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Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons

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All Articles in Congenital, Hereditary, and Neonatal Diseases and Abnormalities

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Persistent Neurobehavioral Traits In A Mouse Model Of Prenatal Ethanol Exposure, Jill M. Lawrence 2017 Ursinus College

Persistent Neurobehavioral Traits In A Mouse Model Of Prenatal Ethanol Exposure, Jill M. Lawrence

Neuroscience Honors Papers

Fetal Alcohol Spectrum Disorders (FASD) effect an estimated 2% of the population, causing a range of symptoms: from craniofacial defects to inhibited cortical growth (May, et al., 2009; Murawski, et al., 2015). Impaired medial forebrain function apparent in FASD is associated with lifelong cognitive behavioral deficits, but these consequences may be avoided with early diagnosis and intervention (Streissguth, et al., 2004). Our goal is to identify early neurobehavioral abnormalities that persist into adulthood that could potentially serve as early indicators for FASD. Mouse models of prenatal ethanol exposure were developed using a voluntary drinking paradigm that introduced a sweetened ethanol ...


High Throughput In Vivo Functional Validation Of Candidate Congenital Heart Disease Genes In Drosophila., Jun-Yi Zhu, Yulong Fu, Margaret Nettleton, Adam Richman, Zhe Han 2017 George Washington University

High Throughput In Vivo Functional Validation Of Candidate Congenital Heart Disease Genes In Drosophila., Jun-Yi Zhu, Yulong Fu, Margaret Nettleton, Adam Richman, Zhe Han

Pediatrics Faculty Publications

Genomic sequencing has implicated large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system is needed to validate gene associations with pathology. We developed a Drosophila-based functional system to screen candidate disease genes identified from Congenital Heart Disease (CHD) patients. 134 genes were tested in the Drosophila heart using RNAi-based gene silencing. Quantitative analyses of multiple cardiac phenotypes demonstrated essential structural, functional, and developmental roles for more than 70 genes, including a subgroup encoding histone H3K4 modifying proteins. We also demonstrated the use of Drosophila to evaluate cardiac phenotypes resulting ...


Promotion Of Early Pediatric Hearing Detection Through Patient Navigation, Matthew L. Bush 2017 University of Kentucky

Promotion Of Early Pediatric Hearing Detection Through Patient Navigation, Matthew L. Bush

Theses and Dissertations--Clinical and Translational Science

Congenital hearing loss is the most common neonatal sensory disorder and it is crucial to diagnose hearing loss as soon as possible after birth in order to facilitate rapid treatment. Universal standards of infant hearing healthcare dictate that infant hearing screening should be completed by one month of age and abnormal screening tests should be followed with definitive audiological testing by three months of age. Obtaining diagnostic testing can be complicated by limited access to care in rural areas, breakdowns in communication, lack of parental support, and poor coordination of care. There is no established method to address appointment non-adherence ...


Abnormal Glycosylation In Joubert Syndrome Type 10., Megan S Kane, Mariska Davids, Michelle R Bond, Christopher J Adams, Megan E Grout, Ian G Phelps, Gilbert Vezina, +several additional authors 2017 George Washington University

Abnormal Glycosylation In Joubert Syndrome Type 10., Megan S Kane, Mariska Davids, Michelle R Bond, Christopher J Adams, Megan E Grout, Ian G Phelps, Gilbert Vezina, +Several Additional Authors

Neurology Faculty Publications

BACKGROUND: The discovery of disease pathogenesis requires systematic agnostic screening of multiple homeostatic processes that may become deregulated. We illustrate this principle in the evaluation and diagnosis of a 5-year-old boy with Joubert syndrome type 10 (JBTS10). He carried the OFD1 mutation p.Gln886Lysfs*2 (NM_003611.2: c.2656del) and manifested features of Joubert syndrome.

METHODS: We integrated exome sequencing, MALDI-TOF mass spectrometry analyses of plasma and cultured dermal fibroblasts glycomes, and full clinical evaluation of the proband. Analyses of cilia formation and lectin staining were performed by immunofluorescence. Measurement of cellular nucleotide sugar levels was performed with high-performance anion-exchange ...


