Are speech-evoked auditory brainstem response (speech-ABR) outcomes influenced by ethnicity?

Due to its objective nature, auditory brainstem response (ABR) evoked by complex stimuli has been gaining attention lately. The present study aimed to compare the speech-evoked auditory brainstem response (speech-ABR) results between two ethnic groups: Malay and Chinese. In addition, it was also of interest to compare the speech-ABR outcomes obtained from the present study with the published Caucasian data. Thirty healthy male adults (15 Malay and 15 Chinese) were enrolled in this comparative study. Speech syllable/da/presented at 80 dBnHL was used to record speech-ABR waveforms from the right ear of each subject. Amplitudes and latencies of speech-ABR peaks (V, A, C, D, E, F and O), as well as composite onset measures (V/A duration, V/A amplitude and V/A slope) were computed and analyzed. When the two ethnic groups were compared, all speech-ABR results were not statistically different from each other (p > 0.05). When the data from the present study were compared with the published Caucasian data, most of the statistical analyses were significant (p < 0.05). That is, Asian subjects revealed significantly higher peak amplitudes, earlier peak latencies, higher V/A amplitudes and steeper V/A slopes than that of Caucasians. The speech-ABR results between Malay and Chinese were found to be essentially similar due to anatomical similarities. Nevertheless, specific normative data for Asian adults are required as their speech-ABR results are different from that of Caucasian males. This issue should be addressed before it can be applied holistically in multiracial countries.     

miRNA-binding site polymorphism in IL-15RA gene in rheumatoid arthritis and systemic lupus erythematosus: correlation with disease risk and clinical characteristics

Clinical Rheumatology - MiRSNPs may interfere with mRNA stability through effects on microRNAs (miRNAs)-mRNA interactions via direct changes in miRNA binding site or effect on the secondary...     

Detection and phasing of single base de novo mutations in biopsies from human in vitro fertilized embryos by advanced whole-genome sequencing

Currently, the methods available for preimplantation genetic diagnosis (PGD) of in vitro fertilized (IVF) embryos do not detect de novo single-nucleotide and short indel mutations, which have been shown to cause a large fraction of genetic diseases. Detection of all these types of mutations requires whole-genome sequencing (WGS). In this study, advanced massively parallel WGS was performed on three 5- to 10-cell biopsies from two blastocyst-stage embryos. Both parents and paternal grandparents were also analyzed to allow for accurate measurements of false-positive and false-negative error rates. Overall, >95% of each genome was called. In the embryos, experimentally derived haplotypes and barcoded read data were used to detect and phase up to 82% of de novo single base mutations with a false-positive rate of about one error per Gb, resulting in fewer than 10 such errors per embryo. This represents a ∼100-fold lower error rate than previously published from 10 cells, and it is the first demonstration that advanced WGS can be used to accurately identify these de novo mutations in spite of the thousands of false-positive errors introduced by the extensive DNA amplification required for deep sequencing. Using haplotype information, we also demonstrate how small de novo deletions could be detected. These results suggest that phased WGS using barcoded DNA could be used in the future as part of the PGD process to maximize comprehensiveness in detecting disease-causing mutations and to reduce the incidence of genetic diseases.Worldwide, more than 5 million babies (Ferraretti et al. 2013) have been born through in vitro fertilization (IVF) since the birth of the first in 1978 (Steptoe and Edwards 1978). Exact numbers are difficult to determine, but it has been estimated that currently 350,000 babies are born yearly through IVF (de Mouzon et al. 2009, 2012; Centers for Disease Control and Prevention 2011; Ferraretti et al. 2013). That number is expected to rise, as advanced maternal age is associated with decreased fertility rates and women in developed countries continue to delay childbirth to later ages. In 95% of IVF procedures, no diagnostic testing of the embryos is performed (https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0). Couples with prior difficulties conceiving or those wishing to avoid the transmission of highly penetrant heritable diseases often choose to perform preimplantation genetic diagnosis (PGD). PGD involves the biopsy of one cell from a 3-d embryo or the recently more preferred method, due to improved implantation success rates (Scott et al. 2013b), of up to 10 cells from a 5- to 6-d blastocyst-stage embryo. Following biopsy, genetic analysis is performed on the isolated cell(s). Currently this is an assay for translocations and the correct chromosome copy number (Hodes-Wertz et al. 2012; Munne 2012; Yang et al. 2012; Scott et al. 2013a; Yin et al. 2013), a unique test designed and validated for each specific heritable disease (Gutierrez-Mateo et al. 2009), or a combination of both (Treff et al. 2013). Importantly, none of these approaches can detect de novo mutations.Advanced maternal age has long been associated with an increased risk of producing aneuploid embryos (Munne et al. 1995; Crow 2000; Hassold and Hunt 2009) and giving birth to a child afflicted with Down syndrome or other diseases resulting from chromosomal copy number alterations. Conversely, children of older fathers have been shown to have an increase in single base and short multibase insertion/deletion (indels) de novo mutations (Kong et al. 2012). Many recent large-scale sequencing studies have found that de novo variations spread across many different genes are likely to be the cause of a large fraction of autism cases (Michaelson et al. 2012; O’Roak et al. 2012; Sanders et al. 2012; De Rubeis et al. 2014; Iossifov et al. 2014), severe intellectual disability (Gilissen et al. 2014), epileptic encephalopathies (Epi4K Consortium and Epilepsy Phenome/Genome Project 2013), and many other congenital disorders (de Ligt et al. 2012; Veltman and Brunner 2012; Yang et al. 2013; Al Turki et al. 2014). Additionally rare and de novo variations have been suggested to be prevalent in patients with schizophrenia (Fromer et al. 2014; Purcell et al. 2014), and Michaelson et al. (2012) found that single base de novo mutations affect conserved regions of the genome and essential genes more often than regions of unknown function. Current targeted approaches to PGD would miss many of these important functional changes within the embryonic DNA sequence, and even a whole-genome sequencing (WGS)–based carrier screen of both parents would not enable comprehensive preimplantation or prenatal diagnoses due to de novo mutations. As more parents delay childbirth into their mid-30s and later, these studies suggest we should try to provide better diagnostic tests for improving the health of newborns. In this study, we demonstrate the use of an advanced WGS process that provides an accurate and phased genome sequence from about 10 cells, allowing highly sensitive and specific detection of single base de novo mutations from IVF blastocyst biopsies.     

