Evaluation of a novel electronic genetic screening and clinical decision support tool in prenatal clinical settings.

"The Pregnancy and Health Profile" (PHP) is a free prenatal genetic screening and clinical decision support (CDS) software tool for prenatal providers. PHP collects family health history (FHH) during intake and provides point-of-care risk assessment for providers and education for patients. This pilot study evaluated patient and provider responses to PHP and effects of using PHP in practice. PHP was implemented in four clinics. Surveys assessed provider confidence and knowledge and patient and provider satisfaction with PHP. Data on the implementation process were obtained through semi-structured interviews with administrators. Quantitative survey data were analyzed using Chi square test, Fisher's exact test, paired t tests, and multivariate logistic regression. Open-ended survey questions and interviews were analyzed using qualitative thematic analysis. Of the 83% (513/618) of patients that provided feedback, 97% felt PHP was easy to use and 98% easy to understand. Thirty percent (21/71) of participating physicians completed both pre- and post-implementation feedback surveys [13 obstetricians (OBs) and 8 family medicine physicians (FPs)]. Confidence in managing genetic risks significantly improved for OBs on 2/6 measures (p values ≤0.001) but not for FPs. Physician knowledge did not significantly change. Providers reported value in added patient engagement and reported mixed feedback about the CDS report. We identified key steps, resources, and staff support required to implement PHP in a clinical setting. To our knowledge, this study is the first to report on the integration of patient-completed, electronically captured and CDS-enabled FHH software into primary prenatal practice. PHP is acceptable to patients and providers. Key to successful implementation in the future will be customization options and interoperability with electronic health records.

2q24 deletions: further characterization of clinical findings and their relation to the SCN cluster.

As the resolution of molecular cytogenetic methods continues to improve, it has become increasingly possible to refine genotype-phenotype correlations based upon gene involvement. We report three new patients with nonrecurrent deletions involving subbands of 2q24. These patients were referred for evaluation of developmental delay, but were found to have unique, nonoverlapping clinical features. Patient 1 presented with infantile seizures, microcephaly, and brain anomalies, along with facial dysmorphism, growth retardation, neuromuscular scoliosis, and later with developmental regression. Array comparative genomic hybridization (aCGH) detected an 8 Mb interstitial deletion encompassing the neuronal sodium channel (SCN) gene cluster. Patient 2 presented with growth retardation, congenital heart defect, and hypotonia. Patient 3 presented with developmental delay and behavioral problems. Patients 2 and 3 had no history of seizures, microcephaly, or brain anomalies and were found to have deletions of 2q24, ∼8 Mb and <500 kb respectively, centromeric to and outside the SCN cluster. It has been demonstrated that mutations and copy number variants (CNVs) affecting the SCN gene cluster result in severe, early-onset seizures. It is however, less clear whether haploinsufficiency of regions outside the SCN cluster may result in phenotypically recognizable and clinically significant features. We discuss additional dosage sensitive genes that may exist outside the SCN cluster. Our and published data indicate that 2q24 deletions not involving the SCN cluster are associated with fewer neurobehavioral problems, but may predispose to congenital malformations.

Characterization of new ACADSB gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening.

Short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency, also known as 2-methylbutyryl-CoA dehydrogenase deficiency, is a recently described autosomal recessive disorder of isoleucine metabolism. Most patients reported thus far have originated from a founder mutation in the Hmong Chinese population. While the first reported patients had severe disease, most of the affected Hmong have remained asymptomatic. In this study, we describe 11 asymptomatic non-Hmong patients brought to medical attention by elevated C5-carnitine found by newborn screening and one discovered because of clinical symptoms. The diagnosis of SBCAD deficiency was determined by metabolite analysis of blood, urine, and fibroblast samples. PCR and bidirectional sequencing were performed on genomic DNA from five of the patients covering the entire SBCAD (ACADSB) gene sequence of 11 exons. Sequence analysis of genomic DNA from each patient identified variations in the SBCAD gene not previously reported. Escherichia coli expression studies revealed that the missense mutations identified lead to inactivation or instability of the mutant SBCAD enzymes. These findings confirm that SBCAD deficiency can be identified through newborn screening by acylcarnitine analysis. Our patients have been well without treatment and call for careful follow-up studies to learn the true clinical impact of this disorder.

