Publications by authors named "Cynthia M Powell"

An increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.

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Purpose: Research is underway worldwide to investigate the feasibility, acceptability, and utility of sequencing-based newborn screening. Different methods have been used to select gene-condition pairs for screening, leading to highly inconsistent gene lists across studies.

Methods: Early Check developed and utilized actionability-based frameworks for evaluating gene-condition pairs for inclusion in newborn panels (panel 1-high actionability, panel 2-possible actionability).

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Native American myopathy (NAM, also known as STAC3 disorder) (OMIM 255995) is an ultra-rare genetic disease impacting multiple body systems. The quality of life and caregiver burden associated with this condition remain poorly characterized. In this study, the Pediatric Quality of Life Inventory and a survey comprised of de novo questions concerning genetic testing, counseling, and caregiver burden were employed to investigate the health-related quality of life (HRQoL) in patients and caregivers with NAM.

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The vast majority of severe (Type 0) spinal muscular atrophy (SMA) cases are caused by homozygous deletions of survival motor neuron 1 (). We report a case in which the patient has two copies of but clinically presents as Type 0 SMA. The patient is an African American male carrying a homozygous maternally inherited missense variant (c.

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Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine biosynthesis due to pathogenic variants in the GAMT gene that lead to cerebral creatine deficiency and neurotoxic levels of guanidinoacetate. Untreated, GAMT deficiency is associated with hypotonia, significant intellectual disability, limited speech development, recurrent seizures, behavior problems, and involuntary movements. The birth prevalence of GAMT deficiency is likely between 0.

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Importance: Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results.

Objective: To compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test.

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Article Synopsis
  • Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder marked by a variety of symptoms including growth delays, upper limb issues, and other systemic problems, primarily caused by mutations in specific genes associated with the cohesin complex.
  • The majority of CdLS cases (over 60%) are linked to mutations in the NIPBL gene, which leads to the most severe form of the syndrome; other cohesin gene mutations typically result in milder symptoms.
  • The study analyzed the genetic factors in 716 individuals with CdLS to better understand the contributions of cohesin complex genes and identify potential new candidate genes, improving knowledge of genetic variations and their effects on CdLS manifestations.
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Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked condition caused by pathogenic variants in the iduronate-2-sulfatase gene. The resulting reduced activity of the enzyme iduronate-2-sulfatase leads to accumulation of glycosaminoglycans that can progressively affect multiple organ systems and impair neurologic development. In 2006, the US Food and Drug Administration approved idursulfase for intravenous enzyme replacement therapy for MPS II.

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Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (, , , , , and ). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families.

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Background: Newborn screening aims to identify individual patients who could benefit from early management, treatment, and/or surveillance practices. As sequencing technologies have progressed and we move into the era of precision medicine, genomic sequencing has been introduced to this area with the hopes of detecting variants related to a vastly expanded number of conditions. Though implementation of genomic sequencing for newborn screening in public health and clinical settings is limited, commercial laboratories have begun to offer genomic screening panels for neonates.

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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.

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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.

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Article Synopsis
  • * The North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project compared the effectiveness of exome sequencing (ES) in healthy newborns and those with conditions, finding high diagnostic confirmation rates for metabolic disorders (88%) but lower rates for hearing loss (18%).
  • * The study identified actionable genetic findings that standard NBS would miss and discovered various pathogenic variants, showcasing both the potential advantages and challenges of integrating genomic sequencing into newborn screening protocols.
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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.

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Article Synopsis
  • An amendment has been released for the paper.
  • The amended version includes updated information or corrections.
  • You can find the link to access the amendment at the top of the original paper.
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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.

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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 .

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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.

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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.

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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.

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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.

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