Evidence from 2100 index cases supports genome sequencing as a first-tier genetic test.

PURPOSE: Genome sequencing (GS) is one of the most comprehensive assays that interrogate single-nucleotide variants, copy number variants, mitochondrial variants, repeat expansions, and structural variants in a single assay. Despite the clear technical superiority, the full clinical utility of GS has yet to be determined. METHODS: We systematically evaluated 2100 clinical GS index cases performed in our laboratory to explore the diagnostic yield of GS as first-tier and as follow-up testing. RESULTS: The overall diagnostic yield was 28% (585/2100). The diagnostic yield for GS as the first-tier test was 26% (294/1146). Among cases with prior non-diagnostic genetic tests, GS provided a diagnosis for 27% (247/910) of cases, including 56 cases with prior exome sequencing (ES). Although re-analysis of previous ES might have resolved the diagnosis in 29 cases, diagnoses for 27 cases would have been missed because of the technical inferiority of ES. Moreover, GS further disclosed additional genetic etiology in 3 out of 44 cases with existing partial diagnosis. CONCLUSION: We present the largest-to-date GS data set of a clinically heterogeneous cohort from a single clinical laboratory. Our data demonstrate that GS should be considered as the first-tier genetic test that has the potential to shorten the diagnostic odyssey.

Psychometric assessment of the Runyankole-translated Marlowe-Crowne Social Desirability Scale among persons with HIV in Uganda.

BACKGROUND: Social desirability can negatively affect the validity of self-reported measures, including underreporting of stigmatized behaviors like alcohol consumption. The Marlowe-Crowne Social Desirability Scale (SDS) is widely implemented and comprised of Denial and Attribution Domains (i.e., tendencies to deny undesirable traits or attribute socially desirable traits to oneself, respectively). Yet, limited psychometric research has been conducted in sub-Saharan Africa, where the prevalence of unhealthy alcohol consumption is high as well as religiosity and hierarchical social norms. To address this gap, we (a) conducted an exploratory study assessing certain psychometric properties of the 28-item SDS (Runyankole-translated) among persons with HIV (PWH) in Uganda, and (b) examined the relationship between social desirability and self-reported alcohol use. METHODS: We pooled baseline data (N = 1153) from three studies of PWH engaged in alcohol use from 2017 to 2021. We assessed the translated scale's construct validity (via confirmatory factor analysis), internal consistency, item performance, differential item functioning by gender, concurrent validity with the DUREL religiosity index domains, and the association between social desirability and self-reported alcohol use. RESULTS: Participants had a mean age of 40.42 years, 63% were men, and 91% had an undetectable HIV viral load. The 28-item SDS had satisfactory construct validity (Model fit indices: RMSEA = 0.07, CFI = 0.84, TLI = 0.82) and internal consistency (Denial Domain ΩTotal = 0.82, Attribution Domain ΩTotal = 0.69). We excluded Item 14 ("I never hesitate to help someone in trouble") from the Attribution Domain, which mitigated differential measurement error by gender and slightly improved the construct validity (Model fit indices: RMSEA = 0.06, CFI = 0.86, TLI = 0.85) and reliability (Attribution Domain ΩTotal = 0.72) of the 27-item modified SDS. Using the 27-item SDS, we found that social desirability was weakly correlated with religiosity and inversely associated with self-reported alcohol use after adjusting for biomarker-measured alcohol use and other confounders (ß = -0.05, 95% confidence interval: -0.09 to -0.01, p-value = 0.03). CONCLUSIONS: We detected and mitigated measurement error in the 28-item Runyankole-translated SDS, and found that the modified 27-item scale had satisfactory construct validity and internal consistency in our sample. Future studies should continue to evaluate the psychometric properties of the Runyankole-translated SDS, including retranslating Item 14 and reevaluating its performance.

Multidisciplinary recommendations for essential baseline functional and laboratory tests to facilitate early diagnosis and management of immune-related adverse events among cancer patients.

