Publications by authors named "Cynthia Powell"

85 Publications

Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study.

JAMA Pediatr 2021 Feb 15:e205906. Epub 2021 Feb 15.

Department of Pediatrics, The Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts.

Importance: A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing.

Objective: To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy.

Design, Setting, And Participants: The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020.

Interventions: Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results.

Main Outcomes And Measures: Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing.

Results: Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes.

Conclusions And Relevance: As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.
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http://dx.doi.org/10.1001/jamapediatrics.2020.5906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885094PMC
February 2021

Outreach to new mothers through direct mail and email: recruitment in the Early Check research study.

Clin Transl Sci 2020 Dec 31. Epub 2020 Dec 31.

RTI International, Research Triangle Park, North Carolina, USA.

Meeting recruitment targets for clinical trials and health research studies is a notable challenge. Unsuccessful efforts to recruit participants from traditionally underserved populations can limit who benefits from scientific discovery, thus perpetuating inequities in health outcomes and access to care. In this study, we evaluated direct mail and email outreach campaigns designed to recruit women who gave birth in North Carolina for a statewide research study offering expanded newborn screening for a panel of rare health conditions. Of the 54,887 women who gave birth in North Carolina from September 28, 2018, through March 19, 2019, and were eligible to be included on the study's contact lists, we had access to a mailing address for 97.9% and an email address for 6.3%. Rural women were less likely to have sufficient contact information available, but this amounted to less than a one percentage point difference by urbanicity. Native American women were less likely to have an email address on record; however, we did not find a similar disparity when recruitment using direct-mail letters and postcards was concerned. Although we sent letters and emails in roughly equal proportion by urbanicity and race/ethnicity, we found significant differences in enrollment across demographic subgroups. Controlling for race/ethnicity and urbanicity, we found that direct-mail letters and emails were effective recruitment methods. The enrollment rate among women who were sent a recruitment letter was 4.1%, and this rate increased to 5.0% among women who were also sent an email invitation.
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http://dx.doi.org/10.1111/cts.12950DOI Listing
December 2020

Newborn Screening and Long-term Outcomes.

Authors:
Cynthia M Powell

Pediatrics 2020 11 13;146(5). Epub 2020 Oct 13.

Division of Genetics and Metabolism, Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

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http://dx.doi.org/10.1542/peds.2020-023663DOI Listing
November 2020

Mindful Mentors: Is a Longitudinal Mind-Body Skills Training Pilot Program Feasible for Pediatric Cardiology Staff?

Glob Adv Health Med 2020 22;9:2164956120959272. Epub 2020 Sep 22.

Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio.

Background: Stress and burnout among medical professionals are common and costly, placing professionals, organizations, and patients at risk.

Objectives: To determine feasibility and acceptability of a longitudinal mind-body skills training initiative to help staff decrease stress and burnout, improve well-being, and empower them to utilize basic mindfulness methods with coworkers, patients, and families.

Methods: Prospective cohort, mixed methods approach. Nurses, doctors, technicians, social workers, child life specialists were eligible to participate. The 12-month curriculum consisted of 16 hours of intensive education/practice over 2 days, with training in mindfulness skills, self-compassion, nonviolent communication, overcoming barriers to practice, and mindful listening/speaking, followed by monthly 1 hour booster/debriefing sessions.

Results: A total of 37 staff participated (RN = 18, MD = 5, Technician = 6, Social Worker = 3, Child life = 3, others = 2) in the initial training, and 24 (65%) completed the 3- and 12-month follow-up surveys. Compared with pretraining scores, there were significant improvements 3 to 12 months after the initial training in stress ( < .0001), distress ( ≤ .04), anxiety ( = .01), self-efficacy in providing non-drug therapies ( < .0001), mindfulness ( = .002), burnout ( < .0001), and confidence in providing compassionate care ( < .0001). In addition, 25 (67%) participants initiated projects incorporating what they learned into staff/patient wellness activities.

Conclusion: This longitudinal pilot program was feasible and was associated with improvements in measures of psychological well-being over the 12-month intervention. The innovative approach of training participants to teach basic techniques to coworkers and other staff can increase the impact of this program beyond any individual participant. Future research will investigate the aspects of implementation and potential effects on patient care and experience.
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http://dx.doi.org/10.1177/2164956120959272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513397PMC
September 2020

Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project.

Am J Hum Genet 2020 10 26;107(4):596-611. Epub 2020 Aug 26.

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the participant's underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders and in 5 out of 28 (∼18%) children with hearing loss. We discovered actionable findings in four participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal-recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in two children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536575PMC
October 2020

Training the next generation of genomic medicine providers: trends in medical education and national assessment.

Genet Med 2020 Oct 18;22(10):1718-1722. Epub 2020 Jun 18.

Department of Human Genetics, University of Chicago, Chicago, IL, USA.

Purpose: To assess the utilization of genetics on the United States Medical Licensing Examination (USMLE®).

Methods: A team of clinical genetics educators performed an analysis of the representation of genetics content on a robust sample of recent Step 1, Step 2 Clinical Knowledge (CK), and Step 3 examination forms. The content of each question was mapped to curriculum recommendations from the peer reviewed Association of Professors of Human and Medical Genetics white paper, Medical School Core Curriculum in Genetics, and the USMLE Content Outline.

Results: The committee identified 13.4%, 10.4%, and 4.4% of Steps 1, 2 and 3 respectively, as having genetics content. The genetics content of the exams became less pertinent to the questions from Step 1 to 3, with decreasing genetics content by exam and increasing percentages of questions identified as having genetics content in the distractors only.

