Medical Genetics Commons^™

Estimating Relationships Between Phenotypes And Subjects Drawn From Admixed Families., Elizabeth M. Blue, Lisa A. Brown, Matthew P. Conomos, Jennifer L. Kirk, Alejandro Q. Nato Jr., Alice B. Popejoy, Jesse Raffa, John Ranola, Ellen M. Wijsman, Timothy Thornton

Alejandro Nato

Background: Estimating relationships among subjects in a sample, within family structures or caused by population substructure, is complicated in admixed populations. Inaccurate allele frequencies can bias both kinship estimates and tests for association between subjects and a phenotype. We analyzed the simulated and real family data from Genetic Analysis Workshop 19, and were aware of the simulation model.

Results: We found that kinship estimation is more accurate when marker data include common variants whose frequencies are less variable across populations. Estimates of heritability and association vary with age for longitudinally measured traits. Accounting for local ancestry identified different true associations ...

Mapping Genes With Longitudinal Phenotypes Via Bayesian Posterior Probabilities, Anthony Musolf, Alejandro Q. Nato Jr., Douglas Londono, Lisheng Zhou, Tara C. Matise, Derek Gordon

Alejandro Nato

Most association studies focus on disease risk, with less attention paid to disease progression or severity. These phenotypes require longitudinal data. This paper presents a new method for analyzing longitudinal data to map genes in both population-based and family-based studies. Using simulated systolic blood pressure measurements obtained from Genetic Analysis Workshop 18, we cluster the phenotype data into trajectory subgroups. We then use the Bayesian posterior probability of being in the high subgroup as a quantitative trait in an association analysis with genotype data. This method maintains high power (>80%) in locating genes known to affect the simulated phenotype for ...

Updates On Epigenetic Alterations To Brca1: Chemosensitivities, Haley Blum

Student Research and Creative Activity Fair

Breast cancer 1, early onset (BRCA1) is a human tumor suppressor gene encoding the BRCA1 protein that maintains genomic integrity. Molecular events may contribute to the loss of BRCA1 function, contributing to site specific tumorigenesis. Loss of BRCA1 function may arise from mutation or epigenetic events. Germline mutations of BRCA1 have been thoroughly implicated in heritable breast and ovarian cancers. More recently, sporadic breast cancer has been shown to be driven by epigenetic alterations to the BRCA1 promoter region, specifically methylation. Breast carcinomas that present with BRCA1 promoter methylation have been associated with triple negative breast cancers, as well as ...

Early Progression Of Krabbe Disease In Patients With Symptom Onset Between 0 And 5 Months., Maria L. Beltran-Quintero, Nicholas A. Bascou, Michele D. Poe, David A. Wenger, Carlos A. Saavedra-Matiz, Matthew J. Nichols, Maria L. Escolar

Department of Neurology Faculty Papers

BACKGROUND: Krabbe disease is a rare neurological disorder caused by a deficiency in the lysosomal enzyme, β-galactocerebrosidase, resulting in demyelination of the central and peripheral nervous systems. If left without treatment, Krabbe disease results in progressive neurodegeneration with reduced quality of life and early death. The purpose of this prospective study was to describe the natural progression of early onset Krabbe disease in a large cohort of patients.

METHODS: Patients with early onset Krabbe disease were prospectively evaluated between 1999 and 2018. Data sources included diagnostic testing, parent questionnaires, standardized multidisciplinary neurodevelopmental assessments, and neuroradiological and neurophysiological tests.

RESULTS: We ...

Innovation And Competition In Advanced Therapy Medicinal Products, Enrique Seoane-Vazquez, Vaishali Shukla, Rosa Rodriguez-Monguio

Pharmacy Faculty Articles and Research

"Advanced therapy medicinal products (ATMPs), including gene therapy, cell therapy, and tissue engineering products, represent a paradigm shift in health care as they have great potential for preventing and treating many diseases (Food and Drug Administration (FDA), 2013). By way of example, only 367 (8.0%) of the 4,603 rare diseases and conditions listed by the NIH Genetic and Rare Diseases Information Center had at least one FDA-approved drug therapy in early 2018. An estimated 3,038 (66.0%) of those rare diseases and conditions are congenital and genetic diseases that could potentially be treated by gene therapy. There ...