High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide array CGH.

Ornithine transcarbamylase (OTC) deficiency is an X-linked inborn error of metabolism characterized by impaired synthesis of citrulline from carbamylphosphate and ornithine. Previously reported data suggest that only approximately 80% of OTC deficiency (OTCD) patients have a mutation identified by OTC gene sequencing. To elucidate the molecular etiology in patients with clinical signs of OTCD and negative OTC sequencing, we subjected their DNA to array comparative genomic hybridization (aCGH) using a custom-designed targeted 44k oligonucleotide array. Whenever possible, parental DNA was analyzed to determine the inheritance or to rule out copy number variants in the OTC locus. DNA samples from a total of 70 OTCD patients were analyzed. Forty-three patients (43/70 or 61.5%) were found to have disease-causing point mutations in the OTC gene. The remaining 27 patients (27/70 or 38.5%) showed normal sequencing results or failure to amplify all or part of the OTC gene. Among those patients, eleven (11/70 or 15.7%) were found to have deletions ranging from 4.5kb to 10.6Mb, all involving the OTC gene. Sixteen OTCD patients (16/70 or 22.8%) had normal sequencing and oligoarray results. Analysis of the deletions did not reveal shared breakpoints, suggesting that non-homologous end joining or a replication-based mechanism might be responsible for the formation of the observed rearrangements. In summary, we demonstrate that approximately half of the patients with negative OTC sequencing may have OTC gene deletions readily identifiable by the targeted oligonucleotide-based aCGH. Thus, the test should be considered in OTC sequencing-negative patients with classic symptoms of the disease.

Neonatal vitamin B12 deficiency secondary to maternal subclinical pernicious anemia: identification by expanded newborn screening.

A neonate with elevated propionylcarnitine on the newborn screen was found to have methylmalonic acidemia due to vitamin B(12) deficiency. The mother was also vitamin B(12)-deficient. This case illustrates the utility of expanded newborn screening for detection of vitamin B(12) deficiency, allowing prompt treatment and prevention of potential sequelae.

Case Definitions for Conditions Identified by Newborn Screening Public Health Surveillance.

Newborn screening (NBS) identifies infants with rare conditions to prevent death or the onset of irreversible morbidities. Conditions on the Health and Human Services Secretary's Recommended Uniform Screening Panel have been adopted by most state NBS programs, providing a consistent approach for identification of affected newborns across the United States. Screen-positive newborns are identified and referred for confirmatory diagnosis and follow-up. The designation of a clinically significant phenotype precursor to a clinical diagnosis may vary between clinical specialists, resulting in diagnostic variation. Determination of disease burden and birth prevalence of the screened conditions by public health tracking is made challenging by these variations. This report describes the development of a core group of new case definitions, along with implications, plans for their use, and links to the definitions that were developed by panels of clinical experts. These definitions have been developed through an iterative process and are piloted in NBS programs. Consensus public health surveillance case definitions for newborn screened disorders will allow for consistent categorization and tracking of short- and long-term follow-up of identified newborns at the local, regional, and national levels.

The influence of maternal disease on metabolites measured as part of newborn screening.