Conclusion: The current distribution of genetics in USMLE licensing examinations reflects traditional curricular approaches with genetics as a basic science course in the early years of medical school and de-emphasizes clinical relevance of the field. These observations support the notion that further integration is required to move genetics into the clinical curriculum of medical schools and the clinical content of USMLE Step exams.
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http://dx.doi.org/10.1038/s41436-020-0855-9DOI Listing
October 2020

Correction: An approach to integrating exome sequencing for fetal structural anomalies into clinical practice.

Genet Med 2020 Aug;22(8):1426

Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-020-0870-xDOI Listing
August 2020

Parental Views on Newborn Next Generation Sequencing: Implications for Decision Support.

Matern Child Health J 2020 Jul;24(7):856-864

Center for Communication Science, RTI International, 3040 E. Cornwallis Road, Research Triangle Park, NC, 27709-2194, USA.

Objective: This study aimed to understand parental decisions, perspectives, values, and beliefs on next generation sequencing in the newborn period (NGS-NBS) to inform the development of a decision aid to support parental decision making in the North Carolina Newborn Exome Sequencing for Universal Screening study.

Methods: We conducted dyadic interviews with 66 current or expectant parents (33 couples) to understand overall decisions about NGS-NBS and reasons for and against learning NGS-NBS results differing by age of onset and medical actionability. Audio recordings were transcribed, coded, and analyzed using qualitative framework analyses.

Results: Favorable views of NGS-NBS included benefits of early intervention, preparedness, child autonomy, and altruism. Unfavorable views were the potential negative effects from early intervention, psychosocial harm, and religious beliefs. Parents universally reported quality of life as important.

Conclusion: Interviews elucidated what is important in deciding to have NGS-NBS. Understanding parental perspectives, values, and beliefs and integrating evidence-based findings into a parent-centric decision aid provides value and support in making decisions related to NGS-NBS, where there is no clear course of action.
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http://dx.doi.org/10.1007/s10995-020-02953-zDOI Listing
July 2020

Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities.

Am J Hum Genet 2020 02 30;106(2):246-255. Epub 2020 Jan 30.

Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany. Electronic address:

Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.
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http://dx.doi.org/10.1016/j.ajhg.2020.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010976PMC
February 2020

Evaluation of X-Linked Adrenoleukodystrophy Newborn Screening in North Carolina.

JAMA Netw Open 2020 01 3;3(1):e1920356. Epub 2020 Jan 3.

RTI International, Research Triangle Park, North Carolina.

Importance: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal genetic disorder in which an accumulation of very long-chain fatty acids leads to inflammatory demyelination in the central nervous system and to adrenal cortex atrophy. In 2016, X-ALD was added to the US Recommended Uniform Screening Panel.

Objective: To evaluate the performance of a single-tier newborn screening assay for X-ALD in North Carolina.

Design, Setting, And Participants: This diagnostic screening study was of all newborn dried blood spot specimens received in the North Carolina State Laboratory of Public Health between January 2 and June 1, 2018, excluding specimens of insufficient quantity or quality. A total of 52 301 specimens were screened for X-ALD using negative ionization high-performance liquid chromatography tandem mass spectrometry to measure C24:0- and C26:0-lysophosphatidylcholine concentrations. Sanger sequencing of the adenosine triphosphate-binding cassette subfamily D member 1 (ABCD1) gene was performed on screen-positive specimens.

Exposures: A medical and family history, newborn physical examination, sequencing of ABCD1 on dried blood spot samples, and plasma analysis of very long-chain fatty acids were obtained for all infants with screen-positive results.

Main Outcomes And Measures: The prevalence of X-ALD in North Carolina and the positive predictive value and false-positive rate for the first-tier assay were determined.

Results: Of 52 301 infants tested (47.8% female, 50.6% male, and 1.7% other or unknown sex), 12 received screen-positive results. Of these 12 infants, 8 were confirmed with a genetic disorder: 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, 1 female infant with a peroxisome biogenesis disorder, and 1 female infant with Aicardi-Goutières syndrome. Four infants were initially classified as having false-positives results, including 3 female infants who were deemed unaffected and 1 male infant with indeterminate results on confirmatory testing. The positive predictive value for X-ALD or other genetic disorders for the first-tier assay was 67%, with a false-positive rate of 0.0057%.

Conclusions And Relevance: This newborn screening pilot study reported results on 2 lysophosphatidylcholine analytes, identifying 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, and 3 infants with other disorders associated with increased very long-chain fatty acids. These results showed successful implementation in a public health program with minimal risk to the population. The findings will support other state laboratories planning to implement newborn screening for X-ALD and related disorders.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.20356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042889PMC
January 2020

An approach to integrating exome sequencing for fetal structural anomalies into clinical practice.

Genet Med 2020 05 24;22(5):954-961. Epub 2020 Jan 24.

Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Purpose: We investigated the diagnostic and clinical performance of trio exome sequencing (ES) in parent-fetus trios where the fetus had sonographic abnormalities but normal karyotype, microarray and, in some cases, normal gene-specific sequencing.

Methods: ES was performed from DNA of 102 anomalous fetuses and from peripheral blood from their parents. Parents provided consent for the return of diagnostic results in the fetus, medically actionable findings in the parents, and identification as carrier couple for significant autosomal recessive conditions.