Histone Deacetylase 3 Coordinates Heart Development Through Stage-Specific Roles In Cardiac Progenitor Cells, Sara L. Lewandowski 2016 University of Massachusetts Medical School

Histone Deacetylase 3 Coordinates Heart Development Through Stage-Specific Roles In Cardiac Progenitor Cells, Sara L. Lewandowski

GSBS Dissertations and Theses

Disruptions in cardiac development cause congenital heart disease, the most prevalent and deadly congenital malformation. Genetic and environmental factors are thought to contribute to these defects, however molecular mechanisms remain largely undefined. Recent work highlighted potential roles of chromatin- modifying enzymes in congenital heart disease pathogenesis. Histone deacetylases, a class of chromatin-modifying enzymes, have developmental importance and recognized roles in the mature heart. This thesis aimed to characterize functions of Hdac3 in cardiac development. We found loss of Hdac3 in the primary heart field causes precocious progenitor cell differentiation, resulting in hypoplastic ventricular walls, ventricular septal defect, and mid- gestational ...


Losing Ground: Awareness Of Congenital Cytomegalovirus In The United States, Sara M. Doutre, Tyson S. Barrett, Janelle Greenlee, Karl R. White 2016 Utah State University

Losing Ground: Awareness Of Congenital Cytomegalovirus In The United States, Sara M. Doutre, Tyson S. Barrett, Janelle Greenlee, Karl R. White

Journal of Early Hearing Detection and Intervention

One in 150 infants is born with cytomegalovirus (CMV) and one in 750 will have lifelong disabilities due to CMV. Even though congenital CMV is the leading viral cause of congenital disabilities and the leading non-genetic cause of childhood hearing loss, most adults have never heard of it. Data from the 2015 and 2016 HealthStylesTM surveys were analyzed and compared to data from similar studies and show an awareness rate of 7% for US adults (5% for men and 9% for women), a statistically significant decrease from 2005 and 2010 studies. Predictors of awareness include gender and education level ...


Native T1 Values Identify Myocardial Changes And Stratify Disease Severity In Patients With Duchenne Muscular Dystrophy., Laura J. Olivieri, Peter Kellman, Robert J. McCarter, Russell R. Cross, Michael S. Hansen, Christopher F. Spurney 2016 George Washington University

Native T1 Values Identify Myocardial Changes And Stratify Disease Severity In Patients With Duchenne Muscular Dystrophy., Laura J. Olivieri, Peter Kellman, Robert J. Mccarter, Russell R. Cross, Michael S. Hansen, Christopher F. Spurney

Pediatrics Faculty Publications

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked, inherited disorder causing dilated cardiomyopathy with variable onset and progression. Currently we lack objective markers of the effect of therapies targeted towards preventing progression of subclinical cardiac disease. Thus, our aim was to compare the ability of native T1 and extracellular volume (ECV) measurements to differentiate risk of myocardial disease in DMD and controls.

METHODS: Twenty boys with DMD and 16 age/gender-matched controls without history predisposing to cardiac fibrosis, but with a clinical indication for cardiovascular magnetic resonance (CMR) evaluation, underwent CMR with contrast. Data points collected include left ventricular ejection ...


In Vivo Correction Of Anaemia In Beta-Thalassemic Mice By Gammapna-Mediated Gene Editing With Nanoparticle Delivery, Raman Bahal, Dale L. Greiner, Michael A. Brehm, Peter M. Glazer 2016 Yale University

In Vivo Correction Of Anaemia In Beta-Thalassemic Mice By Gammapna-Mediated Gene Editing With Nanoparticle Delivery, Raman Bahal, Dale L. Greiner, Michael A. Brehm, Peter M. Glazer

Open Access Articles

The blood disorder, beta-thalassaemia, is considered an attractive target for gene correction. Site-specific triplex formation has been shown to induce DNA repair and thereby catalyse genome editing. Here we report that triplex-forming peptide nucleic acids (PNAs) substituted at the gamma position plus stimulation of the stem cell factor (SCF)/c-Kit pathway yielded high levels of gene editing in haematopoietic stem cells (HSCs) in a mouse model of human beta-thalassaemia. Injection of thalassemic mice with SCF plus nanoparticles containing gammaPNAs and donor DNAs ameliorated the disease phenotype, with sustained elevation of blood haemoglobin levels into the normal range, reduced reticulocytosis, reversal ...


Feasibility Of A Community-Based Sickle Cell Trait Testing And Counseling Program, Ashley Housten, Regina Abel, Terianne Lindsey, Allison King 2016 Washington University School of Medicine in St. Louis

Feasibility Of A Community-Based Sickle Cell Trait Testing And Counseling Program, Ashley Housten, Regina Abel, Terianne Lindsey, Allison King

Journal of Health Disparities Research and Practice

Background: Sickle cell trait (SCT) screening is required at birth in the United States; however, adults rarely know their SCT status prior to having children.