OBJECTIVE: Measurements of neonatal metabolites are commonly used in newborn screening (NBS) programs to detect inborn errors of metabolism. Variation in these metabolites, particularly in infants born preterm (<37 weeks gestation), can result from multiple etiologies. We sought to evaluate the impact of maternal complications of pregnancy and environmental stressors on NBS metabolites. METHODS: We examined 49 metabolic biomarkers obtained from routine NBS in 452 infants born preterm for association with maternal environmental stressors and complications of pregnancy. RESULTS: Neonatal free carnitine (C0, p = 1.4 × 10(-7)), acetylcarnitine (C2, p = 2.7 × 10(-7)), octenoylcarnitine (C8:1, p = 5.2 × 10(-11)) and linoleoylcarnitine (C18:2, p = 9.1 × 10(-7)) were elevated in infants born to preeclamptic mothers. Similar elevations were observed in small for gestational age infants and in infants where labor was not initiated prior to delivery. When accounting for all three factors, associations remained strongest between acylcarnitines and preeclampsia. CONCLUSION: We observed that maternal conditions, particularly preeclampsia, influence NBS biomarkers. This is important for identifying maternal conditions that influence metabolites measured during routine NBS that are also markers of fetal growth and overall health.

Standardizing newborn screening results for health information exchange.

Newborn screening (NBS) is a complex process that has high-stakes health implications and requires rapid and effective communication between many people and organizations. Currently, each NBS laboratory has its own method of reporting results to state programs, hospitals and individual providers, with wide variation in content and format. Pediatric care providers receive reports by mail, email, fax or telephone, depending on whether the results are normal or abnormal. This process is slow and prone to errors, which can lead to delays in treatment. Multiple agencies worked together to create national guidance for reporting newborn screening results with HL7 messages that contain a prescribed set of LOINC and SNOMED CT codes, report quantitative test results, and use standardized units of measure. Several states are already implementing this guidance. If the guidance is used nationally, office EHRs could capture NBS results more efficiently, and regional and national registries could better analyze aggregate results to facilitate improvements in NBS and further research for these rare conditions.

A review of newborn screening in the era of tandem mass spectrometry: what's new for the pediatric neurologist?

Newborn screening has evolved from a single test for a single metabolite to a test that detects more than 90 metabolites on a single blood spot. In the past decade, the panel of newborn-screening disorders has rapidly expanded and will continue to grow as more is discovered about the human genome. It continues to be a very sensitive population screening tool that is susceptible to the status of the infant and the timing of the specimen collection. This review discusses the disorders that should be detected on neonatal bloodspot screening and what pediatric neurologists may see in those that were detected on newborn screening and treated and those that have been untreated.

Feeding and swallowing dysfunction in genetic syndromes.

Children with genetic syndromes frequently have feeding problems and swallowing dysfunction as a result of the complex interactions between anatomical, medical, physiological, and behavioral factors. Feeding problems associated with genetic disorders may also cause feeding to be unpleasant, negative, or even painful because of choking, coughing, gagging, fatigue, or emesis, resulting in the child to stop eating and to develop behaviors that make it difficult, if not impossible, for a parent to feed their child. In addition, limited experiences with oral intake related to the medical or physical conditions, or other variables such as prematurity, often result in a failure of the child's oral motor skills to develop normally. For example, a child with Pierre Robin sequence may be unable to successfully feed orally, initially, due to micrognathia and glossoptosis. Oral-motor dysfunction may develop as a result of both anatomical problems, (e.g., cleft lip/palate), lack of experience (e.g., s/p. surgery), or oral motor abnormalities (e.g., brain malformation). Neuromotor coordination impairments such as those associated with Down syndrome (e.g., hypotonia, poor tongue control, and open mouth posture) frequently interfere with the acquisition of effective oral-motor skills and lead to feeding difficulties. Management of these phenomena is frequently possible, if an appropriate feeding plan exist that allows for three primary factors: (1) feeding program must be safe, (2) feeding program must support optimal growth, and (3) feeding program must be realistic. Researchers have demonstrated the utility of behavioral approaches in the treatment of feeding disorders, such as manipulations in the presentation of foods and drink and consequences for food refusal and acceptance (e.g., praise, extinction, contingent access to preferred foods). However, because a child's failure to eat is not frequently the result of a single cause, evaluation and treatment are typically conducted by an interdisciplinary team usually consisting of a behavioral psychologist, pediatric gastroenterologist, speech pathologist, nutrition, and sometimes other disciplines. This chapter provides an overview of some of the feeding difficulties experience by some of the more common genetic disorders including identification, interventions, and management.