Results: In 21/102 (20.6%) fetuses, ES provided a positive-definitive or positive-probable diagnosis. In 10/102 (9.8%), ES provided an inconclusive-possible result. At least 2/102 (2.0%) had a repeat pregnancy during the study period and used the information from the study for prenatal diagnosis in the next pregnancy. Six of 204 (2.9%) parents received medically actionable results that affected their own health and 3/102 (2.9%) of couples received results that they were carriers for the same autosomal recessive condition.

Conclusion: ES has diagnostic utility in a select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy, variant interpretation, and various types of diagnostic results affecting both fetal and parental health must be addressed by highly tailored pre- and post-test genetic counseling.
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http://dx.doi.org/10.1038/s41436-020-0750-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205580PMC
May 2020

Values clarification and parental decision making about newborn genomic sequencing.

Health Psychol 2020 Apr 30;39(4):335-344. Epub 2019 Dec 30.

Center for Communication Science.

Objective: Using an online decision aid developed to support parental decision making about newborn genomic sequencing, we tested whether adding a values clarification exercise to educational content would improve decision making outcomes and influence intention to pursue genomic sequencing. We also examined whether the effect of values clarification varied depending on one's health literacy level.

Method: In an online experiment, women and men aged 18 to 44 who were either pregnant or had a pregnant partner, were currently trying to get pregnant, or were preparing for a pregnancy within the next 2 years were randomly assigned to complete either a decision aid with educational information about newborn genomic sequencing or a decision aid with the same educational information and a values clarification exercise.

Results: Of the 1,000 participants who completed the decision aid, those who completed the values clarification exercise reported less decision regret, (1, 995) = 6.19, = .01, and were clearer about their personal values, (1, 995) = 6.39, = .01. Moderation analyses revealed that the benefit of values clarification on decisional conflict was particularly evident among participants with lower health literacy, = -3.94, = 1.67, = -2.36, = .018. There was not a significant moderation effect of health literacy and decision aid condition on decision regret.

Conclusions: Adding a values clarification exercise to decision aids for parents making decisions about genomic sequencing may improve the decision-making experience and provide some benefit to individuals with lower health literacy. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/hea0000829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078054PMC
April 2020

FDA oversight of NSIGHT genomic research: the need for an integrated systems approach to regulation.

NPJ Genom Med 2019 10;4:32. Epub 2019 Dec 10.

12Rady Children's Institute for Genomic Medicine, San Diego, CA 92123 USA.

The National Institutes of Health (NIH) funded the Newborn Sequencing In Genomic medicine and public HealTh (NSIGHT) Consortium to investigate the implications, challenges, and opportunities associated with the possible use of genomic sequence information in the newborn period. Following announcement of the NSIGHT awardees in 2013, the Food and Drug Administration (FDA) contacted investigators and requested that pre-submissions to investigational device exemptions (IDE) be submitted for the use of genomic sequencing under Title 21 of the Code of Federal Regulations (21 CFR) part 812. IDE regulation permits clinical investigation of medical devices that have not been approved by the FDA. To our knowledge, this marked the first time the FDA determined that NIH-funded clinical genomic research projects are subject to IDE regulation. Here, we review the history of and rationale behind FDA oversight of clinical research and the NSIGHT Consortium's experiences in navigating the IDE process. Overall, NSIGHT investigators found that FDA's application of existing IDE regulations and medical device definitions aligned imprecisely with the aims of publicly funded exploratory clinical research protocols. IDE risk assessments by the FDA were similar to, but distinct from, protocol risk assessments conducted by local Institutional Review Boards (IRBs), and had the potential to reflect novel oversight of emerging genomic technologies. However, the pre-IDE and IDE process delayed the start of NSIGHT research studies by an average of 10 months, and significantly limited the scope of investigation in two of the four NIH approved projects. Based on the experience of the NSIGHT Consortium, we conclude that policies and practices governing the development and use of novel genomic technologies in clinical research urgently need clarification in order to mitigate potentially conflicting or redundant oversight by IRBs, NIH, FDA, and state authorities.
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http://dx.doi.org/10.1038/s41525-019-0105-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904743PMC
December 2019

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1.

Authors:
Magdalena Koczkowska Tom Callens Yunjia Chen Alicia Gomes Alesha D Hicks Angela Sharp Eric Johns Kim Armfield Uhas Linlea Armstrong Katherine Armstrong Bosanko Dusica Babovic-Vuksanovic Laura Baker Donald G Basel Mario Bengala James T Bennett Chelsea Chambers Lola K Clarkson Maurizio Clementi Fanny M Cortés Mitch Cunningham M Daniela D'Agostino Martin B Delatycki Maria C Digilio Laura Dosa Silvia Esposito Stephanie Fox Mary-Louise Freckmann Christine Fauth Teresa Giugliano Sandra Giustini Allison Goetsch Yael Goldberg Robert S Greenwood Cristin Griffis Karen W Gripp Punita Gupta Eric Haan Rachel K Hachen Tamara L Haygarth Concepción Hernández-Chico Katelyn Hodge Robert J Hopkin Louanne Hudgins Sandra Janssens Kory Keller Geraldine Kelly-Mancuso Aaina Kochhar Bruce R Korf Andrea M Lewis Jan Liebelt Angie Lichty Robert H Listernick Michael J Lyons Isabelle Maystadt Mayra Martinez Ojeda Carey McDougall Lesley K McGregor Daniela Melis Nancy Mendelsohn Malgorzata J M Nowaczyk June Ortenberg Karin Panzer John G Pappas Mary Ella Pierpont Giulio Piluso Valentina Pinna Eniko K Pivnick Dinel A Pond Cynthia M Powell Caleb Rogers Noa Ruhrman Shahar S Lane Rutledge Veronica Saletti Sarah A Sandaradura Claudia Santoro Ulrich A Schatz Allison Schreiber Daryl A Scott Elizabeth A Sellars Ruth Sheffer Elizabeth Siqveland John M Slopis Rosemarie Smith Alberto Spalice David W Stockton Haley Streff Amy Theos Gail E Tomlinson Grace Tran Pamela L Trapane Eva Trevisson Nicole J Ullrich Jenneke Van den Ende Samantha A Schrier Vergano Stephanie E Wallace Michael F Wangler David D Weaver Kaleb H Yohay Elaine Zackai Jonathan Zonana Vickie Zurcher Kathleen B M Claes Marica Eoli Yolanda Martin Katharina Wimmer Alessandro De Luca Eric Legius Ludwine M Messiaen

