Clinical genomic database.

Technological advances have greatly increased the availability of human genomic sequencing. However, the capacity to analyze genomic data in a clinically meaningful way lags behind the ability to generate such data. To help address this obstacle, we reviewed all conditions with genetic causes and constructed the Clinical Genomic Database (CGD) (http://research.nhgri.nih.gov/CGD/), a searchable, freely Web-accessible database of conditions based on the clinical utility of genetic diagnosis and the availability of specific medical interventions. The CGD currently includes a total of 2,616 genes organized clinically by affected organ systems and interventions (including preventive measures, disease surveillance, and medical or surgical interventions) that could be reasonably warranted by the identification of pathogenic mutations. To aid independent analysis and optimize new data incorporation, the CGD also includes all genetic conditions for which genetic knowledge may affect the selection of supportive care, informed medical decision-making, prognostic considerations, reproductive decisions, and allow avoidance of unnecessary testing, but for which specific interventions are not otherwise currently available. For each entry, the CGD includes the gene symbol, conditions, allelic conditions, clinical categorization (for both manifestations and interventions), mode of inheritance, affected age group, description of interventions/rationale, links to other complementary databases, including databases of variants and presumed pathogenic mutations, and links to PubMed references (>20,000). The CGD will be regularly maintained and updated to keep pace with scientific discovery. Further content-based expert opinions are actively solicited. Eventually, the CGD may assist the rapid curation of individual genomes as part of active medical care.

Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly.

BACKGROUND: Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly. OBJECTIVE: To characterise the genotypic and phenotypic findings in individuals with GLI2 variants and clarify clinical findings in individuals with loss-of-function mutations. METHODS: Through the National Institutes of Health and collaborating centres, ∼400 individuals with HPE spectrum disorders, endocrine disorders or craniofacial anomalies were screened for GLI2 mutations. Results were combined with all published cases. We compared the clinical and molecular features of individuals with truncating mutations to individuals with variants of unknown significance (defined as not resulting in protein truncation, reported in normal controls and/or deemed unlikely to be pathogenic by functional prediction software). RESULTS: 112 individuals with variants in GLI2 were identified, with 43 having truncating mutations. Individuals with truncating mutations were more likely to have both pituitary anomalies and polydactyly versus those with variants of unknown significance (p<0.0001 by Fisher's exact test); only 1 of 43 had frank HPE. These individuals were more likely to have recognised penetrance (polydactyly or pituitary anomalies or both) than those without truncating mutations (p=0.0036 by Fisher's exact test). A common facial phenotype was seen in individuals (with midface hypoplasia, cleft lip/palate and hypotelorism) with truncating mutations. CONCLUSIONS: Individuals with truncating mutations in GLI2 typically present with pituitary anomalies, polydactyly and subtle facial features rather than HPE. This will be helpful in screening populations for GLI2 mutations and for counselling affected patients. TRIAL REGISTRATION: 98-HG-0249/04-HG-0093.

Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.

BACKGROUND: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. OBJECTIVE: To characterise genetic and clinical findings in individuals with SHH mutations. METHODS: Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. RESULTS: This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype-phenotype correlations could be established regarding mutation location. CONCLUSIONS: SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.

Clinical geneticists' views of VACTERL/VATER association.

VACTERL association (sometimes termed "VATER association" depending on which component features are included) is typically defined by the presence of at least three of the following congenital malformations, which tend to statistically co-occur in affected individuals: Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities. Although the clinical criteria for VACTERL association may appear to be straightforward, there is wide variability in the way clinical geneticists define the disorder and the genetic testing strategy they use when confronted with an affected patient. In order to describe this variability and determine the most commonly used definitions and testing modalities, we present the results of survey responses by 121 clinical geneticists. We discuss the results of the survey responses, provide a literature review and commentary from a group of physicians who are currently involved in clinical and laboratory-based research on VACTERL association, and offer an algorithm for genetic testing in patients with this association.

Fingertip ultrasound evaluation of umbilical catheter position in the neonatal intensive care unit compared to conventional ultrasound radiography: a preliminary investigation.

OBJECTIVE: The purpose of the study is to compare conventional linear and fingertip ultrasound transducers, for the evaluation of umbilical catheters, with radiography. Fingertip ultrasound transducers have the potential to simplify sonographic examination due to their small size and ability to fit on a finger. STUDY DESIGN: A prospective, IRB approved comparative study was performed. Linear and fingertip sonographic images were obtained around the same time as a radiograph in neonates with umbilical catheters by two board certified pediatric radiologists and a radiology resident. The positions of catheters were then compared across all three modalities. RESULT: A total of 41 catheters were evaluated, which included 14 arterial and 27 venous catheters. Two venous catheters were not identified by the linear transducer and one arterial catheter tip was not identified by the fingertip transducer. CONCLUSION: A fingertip ultrasound probe can be used to evaluate umbilical catheter positioning for potentially faster sonographic examination and decrease the need for repeated radiation.

Disparities exist in the availability of outpatient malaria treatment in Maryland, USA.

BACKGROUND: Prior review of pediatric malaria cases in the Washington, DC area raised concern that there may be systematic barriers to the timely procurement of antimalarial medications for those patients being treated for malaria as outpatients. We hypothesized that the local availability of antimalarial medications was not consistent across communities of differing socioeconomic status. METHODS: We administered a blinded telephone questionnaire to pharmacists in the Maryland suburbs of Washington, DC and assessed the in-stock availability of antimalarial medication. Pharmacies were stratified into categories of population risk, disease incidence, and income. RESULTS: Pharmacies in high-income ZIP codes were more likely to stock first-line therapy medications (93%, p = 0.03) than pharmacies in moderate-income, low-incidence, low-risk ZIP codes (50%). Moderate-income ZIP codes with high-malaria incidence and a high-risk population (67%, p = 0.35) were no more likely to stock first-line antimalarial medications than pharmacies in moderate-income, low-incidence, low-risk areas (50%). In all, only four (9%) pharmacies stocked quinine. Many pharmacists stated the reason for this discrepancy was that they believed the Food and Drug Administration (FDA) had "pulled quinine off the market." CONCLUSIONS: In the United States, disparities exist in the availability of outpatient-antimalarial medications. We recommend that a complete outpatient treatment course is dispensed, or the availability of the medication at the pharmacy that the patient will use is verified prior to departure from the clinic or emergency department. Pharmacists and physicians should be aware that the FDA restrictions on the use of quinine sulfate do not apply to its use for the treatment of malaria.