title: Exome sequencing results in successful diagnosis and treatment of a severe congenital anemia.
abstract: Whole-exome sequencing is increasingly used for diagnosis and identification of appropriate therapies in patients. Here, we present the case of a 3-yr-old male with a lifelong and severe transfusion-dependent anemia of unclear etiology, despite an extensive clinical workup. Given the difficulty of making the diagnosis and the potential side effects from performing interventions in patients with a congenital anemia of unknown etiology, we opted to perform whole-exome sequencing on the patient and his parents. This resulted in the identification of homozygous loss-of-function mutations in the EPB41 gene, encoding erythrocyte protein band 4.1, which therefore causes a rare and severe form of hereditary elliptocytosis in the patient. Based on prior clinical experience in similar patients, a surgical splenectomy was performed that resulted in subsequent transfusion independence in the patient. This case illustrates how whole-exome sequencing can lead to accurate diagnoses (and exclusion of diagnoses where interventions, such as splenectomy, would be contraindicated), thereby resulting in appropriate and successful therapeutic intervention-a major goal of precision medicine.
authors.affiliation: Division of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Lacy
authors.affiliation: Division of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
authors.forename: Jacob C
authors.initials: JC
authors.lastname: Ulirsch
authors.affiliation: Division of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Rachael F
authors.initials: RF
authors.lastname: Grace
authors.affiliation: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Meghan C
authors.initials: MC
authors.lastname: Towne
authors.affiliation: New York Blood Center, New York, New York 10065, USA;
authors.forename: John
authors.initials: J
authors.lastname: Hale
authors.affiliation: New York Blood Center, New York, New York 10065, USA;
authors.forename: Narla
authors.initials: N
authors.lastname: Mohandas
authors.affiliation: Division of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Lux
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;; Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Pankaj B
authors.initials: PB
authors.lastname: Agrawal
authors.affiliation: Division of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Sankaran
keywords: chronic hemolytic anemia; congenital hemolytic anemia