Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13

Exome sequencing is a powerful tool for discovery of the Mendelian disease genes. Previously, we reported a novel locus for autosomal recessive non-syndromic mental retardation (NSMR) in a consanguineous family [Nolan, D.K., Chen, P., Das, S., Ober, C. and Waggoner, D. (2008) Fine mapping of a locus for nonsyndromic mental retardation on chromosome 19p13. Am. J. Med. Genet. A, 146A, 1414-1422]. Using linkage and homozygosity mapping, we previously localized the gene to chromosome 19p13. The parents of this sibship were recently included in an exome sequencing project. Using a series of filters, we narrowed the putative causal mutation to a single variant site that segregated with NSMR: the mutation was homozygous in five affected siblings but in none of eight unaffected siblings. This mutation causes a substitution of a leucine for a highly conserved proline at amino acid 182 in TECR (trans-2,3-enoyl-CoA reductase), a synaptic glycoprotein. Our results reveal the value of massively parallel sequencing for identification of novel disease genes that could not be found using traditional approaches and identifies only the seventh causal mutation for autosomal recessive NSMR.     

National prevalence estimates for cytomegalovirus IgM and IgG avidity and association between high IgM antibody titer and low IgG avidity

Primary cytomegalovirus (CMV) infection of the mother during pregnancy presents risk of CMV infection of the fetus with resulting permanent disability. CMV IgM antibody is generated following primary CMV infection but also can appear during nonprimary CMV infection and is thus of limited diagnostic use by itself. In contrast, the presence of low CMV IgG avidity has been shown to be a unique and reliable serologic indicator of primary CMV infection. We measured CMV IgG and IgM antibody levels and IgG avidity in sera from a population sample of 6,067 U.S. women aged 12 to 49 years from NHANES (National Health and Nutrition Examination Survey). The CMV IgG prevalence was 58% overall and increased strongly with age. The CMV IgM prevalence was 3.0% overall and remained relatively flat across age groups. The prevalence of low IgG avidity was 2.0% overall, decreased sharply with age, and was seen mainly among IgM-positive sera. Fourteen to 18% of the CMV IgM-positive sera were low IgG avidity, presumably representing primary CMV infection. High CMV IgM antibody titer was a strong predictor of low IgG avidity. The ability to reliably identify primary CMV infection during pregnancy is important for management of the pregnancy, including possible treatment options for the fetus. Both IgM and IgG avidity measurements provide useful clinical information for evaluating primary CMV infection, although commercial tests for CMV IgG avidity are not yet widely available in the United States.     

Actual proliferating index in oral squamous cell carcinoma and leukoplakia

Aim: To examine the possible association between epithelial proliferation and disease progression in the oral mucosa using the actual proliferation index. Methods: The actual proliferation index was measured by the Ki‐67 labeling index and argyrophilic nucleolar organizer region count per nucleus. Immunohistochemistry was carried out for Ki‐67 by using the molecular immunology borstel‐1 clone in 20 leukoplakias, 20 oral squamous cell carcinomas, and 10 normal oral mucosae. Results: The argyrophilic nucleolar organizer region count per nucleus, Ki‐67 labeling index, and actual proliferation index were significantly higher in oral squamous cell carcinoma, followed by leukoplakia and normal oral mucosa. Leukoplakia with dysplasia showed a significantly higher Ki‐67 labeling index and actual proliferation index, compared to leukoplakia without dysphasia. There was a significant correlation of Bryne’s histological malignancy grading with the argyrophilic nucleolar organizer region count and the Ki‐67 labeling index. There was a significant positive correlation between the argyrophilic nucleolar organizer region count and the Ki‐67 labeling index among all groups. Conclusions: Leukoplakia or suspected epithelial dysplasia should be stained for argyrophilic nucleolar organizer regions and Ki‐67. The actual proliferation index is not only useful as a prognostic factor, but could also be a promising treatment determining modality for patients with premalignant and malignant lesions.     

