North American Journal of Medicine and Science
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Microarray Reporting: Balancing Laboratory Findings, Clinical Utility and Patient Anxiety
Get PDFCytogenomic microarray has been increasingly applied in prenatal diagnosis with the advantage of higher resolution and faster turn-around time compared with conventional karyotyping. However, the greater information offered by this technology also leads to special challenges and ethical dilemmas for laboratory cytogeneticists, obstetricians, and patients. These issues are most apparent in reporting results of uncertain clinical significance, which are frequently found by cytogenomic microarray. The reporting of such variants may lead to significant obstetrician unease and patient anxiety, particularly as the results of cytogenomic microarray may often be the primary factor in determining whether to terminate a wanted pregnancy. However, cytogeneticists often feel an obligation to report such variants due to laboratory guidelines or avoidance of future legal liability. Here, we discuss several issues specific to interpreting array results in the prenatal setting, including copy-number-variant size and gene content, penetrance, inheritance, region of homozygosity, mosaicism, maternal cell contamination, and clinical correlation. We propose a practical approach for cytogeneticists to balance complete reporting of laboratory findings with predicted clinical utility and minimization of patient anxiety. Our discussion also highlights the importance of establishing a prenatal array database with longitudinal studies to determine phenotypic outcomes related to variants identified on array, and the central role of genetic counseling in the use of prenatal cytogenomic arrays. Incorporation of these elements and a universal reporting framework will be crucial for more seamlessly integrating cytogenomic array analysis into prenatal care
Navigating Web-Based Resources for Genetic Testing of Chromosome Abnormalities, CNVs and Gene Mutations
Get PDFCurrent clinical genetic and genomic testing involves genome-wide evaluation of chromosomal abnormalities, copy number variants (CNVs) and gene mutations. The major challenge facing genetic laboratory directors, physicians and counselors is to distinguish pathogenic variants from variants of unknown clinical significance (VOUS) and benign polymorphic variants. Various genetic and genomic databases were generated and maintained to facilitate the interpretation process. Those databases typically present collections of specific types of genetic abnormalities with cross references all relevant clinical findings and biological knowledge. This paper outlines the prevailing web-based resources used for genetic and genomic testing results interpretation in three categories: chromosomal abnormalities, CNVs, and gene mutations. Routine routes on utilizing these web resources in clinical setting are provided and some limitations are discussed.
Improving Quality of Genetic Testing through Participation in International Proficiency Testing Programs
Get PDFOver the past decade, China has experienced rapid growth in the field of clinical genetic testing. However, considerable variations exist in testing practices among the laboratories, in part due to the lack of comprehensive standards, guidelines, and inter-laboratory proficiency testing programs. Here, we report the quality improvement experience of a major academic genetic testing center in China through participation in American proficiency testing programs for newborn screening and cytogenetics. Our experience highlights the importance of inter-laboratory proficiency testing in improving genetic testing quality, and the needs to develop robust proficiency programs to advance the field of genetics and genomics medicine in China.
Next Generation Direct-acting Antiviral Agents for Hepatitis C Treatment
Get PDFSofosbuvir in combination with peginterferon and ribavirin for 12 weeks is a new treatment paradigm with a 12 week course of therapy leading to high sustained response rates in genotype 1 and 4 infected individuals including high sustained response rates in cirrhotic patients. In addition, genotype 2 and 3 infected individuals now have an all oral regimen of sofosbuvir and ribavirin, which is highly effective in all genotype 2 infected individuals with 12 weeks of therapy. For genotype 3 infected individuals, 24 weeks of the sofosbuvir and ribavirin leads to high sustained virological response rates in most groups. However, cirrhotic genotype 3 infected individuals are going to require additional strategies to optimize SVR rates. It is expected that 2014 should see the presentation of phase 3 data with a variety of combinations of direct acting antiviral agents with the anticipated approval of these combinations occurring in late 2014 or early 2015. Moreover, one should expect that SVR rates above 90% for treatment naive and treatment failure patients should be the expected norm for all patients
Tetrahydrobiopterin Deficiency in Autism Spectrum Disorder