Purpose: Assess feasibility of a community-based SCT education and testing intervention.

Methods: Participants were recruited from eight community sites to complete an educational program and offered a hemoglobin analysis. A genetic counselor met individually with participants to discuss lab results.

Results: Between July 14, 2010 and May 31, 2012, 637 participants completed the educational program. Five hundred seventy (89.5%) provided a blood sample, and 61 (10.9%) had SCT or other hemoglobinopathies. The genetic ...


Ataluren Stimulates Ribosomal Selection Of Near-Cognate Trnas To Promote Nonsense Suppression, Bijoyita Roy, Westley J. Friesen, Yuki Tomizawa, John D. Leszyk, Jin Zhuo, Briana Johnson, Jumana Dakka, Christopher R. Trotta, Xiaojiao Xue, Venkateshwar Mutyam, Kim M. Keeling, James A. Mobley, Steven M. Rowe, David M. Bedwell, Ellen M. Welch, Allan Jacobson 2016 University of Massachusetts Medical School

Ataluren Stimulates Ribosomal Selection Of Near-Cognate Trnas To Promote Nonsense Suppression, Bijoyita Roy, Westley J. Friesen, Yuki Tomizawa, John D. Leszyk, Jin Zhuo, Briana Johnson, Jumana Dakka, Christopher R. Trotta, Xiaojiao Xue, Venkateshwar Mutyam, Kim M. Keeling, James A. Mobley, Steven M. Rowe, David M. Bedwell, Ellen M. Welch, Allan Jacobson

Microbiology and Physiological Systems Publications and Presentations

A premature termination codon (PTC) in the ORF of an mRNA generally leads to production of a truncated polypeptide, accelerated degradation of the mRNA, and depression of overall mRNA expression. Accordingly, nonsense mutations cause some of the most severe forms of inherited disorders. The small-molecule drug ataluren promotes therapeutic nonsense suppression and has been thought to mediate the insertion of near-cognate tRNAs at PTCs. However, direct evidence for this activity has been lacking. Here, we expressed multiple nonsense mutation reporters in human cells and yeast and identified the amino acids inserted when a PTC occupies the ribosomal A site in ...


The Clinical, Biochemical And Genetic Features Associated With Rmnd1-Related Mitochondrial Disease., Yi Shiau Ng, Charlotte L Alston, Daria Diodato, Andrew A Morris, Nicole Ulrick, Stanislav Kmoch, +several additional authors 2016 George Washington University

The Clinical, Biochemical And Genetic Features Associated With Rmnd1-Related Mitochondrial Disease., Yi Shiau Ng, Charlotte L Alston, Daria Diodato, Andrew A Morris, Nicole Ulrick, Stanislav Kmoch, +Several Additional Authors

Neurology Faculty Publications

BACKGROUND: Mutations in the RMND1 (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects.

METHODS: We summarised the clinical, biochemical and molecular genetic investigation of an international cohort of affected individuals with RMND1 mutations. In addition, we reviewed all the previously published cases to determine the genotype-phenotype correlates and performed survival analysis to identify prognostic factors.

RESULTS: We identified 14 new cases from 11 pedigrees that harbour recessive RMND1 mutations, including 6 novel variants: c.533C>A, p.(Thr178Lys); c.565C>T, p.(Gln189*); c ...


Activation Of Target Gene Expression In Neurons By The C. Elegans Rfx Transcription Factor, Daf-19, Katherine P. Mueller 2016 Lawrence University

Activation Of Target Gene Expression In Neurons By The C. Elegans Rfx Transcription Factor, Daf-19, Katherine P. Mueller

Lawrence University Honors Projects

DAF-19, the only RFX transcription factor found in C. elegans, is required for the formation of neuronal sensory cilia. Four isoforms of the DAF-19 protein have been reported, and the m86 nonsense (null) mutation affecting all four isoforms has been shown to prevent cilia formation. Transcriptome analyses employing microarrays of L1 and adult stage worms were completed using RNA from daf-19(m86) worms and an isogenic wild type strain to identify additional putative DAF-19 target genes. Using transcriptional fusions with GFP, we compared the expression patterns of several potential gene targets using fluorescence confocal microscopy. Expression patterns were characterized in ...