Hum Mutat 2020 01 26;41(1):299-315. Epub 2019 Oct 26.

Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
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http://dx.doi.org/10.1002/humu.23929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973139PMC
January 2020

Early Check: translational science at the intersection of public health and newborn screening.

BMC Pediatr 2019 07 17;19(1):238. Epub 2019 Jul 17.

North Carolina State Laboratory of Public Health, Raleigh, NC, USA.

Background: Newborn screening (NBS) occupies a unique space at the intersection of translational science and public health. As the only truly population-based public health program in the United States, NBS offers the promise of making the successes of translational medicine available to every infant with a rare disorder that is difficult to diagnose clinically, but for which strong evidence indicates that presymptomatic treatment will substantially improve outcomes. Realistic NBS policy requires data, but rare disorders face a special challenge: Screening cannot be done without supportive data, but adequate data cannot be collected in the absence of large-scale screening. The magnitude and scale of research to provide this expanse of data require working with public health programs, but most do not have the resources or mandate to conduct research.

Methods: To address this gap, we have established Early Check, a research program in partnership with a state NBS program. Early Check provides the infrastructure needed to identify conditions for which there have been significant advances in treatment potential, but require a large-scale, population-based study to test benefits and risks, demonstrate feasibility, and inform NBS policy.

Discussion: Our goal is to prove the benefits of a program that can, when compared with current models, accelerate understanding of diseases and treatments, reduce the time needed to consider inclusion of appropriate conditions in the standard NBS panel, and accelerate future research on new NBS conditions, including clinical trials for investigational interventions.

Trial Registration: Clinicaltrials.gov registration # NCT03655223 . Registered on August 31, 2018.
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http://dx.doi.org/10.1186/s12887-019-1606-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636013PMC
July 2019

The North Carolina Experience with Mucopolysaccharidosis Type I Newborn Screening.

J Pediatr 2019 08 24;211:193-200.e2. Epub 2019 May 24.

University of North Carolina at Chapel Hill, Chapel Hill,NC.

Objective: To evaluate the performance of a 2-tiered newborn screening method for mucopolysaccharidosis type I (MPS I) in North Carolina.

Study Design: The screening algorithm included a flow injection analysis-tandem mass spectrometry assay as a first-tier screening method to measure α-L-iduronidase (IDUA) enzyme activity and Sanger sequencing of the IDUA gene on dried blood spots as a second-tier assay. The screening algorithm was revised to incorporate the Collaborative Laboratory Integrated Reports, an analytical interpretive tool, to reduce the false-positive rate. A medical history, physical examination, IDUA activity, and urinary glycosaminoglycan (GAG) analysis were obtained on all screen-positive infants.

Results: A total of 62 734 specimens were screened with 54 screen-positive samples using a cut-off of 15% of daily mean IDUA activity. The implementation of Collaborative Laboratory Integrated Reports reduced the number of specimens that screened positive to 19 infants. Of the infants identified as screen-positive, 1 had elevated urinary GAGs and a homozygous pathogenic variant associated with the severe form of MPS I. All other screen-positive infants had normal urinary GAG analysis; 13 newborns had pseudodeficiency alleles, 3 newborns had variants of unknown significance, and 2 had heterozygous pathogenic variants.

Conclusions: An infant with severe MPS I was identified and referred for a hematopoietic stem cell transplant. Newborn IDUA enzyme deficiency is common in North Carolina, but most are due to pseudodeficiency alleles in infants with normal urinary GAG analysis and no evidence of disease. The pilot study confirmed the need for second-tier testing to reduce the follow-up burden.
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http://dx.doi.org/10.1016/j.jpeds.2019.04.027DOI Listing
August 2019

Asymmetric diosmium sawhorse complexes.

Acta Crystallogr C Struct Chem 2019 05 9;75(Pt 5):529-537. Epub 2019 Apr 9.

Chemistry & Biochemistry, Abilene Christian University, ACU Box 28132, Abilene, Texas 79699, USA.

