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

• DOI: 10.1101/mcs.a003384
• Publication Date: 2018-12-17T19:49:20Z
• Authors: David Claassen; Michelle Boals; Kevin M. Bowling; Gregory M. Cooper; Jennifer Cox; Michael Hershfield; Sara Lewis; Marcin Wlodarski; Mitchell J. Weiss; Jeremie H. Estepp
• Keywords: Male; Parents; Ribosomal Proteins; 0301 basic medicine; Adenosine Deaminase; 3. Good health; 03 medical and health sciences; Bone Marrow; Mutation; Exome Sequencing; Humans; Intercellular Signaling Peptides and Proteins; Genetic Testing; Child; Anemia, Hypoplastic, Congenital; Rapid Communication; Anemia, Diamond-Blackfan

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.