Genome Medical Sequencing for Gene Discovery

* INCLUSION CRITERIA: An individual who is affected with a disorder under study and is older than 4 weeks. Our initial list of exemplar disorders has been discontinued; these disorders were examples of those which meet the general attributes for inclusion in this protocol. As stated above, individuals with disorders we choose to investigate under this protocol will generally represent simplex cases with rare phenotypes whose molecular etiology is unknown. In rare instances, we may accept DNA from deceased individuals, including DNA or other saved biological specimens from deceased fetuses/neonates in accordance with Policy 400. These samples may provide us exceptional opportunities to study variants and manifestations of severe genetic overgrowth disorders where the fetus/neonate is unviable due to the severity of manifestations. In the rare circumstance where we plan to accept samples from non-viable fetuses/neonates, we may engage with pregnant mothers to begin consent discussions and coordinate specimen collection. We will only enroll pregnant women who voluntarily donate fetal tissue from invasive prenatal testing, and for which trio analysis is appropriate and necessary. While rare, there may be circumstances in which the scientific objectives (to elucidate the molecular etiology of the proband s genetic condition) would not be possible without analyzing the DNA of the fetus/proband and the biological parents. The conditions set under 45CFR46.205 are met for the inclusion of non-viable neonates: * Vital functions of the neonate will not be artificially maintained; * The research will not terminate the heartbeat or respiration of the neonate; * There will be no added risk to the neonate resulting from the research; * The purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means; and * The legally effective informed consent is obtained in accord with applicable regulations. Family members 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 may be enrolled. 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 INCLUSION: 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. In addition, guardianship for cognitively impaired adult probands must be legally established and proof of guardianship must be supplied prior to that family s enrollment. We request the ability to use this protocol for multiple genetic disorders, without specifically delineating them a priori. We believe this approach to be appropriate because for nearly all inherited disorders, the risks and benefits of GSMS do not substantively differ. This concept was validated by our now-closed protocol 94-HG-0193, which was a broad-based protocol for heritable congenital anomaly disorders, many of which do not fall neatly into a specific diagnostic classification. As mentioned, we may request permission to retain some information about prospective participants who, at the time of their inquiry, may not be eligible for the study but who could become eligible in the future. As these participants will not be signing a consent form, we propose to NOT count these participants in our Inclusion Enrollment Reports but will provide the IRB with a tally of retained records at each Continuing Review. Consent documents for this protocol are available in English and Spanish. In rare instances, we may enroll participants who speak other languages using the NIH Short Written Consent Form Translation. We will not enroll pregnant women, except as outlined in the section above.