Three asymmetric diosmium(I) carbonyl sawhorse complexes have been prepared by microwave heating. One of these complexes is of the type Os(μ-OCR)(μ-OCR')(CO)L, with two different bridging carboxylate ligands, while the other two complexes are of the type Os(μ-OCR)(CO)L, with one axial CO ligand and one axial phosphane ligand. The mixed carboxylate complex Os(μ-acetate)(μ-propionate)(CO)[P(p-tolyl)], (1), was prepared by heating Os(CO) with a mixture of acetic and propionic acids, isolating Os(μ-acetate)(μ-propionate)(CO), and then replacing two CO ligands with two phosphane ligands. This is the first example of an Os sawhorse complex with two different carboxylate bridges. The syntheses of Os(μ-acetate)(CO)[P(p-tolyl)], (3), and Os(μ-propionate)(CO)[P(p-tolyl)], (6), involved the reaction of Os(CO) with the appropriate carboxylic acid to initially produce Os(μ-carboxylate)(CO), followed by treatment with refluxing tetrahydrofuran (THF) to form Os(μ-carboxylate)(CO)(THF), and finally addition of tri-p-tolylphosphane to replace the THF ligand with the P(p-tolyl) ligand. Neutral complexes of the type Os(μ-OCR)(CO)L had not previously been subjected to X-ray crystallographic analysis. The more symmetrical disubstituted complexes, i.e. Os(μ-formate)(CO)[P(p-tolyl)], (8), Os(μ-acetate)(CO)[P(p-tolyl)], (4), and Os(μ-propionate)(CO)[P(p-tolyl)], (7), as well as the previously reported symmetrical unsubstituted complexes Os(μ-acetate)(CO), (2), and Os(μ-propionate)(CO), (5), were also prepared in order to examine the influence of axial ligand substitution on the Os-Os bond distance in these sawhorse molecules. Eight crystal structures have been determined and studied, namely μ-acetato-1κO:2κO'-μ-propanoato-1κO:2κO'-bis[tris(4-methylphenyl)phosphane]-1κP,2κP'-bis(dicarbonylosmium)(Os-Os) dichloromethane monosolvate, [Os(CHO)(CHO)(CHP)(CO)]·CHCl, (1), bis(μ-acetato-1κO:2κO')bis(tricarbonylosmium)(Os-Os), [Os(CHO)(CO)], (2) (redetermined structure), bis(μ-acetato-1κO:2κO')pentacarbonyl-1κC,2κC-[tris(4-methylphenyl)phosphane-1κP]diosmium(Os-Os), [Os(CHO)(CHP)(CO)], (3), bis(μ-acetato-1κO:2κO')bis[tris(4-methylphenyl)phosphane]-1κP,2κP-bis(dicarbonylosmium)(Os-Os) p-xylene sesquisolvate, [Os(CHO)(CHP)(CO)]·1.5CH, (4), bis(μ-propanoato-1κO:2κO')bis(tricarbonylosmium)(Os-Os), [Os(CHO)(CO)], (5), pentacarbonyl-1κC,2κC-bis(μ-propanoato-1κO:2κO')[tris(4-methylphenyl)phosphane-1κP]diosmium(Os-Os), [Os(CHO)(CHP)(CO)], (6), bis(μ-propanoato-1κO:2κO')bis[tris(4-methylphenyl)phosphane]-1κP,2κP-bis(dicarbonylosmium)(Os-Os) dichloromethane monosolvate, [Os(CHO)(CHP)(CO)]·CHCl, (7), and bis(μ-formato-1κO:2κO')bis[tris(4-methylphenyl)phosphane]-1κP,2κP-bis(dicarbonylosmium)(Os-Os), [Os(CHO)(CHP)(CO)], (8).
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http://dx.doi.org/10.1107/S2053229619004236DOI Listing
May 2019

An Age-Based Framework for Evaluating Genome-Scale Sequencing Results in Newborn Screening.

J Pediatr 2019 06 7;209:68-76. Epub 2019 Mar 7.

Department of Genetics, UNC Chapel Hill, Chapel Hill, NC. Electronic address:

Objective: To assess the performance of a standardized, age-based metric for scoring clinical actionability to evaluate conditions for inclusion in newborn screening and compare it with the results from other contemporary methods.

Study Design: The North Carolina Newborn Exome Sequencing for Universal Screening study developed an age-based, semiquantitative metric to assess the clinical actionability of gene-disease pairs and classify them with respect to age of onset or timing of interventions. This categorization was compared with the gold standard Recommended Uniform Screening Panel and other methods to evaluate gene-disease pairs for newborn genomic sequencing.

Results: We assessed 822 gene-disease pairs, enriched for pediatric onset of disease and suspected actionability. Of these, 466 were classified as having childhood onset and high actionability, analogous to conditions selected for the Recommended Uniform Screening Panel core panel. Another 245 were classified as having childhood onset and low to no actionability, 25 were classified as having adult onset and high actionability, 19 were classified as having adult onset and low to no actionability, and 67 were excluded due to controversial evidence and/or prenatal onset.

Conclusions: This study describes a novel method to facilitate decisions about the potential use of genomic sequencing for newborn screening. These categories may assist parents and physicians in making informed decisions about the disclosure of results from voluntary genomic sequencing in children.
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http://dx.doi.org/10.1016/j.jpeds.2018.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535354PMC
June 2019

What is Newborn Screening?

Authors:
Cynthia M Powell

N C Med J 2019 Jan-Feb;80(1):32-36

professor of Pediatrics and Genetics, Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina

Newborn screening is a system that provides early identification and treatment of infants with disorders prior to permanent disability or death. A successful newborn screening program requires skilled effort, understanding, and collaboration by many individuals, from those collecting the blood spots to the child's primary care provider and family.
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http://dx.doi.org/10.18043/ncm.80.1.32DOI Listing
July 2019

A behavior-theoretic evaluation of values clarification on parental beliefs and intentions toward genomic sequencing for newborns.

Soc Sci Med 2021 Feb 9;271:112037. Epub 2018 Nov 9.

RTI International, Research Triangle Park, NC, United States.