Characterization Of Respiratory Phenotype In Very Long-Chain Acyl-Coa Dehydrogenase Deficient Mice., Allison M. Keeler, Kaitlyn Desrochers, Mai K. Elmallah 2016 University of Massachusetts Medical School

Characterization Of Respiratory Phenotype In Very Long-Chain Acyl-Coa Dehydrogenase Deficient Mice., Allison M. Keeler, Kaitlyn Desrochers, Mai K. Elmallah

UMass Center for Clinical and Translational Science Research Retreat

Rationale: Very Long-chain Acyl-CoA dehydrogenase (VLCAD) deficiency the most common inherited long-chain fatty acid disorder. The VLCAD enzyme catalyzes the first step of mitochondrial fatty acid oxidation and loss of the enzyme results in energy deficiency as well as accumulation of long chain fatty acids. Recently, a related enzyme, Long-chain Acyl-CoA dehydrogensase (LCAD), which unlike VLCAD is not highly expressed in metabolic tissues like liver, heart and skeletal muscle, was found to be expressed in the lung and surfactant and lung dysfunction were observed in LCAD deficient mice. Respiratory distress syndrome has been described in other fatty acid oxidation disorders ...


Translating Dosage Compensation To Trisomy 21, Jun Jiang, Yuanchun Jing, Gregory J. Cost, Jen-Chieh Chiang, Heather J. Kolpa, Allison M. Cotton, Dawn M. Carone, Benjamin R. Carone, Meg Byron, Philip D. Gregory, Carolyn J. Brown, Fyodor D. Urnov, Lisa L. Hall, Jeanne B. Lawrence 2016 University of Massachusetts Medical School

Translating Dosage Compensation To Trisomy 21, Jun Jiang, Yuanchun Jing, Gregory J. Cost, Jen-Chieh Chiang, Heather J. Kolpa, Allison M. Cotton, Dawn M. Carone, Benjamin R. Carone, Meg Byron, Philip D. Gregory, Carolyn J. Brown, Fyodor D. Urnov, Lisa L. Hall, Jeanne B. Lawrence

UMass Center for Clinical and Translational Science Research Retreat

Down syndrome is the leading genetic cause of intellectual disabilities, occurring in 1 out of 700 live births. Given that Down syndrome is caused by an extra copy of chromosome 21 that involves over-expression of 400 genes across a whole chromosome, it precludes any possibility of a genetic therapy. Our lab has long studied the natural dosage compensation mechanism for X chromosome inactivation. To “dosage compensate” X-linked genes between females and males, the X-linked XIST gene produces a large non-coding RNA that silences one of the two X chromosomes in female cells. The initial motivation of this study was to ...


Airway Smooth Muscle Pathology In Pompe Disease, Lang Xiong, Allison M. Keeler, Donghai Lui, Kaitlyn Desrochers, Ronghua Zhuge, Mai K. Elmallah 2016 University of Massachusetts Medical School

Airway Smooth Muscle Pathology In Pompe Disease, Lang Xiong, Allison M. Keeler, Donghai Lui, Kaitlyn Desrochers, Ronghua Zhuge, Mai K. Elmallah

UMass Center for Clinical and Translational Science Research Retreat

Pompe disease is a rare autosomal recessive disease which results from a deficiency of acid α-glucosidase (GAA) - an enzyme that degrades lysosomal glycogen. Patients with Pompe disease develop intra-lysosomal accumulation of glycogen in multiple tissues including skeletal muscle, CNS and smooth muscle.

Pulmonary dysfunction is a hallmark of Pompe disease and has classically been attributed to muscle weakness and CNS neuropathology. However, the potential role of respiratory smooth muscles in the respiratory pathology is unknown. Therefore we postulated that GAA deficiency results in airway smooth muscle glycogen accumulation that leads to airway smooth muscle dysfunction.

Using the Pompe mouse model ...


