Genomic sequencing is becoming accurate, fast, and inexpensive, and is rapidly being incorporated into clinical practice. Incidental findings, which result in large numbers from genomic sequencing, are a potential barrier to the utility of this new technology due to their high prevalence and the lack of evidence or guidelines available to guide their clinical interpretation. This unit reviews the definition, classification, and management of incidental findings from genomic sequencing. The unit focuses on the clinical aspects of handling incidental findings, with an emphasis on the key role of clinical context in defining incidental findings and determining their clinical relevance and utility.

This unit provides an overview of the design and analysis of population-based case-control studies of genetic risk factors for complex disease. Considerations specific to genetic studies are emphasized. The unit reviews basic study designs differentiating case-control studies from others, presents different genetic association strategies (candidate gene, genome-wide association, and high-throughput sequencing), introduces basic methods of statistical analysis for case-control data and approaches to combining case-control studies, and discusses measures of association and impact. Admixed populations, controlling for confounding (including population stratification), consideration of multiple loci and environmental risk factors, and complementary analyses of haplotypes, genes, and pathways are briefly discussed. Readers are referred to basic texts on epidemiology for more details on general conduct of case-control studies.

Modern gene-mapping can include linkage studies, which correlate the presence of disease to broad genomic regions in either small or large family units, and association studies, which can narrow the location of a disease-predisposing trait to a single gene using either case-control or family data. This unit provides an overview of key concepts and presents guidelines for collecting diagnostic, epidemiological, and genealogical data from potential study participants. The commentary discusses the use of publicly available data from online resources, methods for evaluating evidence of genetic versus environmental influences in a disease or disease-related endophenotype, and use of e-forms to capture data electronically.

Many patients suffering from developmental disorders have submicroscopic deletions or duplications affecting the copy number of dosage-sensitive genes or disrupting normal gene expression. Many of these changes are novel or extremely rare, making clinical interpretation problematic and genotype/phenotype correlations difficult. Identification of patients sharing a genomic rearrangement and having phenotypes in common increases certainty in the diagnosis and allows characterization of new syndromes. The DECIPHER database is an online repository of genotype and phenotype data whose chief objective is to facilitate the association of genomic variation with phenotype to enable the clinical interpretation of copy number variation (CNV). This unit shows how DECIPHER can be used to (1) search for consented patients sharing a defined chromosomal location, (2) navigate regions of interest using in-house visualization tools and the Ensembl genome browser, (3) analyze affected genes and prioritize them according to their likelihood of haploinsufficiency, (4) upload patient aberrations and phenotypes, and (5) create printouts at different levels of detail. By following this protocol, clinicians and researchers alike will be able to learn how to characterize their patients' chromosomal imbalances using DECIPHER.

One of the most widely used interfaces for the retrieval of information from biological databases is the NCBI Entrez system. Entrez capitalizes on the fact that there are pre-existing, logical relationships between the individual entries found in numerous public databases. The existence of such natural connections, mostly biological in nature, argued for the development of a method through which all the information about a particular biological entity could be found without having to sequentially visit and query disparate databases. Two basic protocols describe simple, text-based searches, illustrating the types of information that can be retrieved through the Entrez system. An alternate protocol builds upon the first basic protocol, using additional, built-in features of the Entrez system, and providing alternative ways to issue the initial query. The support protocol reviews how to save frequently issued queries. Finally, Cn3D, a structure visualization tool, is also discussed.

Biochemical genetics focuses on the pathophysiology, diagnosis, and treatment of inherited metabolic disorders. While individually rare, the combined incidence of these diseases is likely greater than 1:3000 live births. These conditions may present in the neonatal period as an acute, life-threatening illness, or may manifest later in childhood with symptoms of progressive neurodegeneration, skeletal abnormalities, and/or dysmorphia. The purpose of this introductory unit is to provide an overview of the different clinical categories of metabolic disorders, modern diagnostic methods, and treatment options.