Improving The Genetic Diagnosis Of Familial Hypercholesterolemia, Michael Iacocca

Electronic Thesis and Dissertation Repository

Familial hypercholesterolemia (FH) is a genetic disorder of severely elevated low-density lipoprotein (LDL) cholesterol that is widely underdiagnosed and undertreated. To improve the identification of FH and initiate timely and appropriate treatment strategies, genetic testing is becoming increasingly offered worldwide as a central part of diagnosis. I describe three main ways providing a genetic diagnosis in FH can be improved. First, next-generation sequencing (NGS)-based approaches can be used to reliably identify large-scale variant types known as copy number variations (CNVs) in the LDL receptor gene (LDLR); second, NGS methodology can be further applied to extend CNV screening to additional ...

Is Retinal Metabolic Dysfunction At The Center Of The Pathogenesis Of Age-Related Macular Degeneration?, Thierry Léveillard, Nancy J. Philp, Florian Sennlaub

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The retinal pigment epithelium (RPE) forms the outer blood⁻retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE. Lactate taken up by the RPE is converted to pyruvate and ...

Cyclin D1 Integrates G9a-Mediated Histone Methylation., Zhiping Li, Xuanmao Jiao, Gabriele Di Sante, Adam Ertel, Mathew C. Casimiro, Min Wang, Sanjay Katiyar, Xiaoming Ju, D. V. Klopfenstein, Aydin Tozeren, William Dampier, Iouri Chepelev, Albert Jeltsch, Richard G. Pestell

Department of Cancer Biology Faculty Papers

Lysine methylation of histones and non-histone substrates by the SET domain containing protein lysine methyltransferase (KMT) G9a/EHMT2 governs transcription contributing to apoptosis, aberrant cell growth, and pluripotency. The positioning of chromosomes within the nuclear three-dimensional space involves interactions between nuclear lamina (NL) and the lamina-associated domains (LAD). Contact of individual LADs with the NL are dependent upon H3K9me2 introduced by G9a. The mechanisms governing the recruitment of G9a to distinct subcellular sites, into chromatin or to LAD, is not known. The cyclin D1 gene product encodes the regulatory subunit of the holoenzyme that phosphorylates pRB and NRF1 thereby governing ...

Human Survival Motor Neuron Genes Generate A Vast Repertoire Of Circular Rnas, Eric W. Ottesen, Diou Luo, Joonbae Seo, Natalia N. Singh, Ravindra N. Singh

Biomedical Sciences Publications

Circular RNAs (circRNAs) perform diverse functions, including the regulation of transcription, translation, peptide synthesis, macromolecular sequestration and trafficking. Inverted Alu repeats capable of forming RNA:RNA duplexes that bring splice sites together for backsplicing are known to facilitate circRNA generation. However, higher limits of circRNAs produced by a single Alu-rich gene are currently not predictable due to limitations of amplification and analyses. Here, using a tailored approach, we report a surprising diversity of exon-containing circRNAs generated by the Alu-rich Survival Motor Neuron (SMN) genes that code for SMN, an essential multifunctional protein in humans. We show that expression of the ...

Coordinating An Oncology Precision Medicine Clinic Within An Integrated Health System: Lessons Learned In Year One, Michael A. Thompson, Jennifer J. Godden, Deborah Wham, Antony Ruggeri, Michael P. Mullane, Amanda Wilson, Shamsuddin Virani, Scott M. Weissman, Brenda Ramczyk, Pamela Vanderwall, James L. Weese

Journal of Patient-Centered Research and Reviews

Precision medicine is a term describing strategies to promote health and prevent and treat disease based on an individual’s genetic, molecular, and lifestyle characteristics. Oncology precision medicine (OPM) is a cancer treatment approach targeting cancer-specific genetic and molecular alterations. Implementation of an OPM clinical program optimally involves the support and collaboration of multiple departments, including administration, medical oncology, pathology, interventional radiology, genetics, research, and informatics. In this review, we briefly introduce the published evidence regarding OPM’s potential effect on patient outcomes and discuss what we have learned over the first year of operating an OPM program within an ...