Immune checkpoint inhibitors (ICIs) have fundamentally changed the treatment landscape of various cancers. While ICI treatments result in improved survival, quality of life and are cost-effective, the majority of patients experience at least one immune-related adverse event (irAE). Many of these side effects cause little discomfort or are asymptomatic; however, irAEs can affect any organ and are potentially life-threatening. Consequently, early diagnosis and appropriate treatment of irAEs are critical for optimizing long-term outcomes and quality of life in affected patients. Some irAEs are diagnosed according to typical symptoms, others by abnormal findings from diagnostic tests. While there are various guidelines addressing the management of irAEs, recommendations for the early recognition of irAEs as well as the optimal extent and frequency of laboratory tests are mostly lacking. In clinical practice, blood sampling is usually performed before each ICI administration (i.e., every 2-3 weeks), often for several months, representing a burden for patients as well as health care systems. In this report, we propose essential laboratory and functional tests to improve the early detection and management of irAEs and in cancer patients treated with ICIs. These multidisciplinary expert recommendations regarding essential laboratory and functional tests can be used to identify possible irAEs at an early time point, initiate appropriate interventions to improve patient outcomes, and reduce the burden of blood sampling during ICI treatment.

Injection Drug Use and Sexual Risk Behaviors Among People who Inject Drugs in Ukraine: A Random-Intercept Latent Transition Analysis.

HIV transmission in Ukraine is driven in part by unsafe injection drug use and sexual risk behaviors among people who inject drugs. We performed a random-intercept latent transition analysis on responses to 9 binary injection drug use and sexual behavior items from 1195 people who inject drugs with negative HIV status enrolled in a clustered randomized clinical trial of a social network intervention in Odessa, Donetsk, and Nikolayev, Ukraine. We identified 5 baseline classes: "Social injection/equipment-sharing" (11.7%), "Social injection" (25.9%), "High-risk collective preparation/splitting" (17.0%), "Collective preparation/splitting" (11.3%), and "Dealer-facilitated injection" (34.1%). After 12 months, intervention participants were more likely to transition to the "Collective preparation/splitting" class, which featured the fewest risk behaviors. Transitioning from the "Collective preparation/splitting" to the "Social injection/equipment-sharing" class was associated with HIV acquisition for control participants. Research to illuminate the stability of these patterns and how they may benefit from uniquely tailored programming to reduce unsafe behaviors is needed.

Effects of a social network intervention on HIV seroconversion among people who inject drugs in Ukraine: moderation by network gender composition.

BACKGROUND: Women who inject drugs in Ukraine are disproportionately burdened by HIV. To help address the needs of this population, a greater understanding of how interventions may uniquely benefit women who inject drugs is needed. METHODS: Data come from a randomized controlled trial of a social network intervention targeting people who inject drugs in Ukraine (N = 1195). Indexes, plus two of their injection network members, received HIV testing and counseling (control arm) or HIV testing and counseling plus a social network intervention (intervention arm), in which indexes were trained to influence network members' risk behaviors. We used Cox regressions with interaction terms to assess differences in time to HIV seroconversion between arms by network gender composition and gender of the index. For significant interaction terms, we calculated simple effects, generated survival functions using Kaplan-Meier methods, and compared survival curves using log-rank tests. RESULTS: At 12 months, there were 45 seroconversions among women (40.0 [28.3, 51.7] per 100 person years) and 111 among men (28.4 [23.1, 33.6] per 100 person years) in the control arm; there were 27 seroconversions among women (17.1 [10.7, 23.6] per 100 person years) and 77 among men (18.7 [14.5, 22.9] per 100 person years) in the intervention arm. Network gender composition (but not gender of the index) moderated the intervention effect on HIV incidence (p < 0.05). Specifically, the intervention appeared to be even more protective against HIV acquisition as female gender composition increased. In the intervention arm, the HIV seroconversion hazard rate was 44% lower with 1 network female; 61% lower with 2 network females; and 72% lower with 3 network females. CONCLUSIONS: A greater number of women in an injection network, coupled with the provision of risk-reduction strategies, is associated with HIV risk-mitigation, though the mechanisms through which this occurs remain unclear. Findings can support new research and practice directions that prioritize women who inject drugs and more thoughtfully support their health and wellbeing.

Vales+Tú: a cluster-randomized pilot study to reduce workplace injuries among US Latino day laborers.