Decision aids commonly include values clarification exercises to help people consider which aspects of a choice matter most to them, and to help them make decisions that are congruent with their personal values and preferences. Using a randomized online experiment, we examined the influence of values clarification on parental beliefs and intentions about having genomic sequencing for newborns. We recruited 1186 women and men ages 18-44 who were pregnant or whose partner was pregnant or planning to become pregnant in the next two years. Participants (N = 1000) completed one of two versions of an online decision aid developed as part of a larger project examining the technical, clinical, and social aspects of using exome sequencing to screen newborns for rare genetic conditions. The education-only version provided information about using genomic sequencing to screen newborns for medically treatable conditions. The education-plus-values-clarification version included the same information, along with a values clarification exercise in which participants classified as important or unimportant five reasons in support of having and five reasons against having their newborn undergo genomic sequencing. We conducted partial correlations, regression analysis, and MANCOVAs with sex, health literacy, and experience with genetic testing as covariates. Participants who completed the decision aid with the values clarification exercise agreed less strongly with four of the five statements against sequencing compared to participants who viewed the education-only decision aid. The groups did not differ on agreement with reasons in support of sequencing. Agreement with four of five reasons against genomic sequencing was negatively associated with intentions to have their newborn sequenced, whereas agreement with all five reasons in support of sequencing were positively associated with intentions.
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http://dx.doi.org/10.1016/j.socscimed.2018.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509013PMC
February 2021

Combination of exome sequencing and immune testing confirms Aicardi-Goutières syndrome type 5 in a challenging pediatric neurology case.

Cold Spring Harb Mol Case Stud 2018 10 1;4(5). Epub 2018 Oct 1.

Departments of Pediatrics and of Medical Genetics, Duke University, Durham, North Carolina 27705, USA.

Exome sequencing is increasingly being used to help diagnose pediatric neurology cases when clinical presentations are not specific. However, interpretation of equivocal results that include variants of uncertain significance remains a challenge. In those cases, follow-up testing and clinical correlation can help clarify the clinical relevance of the molecular findings. In this report, we describe the diagnostic odyssey of a 4-year-old girl who presented with global developmental delay and seizures, with leukodystrophy seen on MRI. Clinical evaluation, MRI, and comprehensive metabolic testing were performed, followed by whole-exome sequencing (WES), parental testing, follow-up testing, and retrospective detailed clinical evaluation. WES identified two candidate causative pathogenic variants in , a gene associated with the recessive condition Aicardi-Goutières syndrome (AGS) type 5 (OMIM 612952): a previously reported pathogenic variant NM_015474 c.602T>A (p.I201N), maternally inherited, and a rare missense variant of uncertain significance, c.1293A>T(p.L431F). Analysis of type I interferon-related biomarkers demonstrated that the patient has an interferon signature characteristic of AGS. Retrospective detailed clinical evaluation showed that the girl has a phenotype consistent with AGS5, a rare neurological condition. These results further define the phenotypic spectrum associated with specific variants, including heterozygous variants in AGS carriers, and support the idea that autoinflammatory dysregulation is part of the disease pathophysiology. More broadly, this work highlights the issues and methodology involved in ascribing clinical relevance to interpretation of variants detected by WES.
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http://dx.doi.org/10.1101/mcs.a002758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169830PMC
October 2018

Crystal structure of [μ-1κ,:2(1,2,3,4-η)-1,2,3,4-tetra-phenyl-buta-1,3-diene-1,4-di-yl]bis-(tri-carbonyl-osmium)(-).

Acta Crystallogr E Crystallogr Commun 2018 Sep 14;74(Pt 9):1235-1238. Epub 2018 Aug 14.

Department of Chemistry & Biochemistry, Abilene Christian University, Abilene, TX 79699, USA.

In the title complex CHOOs or (μ-η-CPh)Os(CO), one Os atom is part of a metalla-cyclo-penta-diene ring, while the second Os atom is π-bonded to the organic portion of this ring. The distance of 2.7494 (2) Å between the two Os atoms is typical of an Os-Os single bond. Three carbonyl ligands are attached to each Os atom and these six carbonyls adopt an eclipsed conformation. There are no bridging or semibridging CO groups. Two carbonyl ligands and all four phenyl groups are disordered over two slightly different positions for which each atom in the minor components is displaced less than 1 Å from the corresponding atom in the major components. The refined occupancies of the major com-ponents of the carbonyl ligands are 0.568 (16) and 0.625 (13), while those for the phenyl rings are 0.50 (3), 0.510 (12), 0.519 (18), and 0.568 (12).
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http://dx.doi.org/10.1107/S2056989018011179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127685PMC
September 2018

Feline Herpesvirus 1 and Mycoplasma spp. Conventional PCR Assay Results From Conjunctival Samples From Cats in Shelters With Suspected Acute Ocular Infections.

Top Companion Anim Med 2018 Jun 29;33(2):45-48. Epub 2018 May 29.