Sustained Expression With Partial Correction Of Neutrophil Defects 5 Years After Intramuscular Raav1 Gene Therapy For Alpha-1 Antitrypsin Deficiency, Terence R. Flotte, Christian Mueller, Gwladys Gernoux, Alisha Gruntman, Jeffrey D. Chulay, David R. Knop, Noel G. McElvaney, Martha Campbell-Thompson, James M. Wilson 2016 University of Massachusetts Medical School

Sustained Expression With Partial Correction Of Neutrophil Defects 5 Years After Intramuscular Raav1 Gene Therapy For Alpha-1 Antitrypsin Deficiency, Terence R. Flotte, Christian Mueller, Gwladys Gernoux, Alisha Gruntman, Jeffrey D. Chulay, David R. Knop, Noel G. Mcelvaney, Martha Campbell-Thompson, James M. Wilson

UMass Center for Clinical and Translational Science Research Retreat

Alpha-1 antitrypsin (AAT) deficiency is a common monogenic disorder resulting in emphysema, which is currently treated with weekly infusions of protein replacement. We previously reported achieving plasma wild-type (M) AAT concentrations at 2.5-3.8% of the therapeutic level at 1 year after intramuscular (IM) administration of 6×1012vg/kg of a recombinant adeno-associated virus serotype 1 (rAAV1)-AAT vector in AAT-deficient patients, with an associated regulatory T cell (Treg) response to AAV1 capsid epitopes in the absence of any exogenous immune suppression. Here, we report sustained expression at greater than 2% of the therapeutic level for 5 years after ...


Phylogenetic Analysis Of Human Cytomegalovirus Pus27 And Pus28: Ascertaining An Independent Or Linked Evolutionary History, Jessica A. Scarborough 2016 University of San Francisco

Phylogenetic Analysis Of Human Cytomegalovirus Pus27 And Pus28: Ascertaining An Independent Or Linked Evolutionary History, Jessica A. Scarborough

Undergraduate Honors Theses

Human cytomegalovirus (HCMV) is a widespread pathogen that is particularly skilled at evading immune detection and defense mechanisms, largely due to extensive co-evolution with its host’s immune system. One aspect of this co-evolution involves the acquisition of four virally encoded GPCR chemokine receptor homologs, products of the US27, US28, UL33 and UL78 genes. G protein-coupled receptors (GPCR) are the largest family of cell surface proteins, found in organisms from yeast to humans. In this research, phylogenetic analysis was used to investigate the origins of the US27 and US28 genes, which are adjacent in the viral genome. The results indicate ...


Virus-Host Co-Evolution: Determining The Origin Of Human Cytomegalovirus Us27 And Us28, Jessica A. Scarborough, Juliet Spencer, John Paul 2016 University of San Francisco

Virus-Host Co-Evolution: Determining The Origin Of Human Cytomegalovirus Us27 And Us28, Jessica A. Scarborough, Juliet Spencer, John Paul

Creative Activity and Research Day - CARD

G protein-coupled receptors (GPCR) are the largest family of cell surface proteins, found in organisms from yeast to humans. Human cytomegalovirus (HCMV) is a widespread pathogen that is particularly skilled at evading immune detection and defense mechanisms, largely due to extensive co-evolution with its host’s immune system. One aspect of this co-evolution involves the acquisition of four virally encoded GPCR homologs: US27, US28, UL33 and UL78. In this research, phylogenetic analysis was used to investigate the origins of the US27 and US28 genes, which are adjacent in the viral genome. The results indicate that both US27 and US28 share ...


Time Of Year Affects Surgical Outcome Of Pediatric Congenital Heart Disease, Krystin Sinclair 2016 Bryant University

Time Of Year Affects Surgical Outcome Of Pediatric Congenital Heart Disease, Krystin Sinclair

Honors Projects in Science and Technology

Approximately 35,000 children are born in the US each year with Congenital Heart Disease (CHD). Surgical timing for many of these conditions is elective, and the distribution of surgical cases, therefore, varies with time of year. The hypothesis of this project is that time of the year for surgery is associated with mortality, length of hospital stay (LOS), and total hospital costs. A retrospective, cohort study was performed, using the Pediatric Health Information Systems (PHIS) Database to investigate these relationships.


Injury Risk Assessment Of The Femur In Children With Osteogenesis Imperfecta, Jessica Marie Fritz 2016 Marquette University

Injury Risk Assessment Of The Femur In Children With Osteogenesis Imperfecta, Jessica Marie Fritz

Dissertations (2009 -)

Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility and decreased bone mass, which leads to high rates of bone fracture. OI has a prevalence of 1/5,000 to 1/10,000 in the United States. About 90% of persons with OI have a genetic mutation in the coding for collagen type I, which is the major protein of connective tissues, including bone. While its prevalence classifies it as a rare disease, it is the most common disorder of bone etiology. Until recently, little was known about the mechanics and materials of OI bone or their ...


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