Latino day laborers (LDL) are a vulnerable population of workers facing considerable risk for occupational injury. Under the guidance of our Community Advisory Board, we developed and tested the feasibility, acceptability and preliminary effects of Vales+Tú (You Are Worth More), a workplace injury risk-reduction program implemented by promotores on street-corners where LDL seek employment. The program was informed by theoretical perspectives emphasizing individual and group agency and self-determination. A pilot three-arm cluster-randomized community trial was conducted among 75 LDL. The intervention arms consisted of an individualized Brief Motivational Interview, a Group Problem Solving activity and a standard of care control (OSHA safety cards). We met our study goal of 25 LDL per intervention arm, and contacted 88% of participants post intervention. Participants evaluated the interventions favorably. At post-test, the Brief Motivational Interview group reported significant reductions in exposure to workplace hazards and increases in risk-reduction practices. The Group Problem Solving participants showed significant reductions in exposure to hazards (t-test -4.16, p < 0.001). Both intervention groups increased their reliance on corner peers, a measure of social support. Standard of care participants increased in self-efficacy to work safely. Overall, the only significant different between the three study conditions was in self-efficacy. These findings provide evidence of the feasibility and acceptability of Vales+Tú and show preliminary program efficacy. A large-scale replication trial will permit a more formal modeling of the study findings. Clinical Trial Registration (ClinicalTrials.gov): NCT04378348.

This pilot-randomized trial tested the feasibility and initial efficacy of an injury risk-reduction program among Latino day laborers (LDL). The study tested two alternative interventions consisting of a Brief Motivational Interview (Individual) and a Group Problem Solving (Group) conditions that were compared with a Standard-of-Care control group receiving safety cards. We then tested the extent to which the study conditions reduced exposure to workplace hazards and increased safety practices at work. Results indicate that intervening at day labor corners is a feasible intervention strategy acceptable to these immigrant workers. Initial results also indicate that there were multiple within-group significant differences in risk reduction, mostly in the individual condition, and that there was one significant between-group difference in safety self-efficacy at post-test. A larger more rigorous trial can further test the stability of these results and determine the extent to which these intervention approaches can reduce the risk for injury that LDL confront at work.

Economic and financial crisis based on Troika's intervention and potentially avoidable hospitalizations: an ecological study in Portugal.

BACKGROUND: Hospitalisations for Ambulatory Care Sensitive Conditions (ACSC) cause harm to users and to health systems, as these events are potentially avoidable. In 2009, Portugal was hit by an economic and financial crisis and in 2011 it resorted to foreign assistance ("Memorandum of Understanding" (2011-2014)). The aim of this study was to analyse the association between the Troika intervention and hospitalisations for ACSC. METHODS: We analysed inpatient data of all public NHS hospitals of mainland Portugal from 2007 to 2016, and identified hospitalisations for ACSC (pneumonia, chronic obstructive pulmonary disease, hearth failure, hypertensive heart disease, urinary tract infections, diabetes), according to the AHRQ methodology. Rates of hospitalisations for ACSC, the rate of enrollment in the employment center and average monthly earnings were compared among the pre-crisis, crisis and post-crisis periods to see if there were differences. A Spearman's correlation between socioeconomic variables and hospitalisations was performed. RESULTS: Among 8,160,762 admissions, 892,759 (10.94%) were classified as ACSC hospitalizations, for which 40% corresponded to pneumonia. The rates of total hospitalisations and hospitalisations for ACSC increased between 2007 and 2016, with the central and northern regions of the country presenting the highest rates. No correlations between socioeconomic variables and hospitalisation rates were found. CONCLUSIONS: During the period of economic and financial crisis based on Troika's intervention, there was an increase in potentially preventable hospitalisations in Portugal, with disparities between the municipalities. The high use of resources from ACSC hospitalisations and the consequences of the measures taken during the crisis are factors that health management must take into account.

Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next-generation sequencing.

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A-related leukodystrophy, Peroxisomal biogenesis disorders, POLR3-related Leukodystrophy, Vanishing White Matter, and Pelizaeus-Merzbacher Disease. Despite the relative frequency of these conditions, carrier-screening laboratories regularly test only 20 of the 55 leukodystrophy-related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.

SLC6A1 variants identified in epilepsy patients reduce γ-aminobutyric acid transport.

Previous reports have identified SLC6A1 variants in patients with generalized epilepsies, such as myoclonic-atonic epilepsy and childhood absence epilepsy. However, to date, none of the identified SLC6A1 variants has been functionally tested for an effect on GAT-1 transporter activity. The purpose of this study was to determine the incidence of SLC6A1 variants in 460 unselected epilepsy patients and to evaluate the impact of the identified variants on γ-aminobutyric acid (GABA)transport. Targeted resequencing was used to screen 460 unselected epilepsy patients for variants in SLC6A1. Five missense variants, one in-frame deletion, one nonsense variant, and one intronic splice-site variant were identified, representing a 1.7% diagnostic yield. Using a [3 H]-GABA transport assay, the seven identified exonic variants were found to reduce GABA transport activity. A minigene splicing assay revealed that the splice-site variant disrupted canonical splicing of exon 9 in the mRNA transcript, leading to premature protein truncation. These findings demonstrate that SLC6A1 is an important contributor to childhood epilepsy and that reduced GAT-1 function is a common consequence of epilepsy-causing SLC6A1 variants.

