An observational study in Intellectual Disabilities, Congenital Anomaly and Rare Disorders, sponsored by National Human Genome Research Institute (NHGRI). Recruiting at 1 site in United States. Open to participants aged 4 Weeks to 99 Years. Per ClinicalTrials.gov, last updated 2026-11-09.
Sponsored by National Human Genome Research Institute (NHGRI) · Observational
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 "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:
Eligibility:
Design:
Participants in this study will have at least one and in some cases several of the following procedures:
We aim to use genome scale medical sequencing (GSMS, to include exome and 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.
387 studies on the registry are indexed under Intellectual Disability; 105 are open to participants now.
This study's planned enrollment of 2,000 is above the median of 150 across 125 observational studies indexed under Intellectual Disability.
Browse Intellectual Disability studies →National Human Genome Research Institute (NHGRI) is the lead sponsor of 203 studies on the registry; 33 are open to participants now.
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Patients or family probands with genetic cause of disorders that are intractable or difficult to identify with existing technique.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
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. For individuals less than 2 years of age, per NIHCC policy we do not generally admit them and limit our evaluations to outpatient evaluations of generally healthy infants and toddlers. In rare instances, we may accept DNA from deceased individuals, in accordance with Policy 400.
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.
Patients or family probands with genetic cause of disorders that are intractable or difficult to identify with existing technique.
Analyze GSMS results for rare disorders for which genetic causes are known but not fully described
We aim to sequence penetrant cases to study the molecular variations of rare genetic disorders, to better predict pathogenicity and identify new causative variants.
Time frame: Ongoing
Molecular etiology of rare diseases
Identify the genetic cause of disorders that are intractable or difficult to identify with existing techniques, for example, disorders due to new mutations with poor reproductive fitness, through exome or genome sequencing.
Time frame: Ongoing
Plan to share: No
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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