Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons^™

Functional Validation Of Novel Compound Heterozygous Variants In B3gat3 Resulting In Severe Osteopenia And Fractures: Expanding The Disease Phenotype., Florian Job, Shuji Mizumoto, Laurie Smith, Natario Couser, Ashley Brazil, Howard Saal, Melanie Patterson, Margaret Gibson, Sarah E. Soden, Neil A. Miller, Isabelle Thiffault, Carol J. Saunders, Shuhei Yamada, Katrin Hoffmann, Kazuyuki Sugahara, Emily G. Farrow

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: A new disease class of syndromes, described as linkeropathies, which are derived from defects in the glycosaminoglycan-linker region as well as glycosaminoglycan-side chains of proteoglycans is increasingly being recognized as a cause of human disease. Proteoglycans are an essential component of the extracellular matrix. Defects in the enzymatic process of proteoglycan synthesis broadly occur due to the incorrect addition of side chains. Previously, homozygous missense variants within the B3GAT3 gene encoding beta 1,3 glucuronyltransferase 3(GlcAT-I) responsible for the biosynthesis of glycosaminoglycans have been described in 7 individuals.

CASE PRESENTATION: In this study, a 4-year-old patient with a severe phenotype …

A Hypothesis For Using Pathway Genetic Load Analysis For Understanding Complex Outcomes In Bilirubin Encephalopathy, Sean M. Riordan, Douglas C. Bittel, Jean-Baptist Lepichon, Silvia Gazzin, Claudio Tiribelli, Jon F. Watchko, Richard P. Wennberg, Steven Shapiro

Manuscripts, Articles, Book Chapters and Other Papers

© 2016 Riordan, Bittel, Le Pichon, Gazzin, Tiribelli, Watchko, Wennberg and Shapiro.

Genetic-based susceptibility to bilirubin neurotoxicity and chronic bilirubin encephalopathy (kernicterus) is still poorly understood. Neonatal jaundice affects 60-80% of newborns, and considerable effort goes into preventing this relatively benign condition from escalating into the development of kernicterus making the incidence of this potentially devastating condition very rare in more developed countries. The current understanding of the genetic background of kernicterus is largely comprised of mutations related to alterations of bilirubin production, elimination, or both. Less is known about mutations that may predispose or protect against CNS bilirubin neurotoxicity. …

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

Christian Mueller

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 one-time treatment with rAAV1-AAT in …

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 …

Canine Rd3 Mutation Establishes Rod-Cone Dysplasia Type 2 (Rcd2) As Ortholog Of Human And Murine Rd3, Anna V. Kukekova, Orly Goldstein, Jennifer L. Johnson, Malcolm A. Richardson, Susan E. Pearce-Kelling, Anand Swaroop, James S. Friedman, Gustavo D. Aguirre, Gregory M. Acland

Gustavo D. Aguirre, VMD, PhD

Rod-cone dysplasia type 2 (rcd2) is an autosomal recessive disorder that segregates in collie dogs. Linkage disequilibrium and meiotic linkage mapping were combined to take advantage of population structure within this breed and to fine map rcd2 to a 230-kb candidate region that included the gene C1orf36 responsible for human and murine rd3, and within which all affected dogs were homozygous for one haplotype. In one of three identified canine retinal RD3 splice variants, an insertion was found that cosegregates with rcd2 and is predicted to alter the last 61 codons of the normal open reading frame and further extend …

Col9a2 And Col9a3 Mutations In Canine Autosomal Recessive Oculoskeletal Dysplasia, Orly Goldstein, Richard Guyon, Anna Kukekova, Tatyana N. Kuznetsova, Susan E. Pearce-Kelling, Jennifer Johnson, Gustavo D. Aguirre, Gregory M. Acland

Gustavo D. Aguirre, VMD, PhD

Oculoskeletal dysplasia segregates as an autosomal recessive trait in the Labrador retriever and Samoyed canine breeds, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism and severe ocular defects. The disease phenotype resembles human hereditary arthro-ophthalmopathies such as Stickler and Marshall syndromes, although these disorders are usually dominant. Linkage studies mapped drd1 to canine chromosome 24 and drd2 to canine chromosome 15. Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1 and a 1,267-bp deletion mutation in the …

Cloning Of Canine Galactokinase (Galk1) And Evaluation As A Candidate Gene For Hereditary Cataracts In Labrador Retrievers, Duska J. Sidjanin, John L. Mcelwee, Brian Miller, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

We identified a pedigree of Labrador retrievers (LR) that develop hereditary cataracts between 6 and 18 months of age. In humans, galactokinase deficiency is an autosomal recessive disorder characterized by juvenile onset of cataracts.1 In order to evaluate GALK1 as a candidate gene, we cloned and sequenced the canine GALK1 gene and tested a single nucleotide polymorphism (SNP) in the gene for segregation with cataracts in the LR pedigree.