Regulating whole exome sequencing as a diagnostic test.

In the last decade, there has been a flood of new technology in the sequencing arena. The onset of next-generation sequencing (NGS) technology has resulted in the vast increase in genetic diagnostic testing available to the ordering physician. Whole exome sequencing (WES) has become available as a diagnostic test performed in certified clinical laboratories. This has led to increased presence in the diagnostic marketplace, increased consumer awareness, and the question has been raised by various stakeholders to whether there is sufficient stringent regulation of WES and other NGS-based tests. We discuss the various WES services currently available in the marketplace, current regulation of WES as a laboratory developed test, the proposed FDA involvement in its oversight as well as the response of various laboratory groups that provide these diagnostic services. Overall, a rigorous process oversight and assessment of inter-lab reproducibility is strongly warranted for WES as it is used as a diagnostic test, but regulation should be mindful of the excessive administrative burden on academic and smaller diagnostic laboratories.

A comprehensive genomic approach for neuromuscular diseases gives a high diagnostic yield.

OBJECTIVE: Neuromuscular diseases (NMDs) are a group of >200 highly genetically as well as clinically heterogeneous inherited genetic disorders that affect the peripheral nervous and muscular systems, resulting in gross motor disability. The clinical and genetic heterogeneities of NMDs make disease diagnosis complicated and expensive, often involving multiple tests. METHODS: To expedite the molecular diagnosis of NMDs, we designed and validated several next generation sequencing (NGS)-based comprehensive gene panel tests that include complementary deletion and duplication testing through comparative genomic hybridization arrays. Our validation established the targeted gene panel test to have 100% sensitivity and specificity for single nucleotide variant detection. To compare the clinical diagnostic yields of single gene (NMD-associated) tests with the various NMD NGS panel tests, we analyzed data from all clinical tests performed at the Emory Genetics Laboratory from October 2009 through May 2014. We further compared the clinical utility of the targeted NGS panel test with that of exome sequencing (ES). RESULTS: We found that NMD comprehensive panel testing has a 3-fold greater diagnostic yield (46%) than single gene testing (15-19%). Sanger fill-in of low-coverage exons, copy number variation analysis, and thorough in-house validation of the assay all complement panel testing and allow the detection of all types of causative pathogenic variants, some of which (about 18%) may be missed by ES. INTERPRETATION: Our results strongly indicate that for molecular diagnosis of heterogeneous disorders such as NMDs, targeted panel testing has the highest clinical yield and should therefore be the preferred first-tier approach.

The potential clinical value of contrast-enhanced echocardiography beyond current recommendations.

BACKGROUND: Contrast agents are used in resting echocardiography to opacify the left ventricular (LV) cavity and to improve LV endocardial border delineation in patients with suboptimal image quality. If a wider use of contrast-enhanced echocardiography would be adopted instead of the current selective approach, diagnoses such as myocardial ischemia and LV structural abnormalities could potentially be detected earlier. The aim was therefore to retrospectively investigate if contrast-enhanced echocardiography beyond the current recommendations for contrast agent usage affects assessment of wall motion abnormalities, ejection fraction (EF) and detection of LV structural abnormalities. A secondary aim was to evaluate the user dependency during image analysis. METHODS: Experienced readers (n = 4) evaluated wall motion score index (WMSI) and measured EF on greyscale and contrast-enhanced images from 192 patients without indications for contrast-enhanced echocardiography. Additionally, screening for LV structural abnormalities was performed. Repeated measurements were performed in 20 patients by the experienced as well as by inexperienced (n = 2) readers. RESULTS: Contrast analysis resulted in significantly higher WMSI compared to greyscale analysis (p < 0.003). Of the 83 patients, classified as healthy by greyscale analysis, 55% were re-classified with motion abnormalities by contrast analysis. No significant difference in EF classification (≥55%, 45-54%, 30-44%, < 30%) was observed. LV structural abnormalities, such as increased trabeculation (n = 21), apical aneurysm (n = 4), hypertrophy (n = 1) and thrombus (n = 1) were detected during contrast analysis. Intra- and interobserver variability for experienced readers as well as the variability between inexperienced and experienced readers decreased for WMSI and EF after contrast analysis. CONCLUSIONS: Contrast-enhanced echocardiography beyond current recommendations for contrast agent usage increased the number of detected wall motion and LV structural abnormalities. Moreover, contrast-enhanced echocardiography increased reproducibility for assessment of WMSI and EF.

