Pharmacogenetic testing is becoming more common; however, very few quality control and other reference materials that cover alleles commonly included in such assays are currently available. To address these needs, the Centers for Disease Control and Prevention's Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, have characterized a panel of 107 genomic DNA reference materials for five loci (CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1) that are commonly included in pharmacogenetic testing panels and proficiency testing surveys. Genomic DNA from publicly available cell lines was sent to volunteer laboratories for genotyping. Each sample was tested in three to six laboratories using a variety of commercially available or laboratory-developed platforms. The results were consistent among laboratories, with differences in allele assignments largely related to the manufacturer's assay design and variable nomenclature, especially for CYP2D6. The alleles included in the assay platforms varied, but most were identified in the set of 107 DNA samples. Nine additional pharmacogenetic loci (CYP4F2, EPHX1, ABCB1, HLAB, KIF6, CYP3A4, CYP3A5, TPMT, and DPD) were also tested. These samples are publicly available from Coriell and will be useful for quality assurance, proficiency testing, test development, and research. Many laboratories are testing for pharmacogenetic (PGx) markers, common genetic variants that are usually considered only when a patient is likely to be exposed to a Accepted for publication June 21, 2010. R.B., A.E.-B., C.S., A.V., and M.Z. are employees of AutoGenomics (manufacturer of several pharmacogenetic assays used in this study); M.B., A.B., and K.M. are employees of Quest Diagnostics Inc.; J.M. is an employee of Idaho Technology (manufacturer of the reagents used to genotype CYP2C9 and VKORC1 loci for this project);

The superior sensitivity and specificity associated with the use of molecular assays has greatly improved the field of infectious disease diagnostics by providing clinicians with results that are both accurate and rapidly obtained. Herein, we review molecularly based infectious disease diagnostic tests that are Food and Drug Administration approved or cleared and commercially available in the United States as of December 31, 2010. We describe specific assays and their performance, as stated in the Food and Drug Administration's Summary of Safety and Effectiveness Data or the Office of In Vitro Diagnostic Device Evaluation and Safety's decision summaries, product inserts, or peer-reviewed literature. We summarize indications for testing, limitations, and challenges related to implementation in a clinical laboratory setting for a wide variety of common pathogens. The information presented in this review will be particularly useful for laboratories that plan to implement or expand their molecular offerings in the near term.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

The use of molecular genetic tests for heritable conditions is expected to increase in medical settings, where genetic knowledge is often limited. As part of a project to improve the clarity of genetic test result reports to minimize misunderstandings that could compromise patient care, we sought input about format and content from practicing primary care clinicians. In facilitated workgroup discussions, clinicians from pediatric, obstetrics-gynecology, and family practice provided their perspectives about molecular genetic testing with a focus on the laboratory reporting of test results. Common principles for enhancing the readability and comprehension of test result reports were derived from these discussions. These principles address the presentation of patient-and test-specific information, the test result interpretation, and guidance for future steps. Model test result reports for DNA-based cystic fibrosis testing are presented that were developed based on workgroup discussions, previous studies, and professional guidelines. The format of these model test reports, which are applicable to a variety of molecular genetic tests, should be useful for communicating essential information from the laboratory to health care professionals. Medical test results inform clinical decision making and can influence patient and family attitudes and action. The reporting of molecular genetic tests for heritable conditions by the laboratory issuing the report to the health care provider is complex because interpretation of the test result frequently relies on patient-and family-specific information. Studies have shown that proper interpretation of test results can be compromised by practices in both laboratory and clinical settings by factors that relate to the collection and use of patient-and family-specific information, variation and format of test requisitions and result reports, and the competency of medical staff, especially those lacking specialized knowledge of genetics.

Fragile X syndrome , which is caused by expansion of a (CGG) n repeat in the FMR1 gene , occurs in approximately 1:3500 males and causes mental retardation/ behavioral problems. Smaller (CGG) n repeat expansions in FMR1, premutations , are associated with premature ovarian failure and fragile X-associated tremor/ataxia syndrome. An FMR1-sizing assay is technically challenging because of high GC content of the (CGG) n repeat , the size limitations of conventional PCR , and a lack of reference materials available for test development/validation and routine quality Fragile X syndrome (FXS) is the most common inherited cause of mental retardation, with an incidence in males of approximately 1 in 3500 (for a recent review, see http:// genetests.org). Clinical features in males include mental retardation, specific physical characteristics (enlarged testes, large ears, and long face), and behavioral abnormalities, sometimes including autism spectrum disorder. Affected females, with an incidence of approximately 1 in 8000, have mild mental retardation. Our knowledge of the spectrum of phenotypes associated with expansion of the FMR1 gene now also includes premature ovarian failure 1 and fragile X (FX)-associated tremor/ataxia syndrome.2-5 Thus, genetic testing for FX mutations is important at all life stages, prenatally to adulthood.