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Biomedical subjects

Roberta A Pagon

Publications and source records attributed to Roberta A Pagon.

8 recordsLinked to original sources
PubMed2006

GeneTests: an online genetic information resource for health care providers.

OBJECTIVE: This paper describes the GeneTests genetic testing information resource with a focus on the GeneReviews component. METHODS AND FINDINGS: The need for authoritative genetic testing information and issues in the development and maintenance of GeneReviews are discussed: Hampered by lack of currency and content deficits, traditional medical information resources such as textbooks and the published literature are generally inadequate sources of genetic testing information. Problems encountered in developing GeneReviews include the evolution of new authorship models and academic and genetics professionals' skepticism about the quality of Web-based publications. CONCLUSIONS: GeneTests is an authoritative, highly used, and well-regarded resource in the international medical community that is intended for health care providers. Future development issues to address include ways to (1) manage the increasing editing and updating load as content grows and (2) address technical and content issues that need to be considered in displaying GeneReviews as a "just in time" resource in the electronic medical record to achieve the project goal of integrating appropriate use of genetic testing into patient care.

Authorship↗
PubMed2005

Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

Abnormalities, Multiple↗
PubMed2004

Molecular genetic testing for inherited disorders.

This review focuses on molecular genetic testing for heritable disorders. Molecular genetic testing has generated tremendous interest because of the scientific and social hype surrounding the Human Genome Project, the accelerating rate of gene discovery, the quick transition of scientific discoveries into clinically applicable genetic tests and the unique nonmedical applications of genetic testing. All of these developments have been superimposed upon increasing individual autonomy in medical care and the pervasive information-seeking behavior of the Information Age.

DNA Mutational Analysis↗
PubMed2003

Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia.

Campomelic dysplasia (CD) is a semilethal osteochondrodysplasia, characterized by skeletal anomalies that include bending of the long bones, and by XY sex reversal. CD results from haploinsufficiency for the transcription factor SOX9, a key regulator at various steps of cartilage differentiation and of early testis development. Two functional domains are so far recognized for SOX9, a high-mobility group (HMG) DNA-binding domain and a C-terminal transactivation domain. We present two CD patients with de novo mutations in a conserved region preceding the HMG domain. A long-term survivor with the acampomelic form of CD has an A76E amino acid substitution, while a severely affected CD patient had an in-frame deletion of amino acid residues 66-75. The conserved domain has been shown to function in the related transcription factor SOX10 as a DNA-dependent dimerization domain. We show that, like SOX10, SOX9 also binds cooperatively as a dimer to response elements in regulatory regions of some target genes such as the cartilage genes Col11a2 and CD-Rap. Dimerization and the resulting capacity to activate promoters via dimeric binding sites is lost in both mutant SOX9 proteins while other features involved in SOX9 function remained unaltered. These findings establish the dimerization domain as the third domain essential for SOX9 function during chondrogenesis.

Amino Acid Sequence↗
PubMed2002

Micropenis with testicular regression, low LH levels, and poor androgen and HCG responses: a distinct syndrome?

We report three boys, including two brothers, with micropenis and poor phallic growth in response to both exogenous human chorionic gonadotropin (HCG) and testosterone therapy in the newborn period. They exhibited low neonatal testosterone levels that failed to respond to HCG stimulation. These boys displayed a unique gonadotropin profile with reduced luteinizing hormone levels and elevated follicle-stimulating hormone levels. They had small, cryptorchid testes with subsequent testicular regression and atrophy. Moreover, all three boys have developed microcephaly and mild learning delays. We review the hormonal profiles and phenotypes of known causes of micropenis, and compare them to the features of our three patients. Although individuals with similar features may have been described in past series of males with micropenis, the data presented previously were insufficient for classification; thus, we propose that our patients may represent a distinct, not previously recognized, syndrome with either X-linked recessive inheritance or autosomal recessive inheritance with male sex limitation.

Abnormalities, Multiple↗
PubMed2002

GeneTests-GeneClinics: genetic testing information for a growing audience.

The development and usage of two companion NIH-funded genetic testing information databases, GeneTests (www.genetests.org) and GeneClinics (www.geneclinics.org), now merged into one web site, reflect the steadily increasing use of genetic testing and the expanding audience for genetic testing information. Established in 1993 as Helix, a genetics laboratory directory of approximately 110 listings, GeneTests has grown into a database of over 900 tests for inherited diseases, a directory of over 500 international laboratories, a directory of over 1,000 U.S. and international genetics clinics, and a resource for educational/teaching materials and reports of summary genetic test data. GeneClinics, founded in 1997 as an expert-authored, peer-reviewed, disease-specific knowledge base relating genetic testing to patient care, has grown steadily, now containing over 130 expert-authored, peer-reviewed full-text entries relating genetic testing information to diagnosis, management, and genetic counseling of specific inherited diseases. In spring 2001 the two databases were merged and in October 2001 the two web sites were merged for the purpose of seamless navigation into the GeneTests-GeneClinics site (www.genetests.org or www.geneclinics.org); the GeneClinics knowledge base was renamed "GeneReviews" to avoid confusion with the U.S. and international clinic directories. As genetic testing has moved steadily out of research venues and into routine medical practice, the user audience for these databases has become international and expansive and includes healthcare providers, patients, educators, policy makers, and the media. The use of these combined resources has grown to approximately 3,200 visits/day.

Databases, Genetic↗
PubMed2002

Genetic testing for disease susceptibilities: consequences for genetic counseling.

The role of genetic counseling in future testing for inherited susceptibilities for common diseases is debated. Currently, genetic testing, ideally supported by genetic counseling, is most often used to modify the assessment of genetic risk of Mendelian-inherited disease in high-risk individuals for the purpose of personal decision-making. By contrast, it is anticipated that genetic testing will be used to identify increased disease susceptibility in low-risk individuals for the purpose of instituting medical or lifestyle interventions to modify risk for future disease.

Genetic Counseling↗