Human-Like Nsg Mouse Glycoproteins Sialylation Pattern Changes The Phenotype Of Human Lymphocytes And Sensitivity To Hiv-1 Infection, Raghubendra S. Dagur, Amanda Branch-Woods, Saumi Mathews, Poonam S. Joshi, Rolen M. Quadros, Donald W. Harms, Yan Cheng, Shana M. Miles, Samuel J. Pirruccello, Channabasavaiah B. Gurumurthy, Santhi Gorantla, Larisa Y. Poluektova

Journal Articles: Munroe-Meyer Institute

BACKGROUND: The use of immunodeficient mice transplanted with human hematopoietic stem cells is an accepted approach to study human-specific infectious diseases such as HIV-1 and to investigate multiple aspects of human immune system development. However, mouse and human are different in sialylation patterns of proteins due to evolutionary mutations of the CMP-N-acetylneuraminic acid hydroxylase (CMAH) gene that prevent formation of N-glycolylneuraminic acid from N-acetylneuraminic acid. How changes in the mouse glycoproteins' chemistry affect phenotype and function of transplanted human hematopoietic stem cells and mature human immune cells in the course of HIV-1 infection are not known.

RESULTS: We mutated mouse ...

Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward, Ashley L. Cooney, Paul B. Mccray, Patrick L. Sinn

Stead Family Department of Pediatrics Publications

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-regulated anion channel. Although CF is a multi-organ system disease, most people with CF die of progressive lung disease that begins early in childhood and is characterized by chronic bacterial infection and inflammation. Nearly 90% of people with CF have at least one copy of the ΔF508 mutation, but there are hundreds of CFTR mutations that result in a range of disease severities. A CFTR gene replacement approach would be efficacious regardless of the disease-causing mutation. After ...

Chd3 Helicase Domain Mutations Cause A Neurodevelopmental Syndrome With Macrocephaly And Impaired Speech And Language, Lot Snijders Blok, Inderneel Sahai, Philippe M. Campeau

Pediatric Publications and Presentations

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates ...

On The Verge Of Diagnosis: Detection, Reporting, And Investigation Of De Novo Variants In Novel Genes Identified By Clinical Sequencing., Isabelle Thiffault, Maxime Cadieux-Dion, Emily G. Farrow, Raymond Caylor, Neil A. Miller, Sarah E. Soden, Carol J. Saunders

Manuscripts, Articles, Book Chapters and Other Papers

The variable evidence supporting gene-disease associations contributes to the difficulty of accurate variant reporting in a clinical setting. An evidence-based scoring system for evaluating the clinical validity of gene-disease associations, proposed by ClinGen, considers experimental as well as genetic evidence. De novo variants are heavily weighted, given the overall rarity in the genome and their contribution to human disease, however they are reported as "genes of unknown significance" in our center when there is insufficient evidence for the gene-disease assertion. We report a collection of 21 de novo variants in genes of unknown clinical significance ascertained via clinical testing, of ...

Promoting Clinical Breast Evaluations In A Lower Middle–Income Country Setting: An Approach Toward Achieving A Sustainable Breast Health Program, Roziya Buribekova, Irina Shukurbekova, Surayo Ilnazarova, Nekruz Jamshevov, Guldarbogh Sadonshoeva, Saleem Sayani, Aliya Aminmuhammad, Farin Amersi, Sheemain Asaria, Mansoor Saleh, Zohray Talib

Medical College Documents

PURPOSE:
To promote a systems-based approach for the early detection and downstaging of breast cancer at presentation in the remote mountainous region of Gorno Badakhshan Autonomous Oblast (GBAO), Tajikistan, by introducing breast cancer awareness into the community and training health care professionals in clinical breast evaluation (CBE).
METHODS:
Through a public-private partnership between the Ministry of Health, the Aga Khan Health Services, Tajikistan, and the Aga Khan Health Board, we organized breast cancer screening in the community and trained family medicine doctors (FMDs) and family medicine nurses (FMNs) in CBE. We identified and trained CBE master trainers, who, in turn ...

