Genome-wide copy number variations analysis in 64 patients with unexplained intellectual disability / 中华实用儿科临床杂志

Objective To investigate the genetic basis of patients with intellectual disability,and to assess the application of single nucleotide polymorphisms (SNP)-array in the molecular diagnosis of intellectual disability.Methods Sixty-four patients with intellectual disability who were identified in Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region from January 2013 to June of 2015 were enrolled.Genomic DNA was extracted from peripheral blood and was analyzed with Illumina Humancyto SNP-12 300K gene array chip.All identified copy number variants (CNVs) were analyzed with references from databases such as ClinVar,DECIPHER,OMIM and DGV(Database of Genomic Variants),as well as comprehensive literature review from PubMed database to determine the pathogenicity of CNVs.Results Sixteen cases of the above 64 patients were found to have CNVs with genomic alterations,including 6 cases microdeletions/microduplications associated with known syndromes,3 cases microdeletions and microduplications with clear clinical relevance (non-syndrome),1 case numerical chromosome aberration,1 case unbalanced translocation and 5 cases CNVs of unknown clinical significance.The detection rate was 25% (16/64 cases).Among these 16 abnormalities,6 cases of them could not be detected by using karyotyping analysis because their sizes were less than 5 Mb,and the smallest detected missing fragment was 0.53 Mb.Conclusion SNP-array gene chip technique with the advantages of higher efficiency,high-resolution and good accuracy,which can be applied to the genetic diagnosis of intellectual disability.

Application of SNP-array technology in the genetic analysis of pediatric patients with growth retardation / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the value of single nucleotide polymorphism array (SNP-array) for the analysis of pediatric patients with growth retardation.</p><p><b>METHODS</b>One hundred eighty one children with growth retardation were enrolled. DNA was extracted from peripheral samples from the patients, and whole genome copy number variations (CNVs) were detected using Illumina Human Cyto SNP-12. All identified CNVs were further analyzed with reference to databases including ClinGen, ClinVar, DECIPHER, OMIM and DGV as well as comprehensive review of literature from PubMed to determine their pathogenicity.</p><p><b>RESULTS</b>Forty seven patients (26%) with abnormal CNVs were detected, which included 12 known microdeletions/microduplications syndrome (26%), 10 pathogenic non-syndromic CNVs (21%), 3 numerical chromosome aberrations (6%), 3 unbalanced translocations (6%), 4 pathogenic mosaicisms (9%) and 15 cases with unknown clinical significance (32%). After excluding obvious numerical and/or structural chromosomal abnormalities, this study has detected 15 pathogenic microdeletions/microduplications sized 5 Mb or less, which may be missed by routine chromosomal karyotyping. In addition, there were 3 cases with loss of heterozygoisty (LOH) containing known or predicted imprinting genes as well as 2 cases with suspected parental consanguinity.</p><p><b>CONCLUSION</b>SNP-array technology is a powerful tool for the genetic diagnosis of children with growth disorders with advantages of high resolution and improved accuracy.</p>

A novel compound heterozygous mutation causing 3-methylcrotonyl-CoA carboxylase deficiency / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the molecular mechanism for a boy suspected with 3-methylcrotonyl-CoA carboxylase deficiency by neonatal screening.</p><p><b>METHODS</b>PCR and Sanger sequencing were used to identify potential mutations of MCCC1 and MCCC2 genes. SIFT and Polyphen-2 software was used to predict the effect of variant on the protein function and conservation of the variant across various species. Human Splicing Finder and Swiss-PdbViewer4.1.0 were applied to analyze the possible mechanism of the variant.</p><p><b>RESULTS</b>For the proband, a compound heterozygous mutation was discovered in the MCCC1 gene, namely c.539G>T (p.G180V) and c.704_711del (p.A235Vfs*4), which were inherited from his father and mother, respectively. The two mutations have disrupted the protein conformation, which in turn may impact the function of MCC protein.</p><p><b>CONCLUSION</b>The compound heterozygous mutations of the MCCC1 gene may contribute to the 3-methylcrotonyl-CoA carboxylase deficiency manifested by the patient.</p>