Center for Companion Animal Studies in the Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80524, USA. Electronic address:

Signs of ocular infections like discharge and conjunctivitis occur commonly in cats in shelters and feline herpesvirus 1 (FHV-1), Chlamydia felis, Mycoplasma spp, and feline calicivirus (FCV) are thought to be the most common causes. While molecular assays are available to amplify nucleic acids of each of these agents as single tests or in panels, additional information is needed concerning whether the assay results can be used to predict response to treatment. The objectives of this study were to report results for conventional polymerase chain reaction (PCR) assays that amplify nucleic acids of FHV-1, Mycoplasma spp., C. felis, and FCV from cats with signs of acute ocular and upper respiratory infections in an animal shelter and to determine whether the results are associated with treatment responses to topical administration of cidofovir (anti-FHV-1) or oxytetracycline (anti-Mycoplasma spp. and C. felis). Conjunctival samples were collected from both eyes of 60 cats with ocular signs of disease. Total deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) were extracted from each sample and assayed for DNA of FHV-1, Mycoplasma spp., and C. felis and RNA of FCV by conventional PCR assays. Cats were randomized to be administered either oxytetracycline ointment or cidofovir drops in both eyes and a standardized ocular disease score system was used to determine a total ocular score for each cat prior to treatment on Day 0 and on Day 7. Nucleic acids of one or more agents were amplified from one or both eyes from 39 of 60 cats (65%). FHV-1 DNA (21 cats), Mycoplasma spp. DNA (25 cats) or FCV RNA (2 cats) were amplified most commonly. After treatment for 7 days, 32 of 60 cats (53.3%) were considered improved with 27 of 32 cats (84.4%) having ocular scores of 0 (21 cats) or 1 (6 cats). When the results of the FHV-1 PCR assay were compared to cidofovir treatment responses, the positive and negative predictive values of the assay were shown to be 29.4% and 60%, respectively. When the results of the Mycoplasma spp. PCR assay were compared to oxytetracycline treatment responses, the positive and negative predictive values of the assay were shown to be 40% and 38.5%, respectively. The predictive value of conventional PCR assay results for FHV-1 or Mycoplasma spp. DNA was low, suggesting that performing these tests to formulate a treatment protocol has minimal clinical utility in cats with suspected acute ocular infections.
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http://dx.doi.org/10.1053/j.tcam.2018.05.001DOI Listing
June 2018

What Genomic Sequencing Can Offer Universal Newborn Screening Programs.

Authors:
Cynthia M Powell

Hastings Cent Rep 2018 07;48 Suppl 2:S18-S19

Massively parallel sequencing, also known as next-generation sequencing, has the potential to significantly improve newborn screening programs in the United States and around the world. Compared to genetic tests whose use is well established, sequencing allows for the analysis of large amounts of DNA, providing more comprehensive and rapid results at a lower cost. It is already being used in limited ways by some public health newborn screening laboratories in the United States and other countries-and it is under study for broader and more widespread use, including as a core part of newborn screening programs. Sequencing technology has the potential to significantly improve these essential public health programs. For many of the conditions that newborns are already screened for, sequencing can return more specific and more sensitive results. The technology could also enable newborn screening programs to expand the list of rare pediatric conditions that they look for, thereby identifying more infants who can benefit from immediate care.
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http://dx.doi.org/10.1002/hast.878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863503PMC
July 2018

Evaluating parents' decisions about next-generation sequencing for their child in the NC NEXUS (North Carolina Newborn Exome Sequencing for Universal Screening) study: a randomized controlled trial protocol.

Trials 2018 Jun 28;19(1):344. Epub 2018 Jun 28.

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Background: Using next-generation sequencing (NGS) in newborn screening (NBS) could expand the number of genetic conditions detected pre-symptomatically, simultaneously challenging current precedents, raising ethical concerns, and extending the role of parental decision-making in NBS. The NC NEXUS (Newborn Exome Sequencing for Universal Screening) study seeks to assess the technical possibilities and limitations of NGS-NBS, devise and evaluate a framework to convey various types of genetic information, and develop best practices for incorporating NGS-NBS into clinical care. The study is enrolling both a healthy cohort and a cohort diagnosed with known disorders identified through recent routine NBS. It uses a novel age-based metric to categorize a priori the large amount of data generated by NGS-NBS and interactive online decision aids to guide parental decision-making. Primary outcomes include: (1) assessment of NGS-NBS sensitivity, (2) decision regret, and (3) parental decision-making about NGS-NBS, and, for parents randomized to have the option of requesting them, additional findings (diagnosed and healthy cohorts). Secondary outcomes assess parents' reactions to the study and to decision-making.

Methods/design: Participants are parents and children in a well-child cohort recruited from a prenatal clinic and a diagnosed cohort recruited from pediatric clinics that treat children with disorders diagnosed through traditional NBS (goal of 200 children in each cohort). In phase 1, all parent participants use an online decision aid to decide whether to accept NGS-NBS for their child and provide consent for NGS-NBS. In phase 2, parents who consent to NGS-NBS are randomized to a decision arm or control arm (2:1 allocation) and learn their child's NGS-NBS results, which include conditions from standard (non-NGS) NBS plus other highly actionable childhood-onset conditions. Parents in the decision arm use a second decision aid to make decisions about additional results from their child's sequencing. In phase 3, decision arm participants learn additional results they have requested. Online questionnaires are administered at up to five time points.

Discussion: NC NEXUS will use a rigorous interdisciplinary approach designed to collect rich data to inform policy, practice, and future research.

Trial Registration: clinicaltrials.gov, NCT02826694 . Registered on 11 July, 2016.
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http://dx.doi.org/10.1186/s13063-018-2686-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022715PMC
June 2018

Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome.

Am J Med Genet A 2018 04 13;176(4):925-935. Epub 2018 Feb 13.

Department of Pediatrics and Medicine, Columbia University, New York, New York.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.
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http://dx.doi.org/10.1002/ajmg.a.38630DOI Listing
April 2018

Fragile X Newborn Screening: Lessons Learned From a Multisite Screening Study.