Genetic Candidate Variants In Two Multigenerational Families With Childhood Apraxia Of Speech, Peter Beate, Ellen M. Wijsman, Alejandro Q. Nato Jr., Mark M. Matsushita, Kathy L. Chapman, Ian B. Stanaway, John Wolff, Kaori Oda, Virginia B. Gabo, Wendy H. Raskind

Alejandro Nato

Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage ...

Lafora Disease Masquerading As Hepatic Dysfunction, Faisal Inayat, Waqas Ullah, Hanan T. Lodhi, Zarak H. Khan, Ghulam Ilyas, Nouman Safdar Ali, Hafez Mohammad A. Abdullah

Abington Hospital Papers

Lafora disease is fatal intractable progressive myoclonic epilepsy. It is frequently characterized by epileptic seizures, difficulty walking, muscle spasms, and dementia in late childhood or adolescence. We chronicle here an unusual case of an asymptomatic young male soccer player who presented with elevated liver enzymes. Neurological examination was unremarkable. The diagnostic workup for hepatitis, infectious etiologies, autoimmune disorders, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, and other related diseases was inconclusive. He subsequently underwent an uneventful percutaneous liver biopsy. Based on the pathognomonic histopathological findings, Lafora disease was considered the likely etiology. The present study is a unique illustration of ...

Review Of Karyotypic Data From Low Grade Glial Brain Tumors, Specifically Pilocytic Astrocytomas, And Correlation Of Genetic Aberrations With Tumor Recurrence., Linda D. Cooley, Scott C. Smith, Lisa Warren, Melissa Gener, Kevin Ginn, John Herriges

Posters

Abstract: Brain tumors are the most common solid tumor of childhood. Approximately 50% of pediatric CNS tumors are low grade gliomas (WHO grade I or II) and Pilocytic astrocytoma (PA) is the most common accounting for 33% of all gliomas in children 0-14 years and ~18% of all childhood brain tumors. Prognosis with this slow-growing tumor is excellent; 10 year overall survival of ~95%. However, event free survival averages ~50%. Patient age and extent of tumor resection are key prognostic factors; tumor location and size impact resection and outcome. Histopathological features indicate PA is a benign tumor and rarely are ...

Prediction Of Preterm Birth With And Without Preeclampsia Using Mid-Pregnancy Immune And Growth-Related Molecular Factors And Maternal Characteristics, Laura L. Jelliffe-Pawlowski, Larry Rand, Bruce Bedell, Rebecca J. Baer, Scott P. Oltman, Mary E. Norton, Gary M. Shaw, David K. Stevenson, Jeffrey C. Murray, Kelli K. Ryckman

Stead Family Department of Pediatrics Publications

OBJECTIVE: To evaluate if mid-pregnancy immune and growth-related molecular factors predict preterm birth (PTB) with and without (±) preeclampsia.

STUDY DESIGN: Included were 400 women with singleton deliveries in California in 2009-2010 (200 PTB and 200 term) divided into training and testing samples at a 2:1 ratio. Sixty-three markers were tested in 15-20 serum samples using multiplex technology. Linear discriminate analysis was used to create a discriminate function. Model performance was assessed using area under the receiver operating characteristic curve (AUC).

RESULTS: Twenty-five serum biomarkers along with maternal age80% of women with PTB ± preeclampsia with best performance in women with ...

Improving The Sensitivity Of Real-Time Pcr Detection Of Group B Streptococcus Using Consensus Sequence-Derived Oligonucleotides, Ameneh Khatami, Tara M. Randis, Anna Chamby, Thomas A. Hooven, Margaret Gegick, Evan Suzman, Brady A'Hearn-Thomas, Andrew P. Steenhoff, Adam J. Ratner

Stead Family Department of Pediatrics Publications

Group B Streptococcus (GBS) is a perinatal pathogen and an emerging cause of disease in adults. Culture-independent GBS detection relies on polymerase chain reaction (PCR) of conserved genes, including sip. We demonstrate suboptimal sensitivity of the existing sip PCR strategy and validate an improved method based on consensus sequences from >100 GBS genomes.