Trials Today

Conditions

• Intellectual Disabilities
• Congenital Anomaly
• Rare Disorders

Eligibility

Eligible Ages

Between 4 Weeks and 99 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

Criteria

- 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.

Study Contact

Detailed Description

We aim to use genome scale medical sequencing (GSMS, to include exome and whole genome sequencing as appropriate) 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 GSMS 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 GSMS process (what we refer to as secondary variants ). Participants will be offered a return visit to NIH to learn these results. Sequence data generated at the NIH Intramural Sequencing Center (NISC) will be screened by staff in the Biesecker laboratory for sequence variants that conform to the hypothesized inheritance pattern. All sequence variants deemed clinically relevant will be validated in a CLIA-certified laboratory and the results returned to that participant. This protocol is being designed in a way that will provide the long-term potential for pursuing many different clinical projects.