Study of copy number variations in children with unexplained mental retardation/brain development delay

Abstract

Objective By using array-based single nucleotide polymorphisms comparative genomic hybri-dization (SNP-aCGH) to detect and fine mapping copy number variations (CNVs) in children with unexplained mental retardation/brain development delay(MR/BD), then the CNVs were analyzed to determine diagnosis and offer genetic counseling, finally to discuss the application of SNP-aCGH in genetic diagnosis of MR/BD with unknown causes. Methods Ninety-two children with unexplained MR/BD were recruited.SNP-aCGH was used to get CNVs from the whole genome-wide, and the correlation of CNVs and phenotype was analyzed to definit disease genes or pat-hogenic fragment.Statistics was performed to analyze the common phenotype between positive cases(case with CNVs) and negative cases. Results (1) The CNVs were detected in 10 cases with a detection rate of 10.86%, from which 8 cases showed subtelomeric aberration, 5 cases without subtelomeric aberration, and the rate was 8.70%, 5.40%, respectively.The CNVs related to MR/BD involved 10 different subtelomeric regions (9p, 21q, 3p, 2p, 15q, 4p, 12p, 22q, 16p, 17p), and 7 different regions without subtelomeric (1p, 4q, 2p, 14q, 15q, 12q, 22q). The deletions involved 11 zones (size: 1.05-8.80 Mb), and duplications referred to 8 zones(size: 1.33-31.25 Mb). (2)One case was diagnosed as 9p duplication syndrome, for candidate genes: DOCK8, VLDLR.A case was detected with a gene fracture(CRBN). One case was diagnosed as Coffin-Siris syndrome combined with a deletion of 15q26.3-qter, for candidate genes: SOX11 and LINS1, respectively.One case referred to 12p13.3 deletion syndrome, for candidate genes: ELKS, ERC1.One case referred to 22q13.2-qter deletion, for candidate genes: SHANK3.Two cases were diagnosed as ATR-16 syndrome with 17p13.3 deletion syndrome, their candidate genes: HBA1, HBA2, SOX8 for the former, YWHAE, LIS1 for the latter.(3)There were statistically significant differences in comparison of positive cases to the negative ones for growth delay, internal organs deformity, low birth weight infant(LBW) and premature infant(all P<0.05). Conclusions (1)Besides MR/BD in different degrees in all the positive cases, they also showed growth delay, a portion of them with internal organs deformity, low birth weight infant and premature infant.(2)Subtelomeric aberrations are related to MR/BD, while the submicroscopic rearrangement in regions without subtelomeric is suspiciously pathogenic, and need to be further studied.(3)SNP-aCGH can fine mapping the region of CNVs by high resolution from the whole genome-wide, which does contribute to limit the zones for finding pathogenic region and candidate genes, as well as to offer a technology platform for investigating about the correlation of phenotype and genes or CNVs. Key words: Mental retardation/brain development delay; Single nucleotide polymorphisms comparative geno-mic hybridization; Phenotype analysis