Identification of two novel mutations of MUT gene in a Chinese family affected with isolated methylmalonic acidemia / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the molecular etiology for a Chinese family affected with isolated methylmalonic acidemia (MMA).</p><p><b>METHODS</b>Potential mutations of MUT, MMAA and MMAB genes in the proband were screened by PCR and Sanger sequencing. The pathogenicity of identified mutations was analyzed using Polyphen2, SIFT, HSF, DNAMAN 6.0 and Swiss-PdbViewer4.1.0 software.</p><p><b>RESULTS</b>Two novel mutations of the MUT gene, including c.581C>T (p.P194L) and c.1219A>T (p.N407Y), were discovered in the proband, which were inherited respectively from his mother and father. Bioinformatics analysis suggested that both mutations were damaging. The affected codons P194 and N407, both located in the (beta, alpha) 8 barrel domain and to which the substrate methylmalonyl-CoA is bound, are highly conserved across various species. Both mutations can disrupt the space conformation of its protein product, affecting the function of the MCM protein.</p><p><b>CONCLUSION</b>The novel mutations of MUT gene probably underlie the isolated MMA in this family.</p>

Cause of Death Related to Medical Disputes in Yancheng Area：A Study of 60 Autopsy Cases / 法医学杂志

Objective To summarize the pattern and main characteristics of fatal cases related to medical disputes in Yancheng area. Methods Sixty fatal cases of medical disputes were retrospectively analyzed to elucidate the annual incidence, characters of distribution of hospitals, gender and age of the decedents, types of diseases, and cause of death. Results Among 60 fatal cases, most cases happened in health clinics of county, township and village. There were more males than females. The major medical specialties in-volved included internal medicine, surgery, gynecology and pediatrics, with the internal medicine specialty having the highest incidence. Conclusion Police institutions have advantages in investigation of these cas-es in their jurisdictions, which could enhance the ability of local medicolegal examination.

Gene array analysis in 56 cases of children with growth retardation / 临床儿科杂志

Objective To investigate the genetic basis of the children with growth retardation. Methods From January to October 2013, the 56 patients with growth retardation were enrolled in this study. Genomic DNA was extracted from peripheral blood and was analyzed with gene array chips. Results Abnormalities were found in 12 patients (6 cases of sex chromosome abnormalities and 6 cases of autosomal aberration) and the detection rate was 21.4%. Four patients had the copy-number variations of smaller than 2.5Mb in size which could not be found by karyotyping analysis. Conclusions SNP-array gene chip could be used in the genetic diagnosis of growth retardation.

ASS1 gene mutation in a neonate with citrullinemia type I / 中华儿科杂志

<p><b>OBJECTIVE</b>To identify the genetic mutation in ASS1 gene in a Chinese family with citrullinemia typeI, which may provide a basis for the diagnosis and genetic counseling.</p><p><b>METHOD</b>Genomic DNA was isolated from peripheral blood samples of the family members. Mutation analysis of ASS1 gene was carried out by PCR and Sanger sequencing. Biostructural analysis of the mutated ASS1 was completed by Phyre server.</p><p><b>RESULT</b>Double heterozygous mutations in the proband were identified: c.951delT (F317LfsX375) and c.1087C>T (R363W), which were confirmed in the proband's father and mother, respectively. It was found that the c.951delT mutation might change the formation of a dimer or a tetramer and the function of ASS1 protein.</p><p><b>CONCLUSION</b>Double heterozygous mutations for c.951delT and c.1087C>T have been found in a proband with citrullinemia typeI. The c.951delT is a novel mutation in citrullinemia typeI, which may change the configuration of ASS1 protein and result in ASS1 dysfunction.</p>