Get PDFTetrahydrobiopterin is an essential cofactor for critical metabolic pathways, including those involved in the production of monoamine neurotransmitters and nitric oxide. Cerebrospinal fluid studies suggest that tetrahydrobiopterin concentrations in the central nervous system (CNS) may be lower in children with autism spectrum disorder (ASD) as compared to typically developing children. Clinical trials, including double-blind placebo controlled studies, suggest that oral tetrahydrobiopterin supplementation is therapeutic in children with ASD. Despite these previous studies, no clinical description of children with ASD and CNS tetrahydrobiopterin deficiency has been published. A series of six patients with ASD who were found to have CNS tetrahydrobiopterin deficiency is described. Most (83%) had global developmental delay while two (33%) had slow regression into an autism phenotype and only one (17%) had epilepsy. The pattern of metabolic abnormalities was not consistent with a primary disorder of pterin production. Overall, this case series suggests that children with ASD can have a CNS deficiency in tetrahydrobiopterin and that this deficiency is probably not a primary disorder of tetrahydrobiopterin production, but rather most likely secondary to reduced precursor availability, reduced recycling and/or increased utilization due to other multifactorial abnormalities associated with ASD such as abnormalities in CNS folate and/or oxidative stress
Seasonality of Influences on Disorders of Psychological Development: A Synopsis
No full textThere are many contributing factors to the development of disorders of psychological development that can interact in a complicated way to cause alterations of gene expression that result in autism, schizophrenia, or other disorders. It is therefore important to consider the environment in which we live, with its changing seasons and their manifestation of changes in infectious disease rates, the survival of pathogens outside the host, host behavior, altered immune response of mammals, and the abundance of vectors and non-human hosts of diseases. The accumulated impact of these forces on a developing human fetus can cause abnormal brain development, which, after birth, can later manifest as a disorder of psychological development such as autism or schizophrenia. While the scientific literature confirms a seasonality to the birth of individuals who later develop schizophrenia, there are conflicting data regarding a seasonality of birth for autism. Similarities between autism and schizophrenia are presented, in addition to influences affecting psychological development, including infectious disease, genetics, sunlight and vitamin D, pregnancy, immunology, and gland and system dysfunction
Involvement of Voltage-Gated Ca2+ Channels in Autism Spectrum Disorders
Get PDFSubstantial evidence suggests that mutated voltage-gated L-type Ca2+ channel subunit CaV1.2 (CACNAIC) is involved in pathophysiology of autism spectrum disorder (ASD), as exemplified by recent findings that mutated CACNAIC and other L-type Ca2+ channels play an important role in pathophysiology of Timothy Syndrome and Fragile X Syndrome, genetic syndromes of ASD. This review will focus on recent advances in our understanding of the genetic mutation of the CaV1.2 L-type channels in ASD, and highlight the potential roles of CaV1.2 channels in the pathogenesis of ASD.
Neuroinflammation and Autism
Get PDFThe incidence of autism spectrum disorder (ASD) has increased significantly in the past decades, now affecting 1 out of 68 children in USA. The complexity of this disorder and the unclear mechanisms have hindered the development of an effective therapeutic regimen. Recent studies have suggested that neuro-inflammation plays an important role in the pathogenesis of ASD. A literature review was conducted to examine the evidence of various central immune processes involved in ASD. Conventional and novel medications for ASD treatment were summarized
Furosemide Induced Bullous Pemphigoid Associated with Antihistone Antibodies
Get PDFAn 81 year old man developed tense blisters on his abdomen and thighs several months after starting oral furosemide. Routine histologic studies revealed subepidermal bullae filled with eosinophils and neutrophils typical of bullous pemphigoid. Direct immunofluoresence studies revealed weak linear deposits of IgG and trace C3 along the dermal-epidermal junction along with a striking in vivo ANA reaction. ELISA studies to BP180 and BP230 antigens were negative although a low titer of IgG4 was noted in the blister roof on 1M NaCl split skin. A homogenous pattern of ANA on Hep2 cells was detected at a titer of > 5120. Antibodies to histone were very high when detected with ELISA. The clinical and pathologic findings are consistent with drug induced bullous pemphigoid. The associated drug induced lupus erythematosus-like immunopathologic findings are unusual and illustrate the broad range of changes that may occur. Furosemide induced bullous pemphigoid and the significance of antihistone antibodies in drug induced autoimmune disease will be reviewed.
Study of the Application of Clinical Pathways in Varicella, Acute Bacillary Dysentery, Measles, Scarlet Fever, and Rubella
Get PDFIn order to explore the clinical pathways that fit the actual situation of our country and department of infectious diseases, an analysis was performed to evaluate the effectiveness of clinical pathways for varicella, acute bacillary dysentery, measles, scarlet fever and rubella when compared with traditional standard medical care. Using a retrospective comparative study design, varicella, acute bacillary dysentery, measles, scarlet fever and rubella patients who were managed on a clinical pathway (clinical pathway group) were compared with a retrospective group of patients who received traditional medical care (control group) prior to the pathway's implementation. The following outcomes were measured: length of hospital stay, hospitalization costs. There was a significant reduction in the median hospitalization costs in the clinical pathway group patients in all five infectious diseases (P<0.05). The clinical pathway group's length of hospital stay for varicella, measles, acute bacillary dysentery and rubella were significantly shorter than the control group (P<0.05). The implementation of clinical pathways in varicella, acute bacillary dysentery, measles, scarlet fever and rubella might contribute to better quality of care and cost-effectiveness