Pediatrics 2017 Jun;139(Suppl 3):S216-S225

Center for Newborn Screening, Ethics, and Disability Studies, RTI International, Research Triangle Park, North Carolina.

Background: Delays in the diagnosis of children with fragile X syndrome (FXS) suggest the possibility of newborn screening as a way to identify children earlier. However, FXS does not have a proven treatment that must be provided early, and ethical concerns have been raised about the detection of infants who are carriers. This article summarizes major findings from a multisite, prospective, longitudinal pilot screening study.

Methods: Investigators in North Carolina, California, and Illinois collaborated on a study in which voluntary screening for FXS was offered to parents in 3 birthing hospitals. FXS newborn screening was offered to >28 000 families to assess public acceptance and determine whether identification of babies resulted in any measurable harms or adverse events. Secondary goals were to determine the prevalence of carrier gene expansions, study the consent process, and describe early development and behavior of identified children.

Results: A number of publications have resulted from the project. This article summarizes 10 "lessons learned" about the consent process, reasons for accepting and declining screening, development and evaluation of a decision aid, prevalence of carriers, father participation in consent, family follow-up, and maternal reactions to screening.

Conclusions: The project documented public acceptance of screening as well as the challenges inherent in obtaining consent in the hospital shortly after birth. Collectively, the study provides answers to a number of questions that now set the stage for a next generation of research to determine the benefits of earlier identification for children and families.
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http://dx.doi.org/10.1542/peds.2016-1159HDOI Listing
June 2017

Parental preferences toward genomic sequencing for non-medically actionable conditions in children: a discrete-choice experiment.

Genet Med 2018 02 3;20(2):181-189. Epub 2017 Aug 3.

RTI International, Research Triangle Park, Durham, North Carolina, USA.

PurposeApplication of whole-exome and whole-genome sequencing is likely to increase in clinical practice, public health contexts, and research. We investigated how parental preference for acquiring information from genome-scale testing is influenced by the characteristics of non-medically actionable genetic disorders in children, as well as whether the preferences differed by gender and between African-American and white respondents.MethodsWe conducted a Web-based discrete-choice experiment with 1,289 parents of young children. Participants completed "choice tasks" based on pairs of profiles describing sequencing results for hypothetical genetic disorders, selected the profile in each pair that they believed represented the information that would be more important to know, and answered questions that measured their level of distress.ResultsKnowing the likelihood that the disorder would develop given a true-positive test result was most important to parents. Parents showed greater interest in learning sequencing results for disease profiles with more severe manifestations. This was associated with greater distress. Differences by gender and race reflected small differences in magnitude, but not direction.ConclusionParents preferred to learn results about genetic disorders with more severe manifestations, even when this knowledge was associated with increased distress. These results may help clinicians support parental decision making by revealing which types of sequencing results parents are interested in learning.
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http://dx.doi.org/10.1038/gim.2017.93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868968PMC
February 2018

Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion syndrome.

Am J Med Genet A 2017 Oct 27;173(10):2720-2724. Epub 2017 Jul 27.

Department of Pediatrics, Division of Genetics and Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Mitochondrial DNA depletion syndrome 5 (MIM 612073) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the beta subunit of the succinate-CoA ligase gene located within the 13q14 band. We describe two siblings of Hispanic descent with SUCLA2-related mitochondrial depletion syndrome (encephalomyopathic form with methylmalonic aciduria); the older sibling is additionally affected with trisomy 21. SUCLA2 sequencing identified homozygous p.Arg284Cys pathogenic variants in both patients. This mutation has previously been identified in four individuals of Italian and Caucasian descent. The older sibling with concomitant disease has a more severe phenotype than what is typically described in patients with either SUCLA2-related mitochondrial depletion syndrome or Down syndrome alone. The younger sibling, who has a normal female chromosome complement, is significantly less affected compared to her brother. While the clinical and molecular findings have been reported in about 50 patients affected with a deficiency of succinate-CoA ligase caused by pathogenic variants in SUCLA2, this report describes the first known individual affected with both a mitochondrial depletion syndrome and trisomy 21.
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http://dx.doi.org/10.1002/ajmg.a.38351DOI Listing
October 2017

Prenatal exome sequencing in anomalous fetuses: new opportunities and challenges.

Genet Med 2017 11 18;19(11):1207-1216. Epub 2017 May 18.

Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

PurposeWe investigated the diagnostic and clinical performance of exome sequencing in fetuses with sonographic abnormalities with normal karyotype and microarray and, in some cases, normal gene-specific sequencing.MethodsExome sequencing was performed on DNA from 15 anomalous fetuses and from the peripheral blood of their parents. Parents provided consent to be informed of diagnostic results in the fetus, medically actionable findings in the parents, and their identification as carrier couples for significant autosomal recessive conditions. We assessed the perceptions and understanding of exome sequencing using mixed methods in 15 mother-father dyads.ResultsIn seven (47%) of 15 fetuses, exome sequencing provided a diagnosis or possible diagnosis with identification of variants in the following genes: COL1A1, MUSK, KCTD1, RTTN, TMEM67, PIEZO1 and DYNC2H1. One additional case revealed a de novo nonsense mutation in a novel candidate gene (MAP4K4). The perceived likelihood that exome sequencing would explain the results (5.2 on a 10-point scale) was higher than the approximately 30% diagnostic yield discussed in pretest counseling.ConclusionExome sequencing had diagnostic utility in a highly select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy and variant interpretation must be addressed by highly tailored pre- and posttest genetic counseling.
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http://dx.doi.org/10.1038/gim.2017.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675748PMC
November 2017