Current Protocols in Human Genetics

Spector, Jacob D.; Wiita, Arun P.

2020 Current Protocols in Human Genetics

doi: 10.1002/cphg.106pmid: 33170544

DNA copy number variants (CNVs) are routinely evaluated as part of clinical diagnosis in both the prenatal and postnatal genetic settings. Current guidelines for interpreting the potential clinical significance of these CNVs, typically identified by chromosomal microarray, focus entirely on genes localized within the CNV region. However, recent work has suggested that some CNVs can actually produce clinical impacts by influencing transcription of genes outside the CNV region. These alterations of transcription appear to occur by disrupting the composition of DNA topologically associated domains (TADs), which strongly influence contacts between gene promoters and their associated enhancers. Here we present a set of detailed protocols for the use of the free software tool ClinTAD (https://www.clintad.com). This decision‐support software allows for prediction as to whether a given CNV may potentially disrupt a TAD boundary, and offers phenotype matching to genes near, but not within the CNV region, whose expression could be influenced by altered TAD architecture and that have phenotypic impacts related to that reported in a given patient. Our protocols here provide specific examples of how to implement these tools. In addition, the software has the capability to impact genomic research by evaluating multiple cases in parallel. We propose that this decision‐support tool can benefit and improve genetic diagnosis. © 2020 Wiley Periodicals LLC.

Greenwood, Anna K.; Montgomery, Kelsey S.; Kauer, Nicole; Woo, Kara H.; Leanza, Zoe J.; Poehlman, William L.; Gockley, Jake; Sieberts, Solveig K.; Bradic, Ljubomir; Logsdon, Benjamin A.; Peters, Mette A.; Omberg, Larsson; Mangravite, Lara M.

2020 Current Protocols in Human Genetics

doi: 10.1002/cphg.105pmid: 33085189

The AD Knowledge Portal (adknowledgeportal.org) is a public data repository that shares data and other resources generated by multiple collaborative research programs focused on aging, dementia, and Alzheimer's disease (AD). In this article, we highlight how to use the Portal to discover and download genomic variant and transcriptomic data from the same individuals. First, we show how to use the web interface to browse and search for data of interest using relevant file annotations. We demonstrate how to learn more about the context surrounding the data, including diagnostic criteria and methodological details about sample preparation and data analysis. We present two primary ways to download data—using a web interface, and using a programmatic method that provides access using the command line. Finally, we show how to merge separate sources of metadata into a comprehensive file that contains factors and covariates necessary in downstream analyses. © 2020 The Authors.

2020 Current Protocols in Human Genetics

doi: 10.1002/cphg.91

Nalbandian, Katarena; Piña‐Aguilar, Raul E.; Morton, Cynthia C.

2020 Current Protocols in Human Genetics

doi: 10.1002/cphg.107pmid: 33369263

Novel cytogenetic tools are increasingly based on genome sequencing for detecting chromosomal abnormalities. Different sequence‐based techniques optimized for diagnosis of structural variants can be useful for narrowing down the localization of breakpoints of chromosomal abnormalities, but do not offer nucleotide resolution of breakpoints for proper interpretation of gene disruption. This protocol presents the characterization of structural variants at nucleotide resolution using Sanger sequencing after low‐pass large‐insert genome sequencing or other long‐molecule methods. © 2020 Wiley Periodicals LLC.

Botkin, Jeffrey R.

2020 Current Protocols in Human Genetics

doi: 10.1002/cphg.104pmid: 33202103

Genetic research often utilizes or generates information that is potentially sensitive to individuals, families, or communities. For these reasons, genetic research may warrant additional scrutiny from investigators and governmental regulators, compared to other types of biomedical research. The informed consent process should address the range of social and psychological issues that may arise in genetic research. This article addresses a number of these issues, including recruitment of participants, disclosure of results, psychological impact of results, insurance and employment discrimination, community engagement, consent for tissue banking, and intellectual property issues. Points of consideration are offered to assist in the development of protocols and consent processes in light of contemporary debates on a number of these issues. © 2020 Wiley Periodicals LLC.