Blinded By The Light: Retinal Phototoxicity In The Context Of Safety Studies, Maria Cristina De Vera Mudry, Sven Kronenberg, Shun-Ichiro Komatsu, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

No abstract provided.

Canine Multifocal Retinopathy In The Australian Shepherd: A Case Report, Ingo Hoffmann, Karina E. Guziewicz, Barbara Zangerl, Gustavo D. Aguirre, Christian Y. Mardin

Gustavo D. Aguirre, VMD, PhD

A 1-year-old Australian Shepherd (AS) was presented for a routine hereditary eye examination. During the examination multiple raised, brown to orange lesions were noted in the fundus, which could not be attributed to a known retinal disease in this breed. As they clinically most closely resembled canine multifocal retinopathy (cmr) and no indication of an acquired condition was found, genetic tests for BEST1 gene mutations were performed. These showed the dog to be homozygous for the cmr1 (C73T/R25X) gene defect. Furthermore, ultrasound (US), electroretinography (ERG), and optical coherence tomography were performed, confirming changes typical for cmr. Subsequently, the AS pedigree …

Renal And Cardiovascular Morbidities Associated With Apol1 Status Among African-American And Non-African-American Children With Focal Segmental Glomerulosclerosis., Robert P. Woroniecki, Derek K. Ng, Sophie Limou, Cheryl A. Winkler, Kimberly J. Reidy, Mark Mitsnefes, Matthew G. Sampson, Craig S. Wong, Bradley A. Warady, Susan L. Furth, Jeffrey B. Kopp, Frederick J. Kaskel

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND AND OBJECTIVES: African-American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how APOL1 genotypes contribute to kidney disease risk, progression, and cardiovascular morbidity in children.

DESIGN SETTING PARTICIPANTS AND MEASUREMENTS: We examined the prevalence of APOL1 genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1-16 years with mild to moderate kidney disease.

RESULTS: A total of 140 AA children in the CKiD study were genotyped. High …

Diagnostics Of Primary Immunodeficiencies Through Next-Generation Sequencing., Vera Gallo, Laura Dotta, Giuliana Giardino, Emilia Cirillo, Vassilios Lougaris, Roberta D'Assante, Alberto Prandini, Rita Consolini, Emily G. Farrow, Isabelle Thiffault, Carol J. Saunders, Antonio Leonardi, Alessandro Plebani, Raffaele Badolato, Claudio Pignata

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Recently, a growing number of novel genetic defects underlying primary immunodeficiencies (PIDs) have been identified, increasing the number of PID up to more than 250 well-defined forms. Next-generation sequencing (NGS) technologies and proper filtering strategies greatly contributed to this rapid evolution, providing the possibility to rapidly and simultaneously analyze large numbers of genes or the whole exome.

OBJECTIVE: To evaluate the role of targeted NGS and whole exome sequencing (WES) in the diagnosis of a case series, characterized by complex or atypical clinical features suggesting a PID, difficult to diagnose using the current diagnostic procedures.

METHODS: We retrospectively analyzed …

The Challenge Of Analyzing The Results Of Next-Generation Sequencing In Children., Isabelle Thiffault, John Lantos

Manuscripts, Articles, Book Chapters and Other Papers

In recent years, next-generation sequencing technologies have revolutionized approaches to genetic studies. Whole-exome or whole-genome sequencing allows diagnoses in many patients who have complex phenotypes and unusual clinical presentations. As genomic and exomic testing expands in both the research and clinical settings, pediatricians will need to understand the technology of next-generation sequencing and the complexity of interpreting genomic variants relevant to patient phenotypic features. This article briefly explains the technology by which genomes are sequenced and discusses some of the complexity related to interpreting genomic variants. We conclude with some thoughts on the clinical applications of such testing.

Whole-Genome Sequencing And Disability In The Nicu: Exploring Practical And Ethical Challenges., Michael J. Deem

Manuscripts, Articles, Book Chapters and Other Papers

Clinical whole-genome sequencing (WGS) promises to deliver faster diagnoses and lead to better management of care in the NICU. However,several disability rights advocates have expressed concern that clinical use of genetic technologies may reinforce and perpetuate stigmatization of and discrimination against disabled persons in medical and social contexts. There is growing need, then, for clinicians and bioethicists to consider how the clinical use of WGS in the newborn period might exacerbate such harms to persons with disabilities. This article explores ways to extend these concerns to clinical WGS in neonatal care. By considering these perspectives during the early phases of …