Complexities of genetic diagnosis illustrated by an atypical case of congenital hypoplastic anemia

Cold Spring Harb Mol Case Stud. 2018 Dec 17;4(6):a003384. doi: 10.1101/mcs.a003384. Print 2018 Dec.

Abstract

Diamond-Blackfan Anemia (DBA) is a rare polygenic disorder defined by congenital hypoplastic anemia with marked decrease or absence of bone marrow erythroid precursors. Identifying the specific genetic etiology is important for counseling and clinical management. A 6-yr-old boy with a clinical diagnosis of DBA has been followed by our pediatric hematology team since birth. His clinical course includes transfusion-dependent hypoplastic anemia and progressive autoimmune cytopenias. Genetic testing failed to identify a causative mutation in any of the classical DBA-associated genes. He and his parents underwent trio whole-exome sequencing (WES) with no genetic etiology identified initially. Clinical persistence and suspicion led to testing for adenosine deaminase 2 (ADA2) activity and whole-genome sequencing (WGS) that identified compound heterozygous pathogenic mutations in the ADA2-encoding CECR1 gene, a recently appreciated etiology for congenital hypoplastic anemia. This case illustrates current challenges in genetic testing and how they can be overcome by multidisciplinary expertise in clinical medicine and genomics.

Keywords: congenital hypoplastic anemia; congenital neutropenia.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / genetics*
  • Anemia, Diamond-Blackfan / diagnosis
  • Anemia, Diamond-Blackfan / genetics*
  • Anemia, Hypoplastic, Congenital / diagnosis
  • Anemia, Hypoplastic, Congenital / genetics*
  • Bone Marrow / physiopathology
  • Child
  • Exome Sequencing
  • Genetic Testing / methods
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Male
  • Mutation
  • Parents
  • Ribosomal Proteins

Substances

  • Intercellular Signaling Peptides and Proteins
  • Ribosomal Proteins
  • ribosomal protein S19
  • ADA2 protein, human
  • Adenosine Deaminase