Clinical and Laboratory Findings in Iranian Patients with Leukocyte Adhesion Deficiency (Study of 15 Cases)

Leukocyte adhesion deficiency type I (LAD I) is a rare, inherited, autosomal recessive, immunodeficiency disease caused by the combined loss of expression on the surface of leukocytes of the leukocyte integrins. We describe the clinical and laboratory findings for 15 patients with LAD I. The range of patients’ ages was from 10 month to 14 years (median 4 years) and 93.3% of their parents had consanguineous marriages. The most commonly occurred manifestations were: recurrent infections (93.3%), poor wound healing (86%), oral ulcers (86%), and skin abscesses (80%). The most specific laboratory findings were defect in CD18 in all of 15 patients. The most common symptoms in these patients are poor wound healing and oral ulcer, so, the clinical physicians should pay special attention to these symptoms. Furthermore, because of considerable rate of consanguineous marriages in parents of LAD patients, we suggested more genetic studies on this disease and genetic consultation for these families. An erratum to this article can be found at     

Stratification of pedigrees multiplex for systemic lupus erythematosus and for self-reported rheumatoid arthritis detects a systemic lupus erythematosus susceptibility gene (SLER1) at 5p15.3

OBJECTIVE: Arthritis is a common manifestation in systemic lupus erythematosus (SLE), appearing in approximately 85% of patients. Often, the polyarthritis at presentation of SLE cannot be distinguished from rheumatoid arthritis (RA) by physical examination or history. Indeed, physicians initially tell many SLE patients that they have RA (one source of "self-reported RA"), only to have SLE established later. In addition, RA aggregates in families with an SLE proband. We predicted that pedigrees multiplex for both SLE and for self-reported RA would better isolate particular genetic effects. If this proved to be true, we would then use the increased genetic homogeneity to more easily reveal genetic linkage. METHODS: From a collection of 160 pedigrees multiplex for SLE, we selected 36 pedigrees that also contained >or=2 members with self-reported RA (19 pedigrees were African American, 14 were European American, and 3 were of other ethnic origin). Data from a genome scan of 307 microsatellite markers were evaluated for SLE linkage by contemporary genetic epidemiologic techniques. RESULTS: The most significant evidence of linkage to SLE was obtained at 5p15.3 in the European American pedigrees by both parametric (logarithm of odds [LOD] score 6.2, P = 9.3 x 10(-8)) and nonparametric (LOD score 6.9, P = 1.7 x 10(-8)) methods. The best-fitting model for this putative SLE gene in this region was a recessive gene with a population frequency of 5% and with 50% penetrance in females and 15% penetrance in males at virtually 100% homogeneity. CONCLUSION: For a genetically complex disease phenotype, an unusually powerful linkage has been found with SLE at 5p15.3 in European American pedigrees multiplex for SLE and for self-reported RA. This result predicts the presence of a gene at the top of chromosome 5 in this subset of patients that is important for the pathogenesis of SLE.