Genetic and Clinical Studies of Congenital Anomaly Syndromes
We aim to delineate the range of severity, natural history, molecular etiology, and
pathophysiology of Pallister-Hall syndrome (PHS), Greig cephalopolysyndactyly syndrome
(GCPS), McKusick-Kaufman syndrome (MKS), Bardet-Biedl syndrome (BBS), Oro-facial digital
syndromes (OFDs), and other overlapping phenotypes. These disorders comprise a syndrome
community of overlapping manifestations and we hypothesize that this is a reflection of a
common mechanistic pathway. This hypothesis be addressed by a combined clinical-molecular
approach where we bring up to 50-100 patients with each disorder to the NIH clinical center
for a comprehensive clinical evaluation with follow-up at a frequency appropriate to the
disorder. Specimens will be collected and evaluated in the laboratory by linkage analysis,
physical mapping, candidate gene characterization, mutation screening, and cell biologic
studies of normal mutant proteins.
We aim to use the power of modern molecular genetics and clinical research to delineate the
range of severity, natural history, molecular etiology, and pathophysiology of a number of
congenital anomaly syndromes. The goal of the research is to develop a knowledge base that
allows proper clinical and molecular diagnosis of patients with rare congenital anomaly
disorders. Our paradigm is the previous work we have done with Pallister-Hall syndrome (PHS)
and Greig cephalopolysyndactyly syndrome (GCPS), where we have successfully used a combined
clinical-molecular approach. Using this strategy, we have brought 50-100 patients or
families with these disorders to the NIH clinical center (NIH CC) for a comprehensive
clinical evaluation with follow-up at a frequency appropriate to the disorder. We have also
clinically and/or molecularly evaluated many additional patients with atypical or
non-classic presentations of PHS and GCPS and have conducted exploratory studies of other
phenotypes to determine how they might fit into the more general models generated to explain
PHS and GCPS. We are currently generalizing this approach to a number of disorders including
talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena
cava (TARP) syndrome. Specimens from patients participating in both the laboratory and
clinical arms of the protocol will be collected and evaluated in the laboratory by linkage
analysis, physical mapping, candidate gene characterization, mutation screening and targeted
exome sequencing, and cell biologic studies of normal and mutant proteins.
Study Type †
Study Design †
Primary Outcome Measure †
Secondary Outcome Measure †
Study Arms / Comparison Groups
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Status †
Estimated Enrollment †
Start Date †
August 18, 1994
January 7, 2016
Primary Completion Date
Eligibility Criteria †
- INCLUSION CRITERIA:
Subjects with clinical manifestations of a congenital anomaly or craniofacial syndrome, or
a single congenital anomaly that is also seen as part of a congenital anomaly syndrome
will be considered eligible for participation in this protocol.
Blood will also be requested on unaffected relatives that could be informative for linkage
studies or for determining co-segregation of mutations within families. Subjects of either
gender and all ethnic and racial groups will be accepted.
Prenatal specimens (amniocentesis or CVS) will be accepted if they are previously acquired
for clinically indicated reasons. Cord blood or placenta specimens may be accepted if they
(or a part of them) are not needed for clinical purposes.
Specimens from patients collected at outside institutions may be accepted into the study
if they were collected under an IRB-approved protocol at an MPA or FWA institution.
Coded specimens (specimens linked to identifiers but without personal identifiers attached
to the sample) may be acquired from other NIH investigators, analyzed, and returned as
research results to that investigator.
Patients with typical GCPS or PHS who have demonstrated GLI3 mutations may be excluded
from this study. Patients with phenotypes and disorders with a high risk/benefit ratio
such as late-onset, neurodegenerative, psychiatric, and cancer-predisposition disorders
will be excluded from participation. Similarly, patients who are medically fragile or
unable to tolerate travel to the NIH CC will not routinely be eligible for participation.
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.
N/A - N/A
Accepts Healthy Volunteers
Location Countries †
NCT ID †
Secondary IDs ††
Study Sponsor †
National Human Genome Research Institute (NHGRI)
Principal Investigator: Leslie G Biesecker, M.D., National Human Genome Research Institute (NHGRI)
Information Provided By
January 7, 2016
First Received Date †
November 3, 1999
Last Updated Date
April 19, 2017
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.