Stress Analysis of Axial and Tilted Implants in Full-arch Fixed Dentures Under Different Abutment Conditions.

The aim of this study was to evaluate the stress distribution on full-arch prostheses, considering axial implants and tilted implants with or without abutments. Two photoelastic models were made, being that in 1 model the implants were inserted perpendicular, whereas in the other model 2 implants were inserted perpendicular and 2 implants were inserted with tilting 30° to the distal area. The prosthetic situations were evaluated: A-axial implants and nonsegmented full-arch prosthesis; B-axial implants and segmented full-arch prosthesis; C-tilted distal implants and nonsegmented full-arch prosthesis; D-tilted distal implants and segmented full-arch prosthesis, and was applied an axial load of 100 N at 5 points. The results showed greater stress concentration for axial implants than tilted implants in anterior and posterior loading. There was no difference in stress distribution to the use of abutment in the tilted implants. Shorter cantilever with tilted implants improved the stress distribution; the use of abutment did not influence the stress distribution.

Paint booth waste as an alternative aggregate for the production of interlocking concrete blocks.

Inadequate disposal of hazardous waste results risks to the environment and human health. Although the use of hazardous waste in new processes and/or products has received limited attention in the literature, there is still significant potential to be investigated. Reducing the usage of natural resources and waste management are important for sustainable practices during concrete production. This study investigated the mechanical and leaching behavior of paint booth waste (PBW) as a partial substitute (10, 20, 30 and 40%) of coarse aggregate in concrete mixtures for the manufacture of interlocking blocks. A sample of PBW used in this research differs from those in the literature due to its granulometry characterized by aggregates of different sizes. Concrete consistency, compressive strength, water absorption, X-ray diffraction, scanning electron microscopy, and leaching tests were carried out. The PBW did not influence the consistency in the fresh state of the concrete. The blocks with smaller substitutions (10 and 20%) presented denser structures and with greater strengths, surpassing 35 MPa after 28 days. Higher levels of PBW resulted in more porous concrete blocks with greater water absorption. The concrete-PBW mixtures showed no metal toxicity, i.e., the incorporation of this waste in the construction material avoided metal leaching. Concrete blocks with up to 20% PBW demonstrated satisfactory mechanical and environmental performance.

Awareness of the impact of sex and gender in the disease risk and outcomes in hematology and medical oncology-a survey of Swiss clinicians.

BACKGROUND: Although male and female cancer patients are distinct in many ways, there is a limited understanding in the differences between male and female biology and differing pharmacokinetic responses to cancer drugs. In fact, sex and gender are currently not considered in most treatment decisions in the fields of oncology and hematology. The lack of knowledge about potential sex differences in both disciplines may lead to differences in treatment efficacy, toxicity, and the overall survival (OS) of patients. AIM: To evaluate their awareness about sex and gender in clinical practice we surveyed Swiss hematologists and oncologists from September to November 2022. METHODS: We collected data about the clinical knowledge, experimental research, palliative care, quality of life, as well as the participant perception of the importance of sex and gender. We identified 767 eligible clinicians, of whom 150 completed the survey (20% response rate). RESULTS: While most participants agreed that sex and gender were relevant when treating patients, it became clear that fewer participants knew about sex and gender differences in treatment toxicity and survival, which in turn would affect the treatment of their patients. Most participants agreed that this topic should be integrated into continuing education and research. CONCLUSION: Our findings indicate the need for more awareness and training on sex and gender in cancer research and clinical care among oncologists and hematologists. Ideally, by better educating medical students and health professionals, a demand is created for improving research policies, publications and therefore patient care.

Performance of castor oil polyurethane resin in composite with the piassava fibers residue from the Amazon.

