Whole Genome Medical Sequencing for Genome Discovery

Background:

- A number of rare inherited diseases affect only a few patients, and the genetic causes of these conditions remain unknown. Researchers are studying the use of a new technology called whole genome sequencing to learn which gene or genes cause these conditions. Understanding the genes that cause these diseases is important to improve diagnosis and treatment of affected patients.

Objectives:

• To identify the genetic cause of disorders that are difficult to identify with existing techniques.
• To develop best practices for the medical and counseling challenges of whole genome sequencing.

Eligibility:

• Individuals who have one of the rare disorders under consideration in this study. These conditions are generally those in which the genetic cause of the disorder is unknown. The eligibility of most individual participants will be decided on a case-by-case basis by the researchers.
• Family members of affected individuals, if that family member (often a parent) may provide genetic information.

Design:

• Participants in this study will have at least one and in some cases several of the following procedures:
• A medical genetics evaluation.
• Other tests that may include x-rays, magnetic resonance imaging (MRI) exams, and consultations with other doctors. Not all studies are necessary for each person, but the information from the tests may be required to proceed with some of our gene sequencing studies.
• Clinical photographs to document certain aspects of the disorder.
• Blood and skin biopsy samples, or other tissue samples, as required by the study doctors.
• Genetic testing, as decided by the researchers. However, most participants in this study can expect to undergo whole genome sequencing, which is a technique to study all of a person's genes.
• Some participants may be asked to take part in a telephone interview and/or a web-based survey.
• Participants will have choices about what kinds of results from whole genome sequencing they wish to learn.
• After the tests have been completed and the results of the genetic studies are known, participants will be offered a return visit to the National Institutes of Health to learn these results. During this visit, participants will be asked to complete surveys and participate in interviews related to their decisions to participate in the study and to learn individual genetic test results.

We aim to use whole-genome medical sequencing (WGMS) to discover causative molecular lesions for a set of rare, severe phenotypes hypothesized to be caused by either somatic mutations, germline de novo heterozygous mutations, germline inherited recessive, or germline inherited dominant mutations in currently unknown or uncharacterized genes. The goal of this research is threefold: to identify causative sequence variants for disorders whose molecular etiology was previously unknown, to apply this insight to both the rare disorders under study and more common phenotypes, and to enhance the study of mutation on a genome-wide level.

We plan to recruit approximately three to six affected individuals along with both parents for each phenotype under study. Prospectively recruited trios will be brought to the NIH Clinical Center for brief clinical evaluations and molecular evaluation. Each trio will be consented to whole genome sequencing with the option to learn clinically relevant results, that is, those that explain the disorder in question (what we refer to as the primary variant') as well as other clinically relevant findings discovered incidentally as part of the WGMS process (what we refer to as secondary variants ). Participants will be offered a return visit to NIH to learn these results, and will be asked to complete surveys and participate in interviews related to their decisions about participation in the study and to learn individual genotype results.

The NIH Intramural Sequencing Center (NISC) will screen for sequence variants that conform to the hypothesized inheritance pattern. These variants will be validated, for example by using trios for de novo phenotypes, or with additional cases. We have started developing analytic algorithms to distinguish potentially pathogenic genetic alterations from normal variation. All sequence variants deemed clinically relevant will be validated in a CLIA-certified laboratory and the results returned to that participant, should they choose to learn these findings. This protocol is being designed in a way that will provide the long-term potential for pursuing many different clinical projects.

• Multiple Congenital Anomaly Syndromes
• Congenital Disorders
• Inherited Diseases

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• INCLUSION CRITERIA:
• An individual who is affected with a disorder under study. We have provided a list of exemplar disorders in Appendix A. As stated above, these individuals will generally represent simplex cases with rare phenotypes whose molecular etiology is unknown.
• A family member of an affected individual where that family member (often a parent) is potentially informative or useful for linkage or other bioinformatic analyses of genetic variants. Probands who are minors or decisionally-impaired adults are eligible if they have a parent or legal guardian who has authority to sign a consent form on their behalf.

EXCLUSION CRITERIA:

• Probands who are adults and decisionally-impaired are ineligible if they do not have a legal guardian who has authority to sign a consent form on their behalf.
• Subjects who have known, significant affective or psychiatric disorders that, in the judgment of the team, may impair their ability to understand and appropriately use complex medical and genetic information will be considered decisionally-impaired and will be ineligible unless they have appointed (or, in the case of minor children, are in the custody of) an appropriate surrogate decision-maker.