Vascular endothelial growth factor gene polymorphisms in North Indian patients with recurrent miscarriages

The association of four common polymorphisms of vascular endothelial growth factors (VEGF) with recurrent miscarriages(RM) was evaluated in North Indian women for 200 patients with RM and 200 controls. The subjects were genotyped for the polymorphisms 2578C/A, 2549 18-bp I/D, 1154G/A and +936C/T. Association of VEGF genotypes, alleles and haplotypes with recurrent miscarriage were evaluated by Fisher’s exact test. 1154G/A and +936C/T modified the risk of RM. The 1154A allel and +936T allel significantly increased the risk of RM (OR = 1.485, P = 0.0210, 95% CI 1.072–2.057 and OR = 1.869, P = 0.0054, 95% CI 1.214–2.876 respectively). Risk was further increased when –1154A/A genotype and +936C/T genotype were considered (OR = 2.0, P = 0.0310,95% CI 1.068–3.747 and OR = 1.716, P = 0.0293, 95% CI 1.058–2.784 respectively). However, no association was found between 2578C/A or 2549 18-bp I/D and RM. Four haplotypes, AIAC, ADAC, CIAT and ADGT, were found to predispose to RM while the haplotypes CIAC, CDGT and ADGC were found to show protective effect. In conclusion, two common polymorphisms of the VEGF gene,1154G/A and +936C/T, increase the risk of RM in North Indian women. RM is also predisposed in the presence of haplotypes AIAC,ADAC, CIAT and ADGT.     

A case of three synchronous primary tumors demonstrated by F-18 FDG PET

We present an F-18 FDG PET scan which demonstrates 3 synchronous primary malignancies. The patient is a 61-year-old man who presented with weight loss and dysphagia. He was initially diagnosed with squamous cell carcinoma of the midesophagus, and was then found to have an adenocarcinoma in the right lung. A staging PET scan additionally showed increased left tonsillar uptake. Subsequent biopsy confirmed squamous cell carcinoma of the left tonsil. The demonstration of 3 synchronous primaries by PET is probably rare.     

Complementary, holistic, and integrative medicine: Crohn disease

Although the use of CAM in pediatric CD is common, quality evidence-based research is limited. There is clearly a need for further randomized controlled trials. The role of psychosocial distress in children with CD should not be overlooked and thus biobehavioral techniques should be considered and incorporated when possible. Considering the potential for growth failure and need for surgical intervention in CD, any CAM therapies that are not harmful should be used only in combination with conventional medical treatment. The importance of all health care providers partnering with their patients and asking about CAM use, as well as maintaining an awareness of efficacy, safety, harm, drug-supplement interactions, and appropriate referral sources, should be kept in mind when caring for those afflicted with this chronic disease.     

Drawing the history of the Hutterite population on a genetic landscape: inference from Y-chromosome and mtDNA genotypes

Although the North American Hutterites trace their origins to South Tyrol, no attempts have been made to examine the genetic migration history of the Hutterites before emigrating to the United States in the 1870s. To investigate this, we studied 9 microsatellite loci and 11 unique event polymorphism (UEP) markers on the Y-chromosome, the hypervariable region I (HVRI) of the mitochondrial DNA (mtDNA), as well as the complete mtDNA genome of Hutterite and South Tyrolean samples. Only 6 out of 14 Y-chromosome UEP+microsatellite haplotypes and 3 out of 11 mitochondrial haplotypes that were present in the Hutterites were also present in the South Tyrolean population. The phylogenetic relationships inferred from Y-chromosome and mtDNA databases show that the Hutterites have a unique genetic background related to a similar extent to central and eastern European populations. An admixture analysis indicates, however, a relatively high genetic contribution of central European populations to the Hutterite gene pool. These results are consistent with historical records on Hutterite migrations and demographic history. In addition, our data reveal similar numbers of Y and mitochondrial haplotypes in Hutterite male and female founders, respectively. The Hutterite male and female gene pools are similar with respect to genetic diversity and genetic distance measures and comparable with respect to their origins, suggesting a similar evolutionary history.     

MicroRNAs in inner ear biology and pathogenesis

MicroRNAs (miRNA) are a group of small noncoding RNAs that regulate gene expression. The discovery of these small RNAs has added a new layer of complexity to molecular biology. Every day, new advances are being made in understanding the biochemistry and genetics of miRNAs and their roles in cellular function and homeostasis. Studies indicate diverse roles for miRNAs in inner ear biology and pathogenesis. This article reviews recent developments in miRNA research in the field of inner ear biology. A brief history of miRNA discovery is discussed, and their genomics and functional roles are described. Advances in the understanding of miRNA involvement in inner ear development in the zebrafish and the mouse are presented. Finally, this review highlights the potential roles of miRNAs in genetic hearing loss, hair cell regeneration, and inner ear pathogenesis resulting from various pathological insults.