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Genetic and Clinical Studies of Congenital Anomaly Syndromes

Open (Enrolling)
Malformations, Multiple Abnormalies, Polydactyly

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Trial Information

Genetic and Clinical Studies of Congenital Anomaly Syndromes

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.

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.

Type of Study:


Study Design:


Principal Investigator

Leslie G Biesecker, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Human Genome Research Institute (NHGRI)


United States: Federal Government

Study ID:




Start Date:

August 1994

Completion Date:

Related Keywords:

  • Malformations
  • Multiple Abnormalies
  • Polydactyly
  • Abnormalities, Multiple
  • Hypothalamic Hamartoma
  • Polysyndactyly
  • Autosomal Dominant
  • Mutation
  • Gelastic
  • Gelastic Seizure
  • Hypothalamic
  • Malformations
  • Polydactyly
  • Pallister-Hall Syndrome
  • Congenital Abnormalities
  • Polydactyly
  • Pallister-Hall Syndrome



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892
Cedars Sinai Medical Center Los Angeles, California  90048-1804
Greenwood Genetics Center Greenwood, South Carolina  29646