The use of castor oil in producing polyurethane resins has been identified as one of the most promising options for the industry. The piassava fibers waste generated by the industry on a large scale presents excellent properties as a reinforcing agent due to its high lignin content characterized by chemical tests and FTIR. Composite boards consisting of a higher content of mercerized piassava fibers (10 mm, 85 wt.%) reinforced polyurethane castor oil-based resin (prepolymer (PP) and polyol (OM)) exhibited excellent performance. Composites with these properties have strong potential for medium-density applications ranging from biomedical prosthetics to civil partition walls and insulation linings. Alkali treatment removed the superficial impurities of piassava fibers, activating polar groups, and physical characterization reported excellent performance for all composites. Among the composites, the CP3 sample (composite reinforced with piassava fibers (85 wt.% fibers; 1.2:1-PP:OM)) stood out with higher density and lower swelling and water absorption percentage than other composites. FTIR results indicated NCO traces after the resin cured in the PU3 (1.2:1-PP:OM), possibly contributing to the interaction with the fibers. DMA results reported relevant information about more flexibility to CP1 (composite reinforced with piassava fibers (85 wt.% fibers; 0.8:1-PP:OM)) and CP3 than CP2 (composite reinforced with piassava fibers (85 wt.% fibers; 1:1-PP:OM)). The results suggest that the proper combination with natural products must lead to composites with potential applications as engineering materials.

Focused Exome Sequencing Gives a High Diagnostic Yield in the Indian Subcontinent.

The genetically isolated yet heterogeneous and highly consanguineous Indian population has shown a higher prevalence of rare genetic disorders. However, there is a significant socioeconomic burden for genetic testing to be accessible to the general population. In the current study, we analyzed next-generation sequencing data generated through focused exome sequencing from individuals with different phenotypic manifestations referred for genetic testing to achieve a molecular diagnosis. Pathogenic or likely pathogenic variants are reported in 280 of 833 cases with a diagnostic yield of 33.6%. Homozygous sequence and copy number variants were found as positive diagnostic findings in 131 cases (15.7%) because of the high consanguinity in the Indian population. No relevant findings related to reported phenotype were identified in 6.2% of the cases. Patients referred for testing due to metabolic disorder and neuromuscular disorder had higher diagnostic yields. Carrier testing of asymptomatic individuals with a family history of the disease, through focused exome sequencing, achieved positive diagnosis in 54 of 118 cases tested. Copy number variants were also found in trans with single-nucleotide variants and mitochondrial variants in a few of the cases. The diagnostic yield and the findings from this study signify that a focused exome test is a good lower-cost alternative for whole-exome and whole-genome sequencing and as a first-tier approach to genetic testing.

Free the data: one laboratory's approach to knowledge-based genomic variant classification and preparation for EMR integration of genomic data.

Current technology allows clinical laboratories to rapidly translate research discoveries from small patient cohorts into clinical genetic tests; therefore, a potentially large proportion of sequence variants identified in individuals with clinical features of a genetic disorder remain unpublished. Without a mechanism for clinical laboratories to share data, interpretation of sequence variants may be inconsistent. We describe here the two components of Emory Genetics Laboratory's (EGL) in-house developed data management system. The first is a highly curated variant database with a data structure designed to facilitate sharing of information about variants identified at EGL with curated databases. This system also tracks changes in variant classifications, creating a record of previous cases in need of updated reports when a classification is changed. The second component, EmVClass, is a Web-based interface that allows any user to view the inventory of variants classified at EGL. These software tools provide a solution to two pressing issues faced by clinical genetics laboratories: how to manage a large variant inventory with evolving variant classifications that need to be communicated to healthcare providers and how to make that inventory of variants freely available to the community.

Molecular diagnostic testing for congenital disorders of glycosylation (CDG): detection rate for single gene testing and next generation sequencing panel testing.

Congenital disorders of glycosylation (CDG) are comprised of over 60 disorders with the majority of defects residing within the N-glycosylation pathway. Approximately 20% of patients do not survive beyond five years of age due to widespread organ dysfunction. A diagnosis of CDG is based on abnormal glycosylation of transferrin but this method cannot identify the specific gene defect. For many individuals diagnosed with CDG the gene defect remains unknown. To improve the molecular diagnosis of CDG we developed molecular testing for 25 CDG genes including single gene testing and next generation sequencing (NGS) panel testing. From March 2010 through November 2012, a total of 94 samples were referred for single gene testing and 68 samples were referred for NGS panel testing. Disease causing mutations were identified in 24 patients resulting in a molecular diagnosis rate of 14.8%. Coverage of the 24 CDG genes using panel testing and whole exome sequencing (WES) was compared and it was determined that many exons of these genes were not adequately covered using a WES approach and a panel approach may be the preferred first option for CDG patients. A collaborative effort between physicians, researchers and diagnostic laboratories will be very important as NGS testing using panels and exome becomes more widespread. This technology will ultimately improve the molecular diagnosis of patients with CDG in hard to solve cases.