detectable, providing a powerful tool for the diagnosis of ID/DD and MCA. At present, a large number of studies have confirmed the effectiveness of these two technologies for unexplained mental retardation in patients with pathological CNVs (pCNVs) abroad, and defined nearly100kinds of microdeletions or microduplications. During the years of2010to2012, we applied the SNP array platform to carry out the genetic etiologies for unexplained patients with ID/DD and MCA patients who came from Hunan jiahui Genetics hospital.Objective:Applying the single nucleotide polymorphisms microarray (SNP array), to perform the genome-wide copy number variation detection to patients with unexplained ID/DD and MCA. Analysis the relationship of rare CNVs and ID/DD/MCA, find the origins of rare pCNVs and provide the theoretical basis for genetic counseling, risk assessment and prenatal diagnosis.Methods:Choose patients with unexplained ID/DD/MCA, prepare the chromosomes and cell suspension, extract the gDNA from peripheral blood. Applying SNP array to detect CNVs, compare the CNVs datas to Database of Genomic Variants (DGV), Decipher database, Online Mendelian Inheritance in Man (OMIM) and PUBMED, classify the CNVs into beghin, pathological and uncertain. To find the origin of pCNVs by using FISH to the propositus and his/her parents. Results:In this research, we have collected373patients with ID/DD/MCA,86rare CNVs were found in69patients (18.5%).25cases (36%,25/69) with aberrations involve telomeres or subtelomeric, the other44cases (64%,44/69) rearrangments of the middle regions of chromosomes. The sizes of deleted pCNVs (61/86,70.9%) are between0.62Mb and20Mb, duplicated pCNVs (19/86,22%) are between1.3Mb and19Mb,80%of pCNVs are between1Mb and10Mb.32/86(37.2%) pCNVs are located within known microdeletion or microduplication syndromes,4/86(4.7%) pCNVs are regions associated with Autism Spectrum Disorders (ASD). We define50new pCNVs FISH was done to all patients with pCNVs, and we had analysed39patients and their parents to find the origins of pCNVs, de novo pCNVs account for69%(27/39), paternal pCNVs account for12.8%(5/39), and maternal pCNVs account for17.9%(7/39).Conclusions:Genome-wide copy number variations contribute a large amount of genetic etiology to patients with ID/DD/MCA. In this research we combined SNP array and FISH technologies to definite etiological diagnosis of18.5%(69/373), provide the theoretical basis for genetic counseling, risk assessment and prenatal diagnosis. And we identify50new pCNVs, expaned the numbers of reported pCNVs, and provide clues to the discovery of the new syndrome. As a high-throughput technique, SNP array provides a fast and effective etiological diagnosis for ID/DD/MCA. |
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