Whole-exome sequencing enables correct diagnosis and surgical management of rare inherited childhood anemia

Monica Khurana, Donna Edwards, Frederick Rescorla, Caroline Miller, Ying He, Elizabeth Sierra Potchanant, Grzegorz Nalepa

Research output: Contribution to journalArticle

Abstract

Correct diagnosis of inherited bone marrow failure syndromes is a challenge because of the significant overlap in clinical presentation of these disorders. Establishing right genetic diagnosis is crucial for patients' optimal clinical management and family counseling. A nondysmorphic infant reported here developed severe transfusion-dependent anemia and met clinical criteria for diagnosis of Diamond-Blackfan anemia (DBA). However, whole-exome sequencing demonstrated that the child was a compound heterozygote for a paternally inherited pathogenic truncating variant (SPTA1c.4975 C>T) and a novel maternally inherited missense variant of uncertain significance (SPTA1c.5029 G>A) within the spectrin gene, consistent with hereditary hemolytic anemia due to disruption of red blood cell (RBC) cytoskeleton. Ektacytometry demonstrated abnormal membrane flexibility of the child's RBCs. Scanning electron microscopy revealed morphological aberrations of the patient's RBCs. Both parents were found to have mild hereditary elliptocytosis. Importantly, patients with severe RBC membrane defects may be successfully managed with splenectomy to minimize peripheral destruction of misshapen RBCs, whereas patients with DBA require lifelong transfusions, steroid therapy, or hematopoietic stem cell transplantation. As suggested by the WES findings, splenectomy rendered our patient transfusion-independent, improving the family's quality of life and preventing transfusion-related iron overload. This case illustrates the utility of whole-exome sequencing in clinical care of children with genetic disorders of unclear presentation.

Original languageEnglish (US)
JournalCold Spring Harbor molecular case studies
Volume4
Issue number5
DOIs
StatePublished - Oct 1 2018

Fingerprint

Exome
Anemia
Diamond-Blackfan Anemia
Splenectomy
Hereditary Elliptocytosis
Erythrocytes
Congenital Hemolytic Anemia
Spectrin
Inborn Genetic Diseases
Iron Overload
Hematopoietic Stem Cell Transplantation
Heterozygote
Child Care
Cytoskeleton
Electron Scanning Microscopy
Counseling
Parents
Steroids
Quality of Life
Cell Membrane

Keywords

  • anemic pallor
  • congenital hemolytic anemia
  • microspherocytosis
  • reticulocytopenia
  • unconjugated hyperbilirubinemia

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Whole-exome sequencing enables correct diagnosis and surgical management of rare inherited childhood anemia. / Khurana, Monica; Edwards, Donna; Rescorla, Frederick; Miller, Caroline; He, Ying; Sierra Potchanant, Elizabeth; Nalepa, Grzegorz.

In: Cold Spring Harbor molecular case studies, Vol. 4, No. 5, 01.10.2018.

Research output: Contribution to journalArticle

Khurana, Monica ; Edwards, Donna ; Rescorla, Frederick ; Miller, Caroline ; He, Ying ; Sierra Potchanant, Elizabeth ; Nalepa, Grzegorz. / Whole-exome sequencing enables correct diagnosis and surgical management of rare inherited childhood anemia. In: Cold Spring Harbor molecular case studies. 2018 ; Vol. 4, No. 5.
@article{f0db57ef6068455b8012d0b353963999,
title = "Whole-exome sequencing enables correct diagnosis and surgical management of rare inherited childhood anemia",
abstract = "Correct diagnosis of inherited bone marrow failure syndromes is a challenge because of the significant overlap in clinical presentation of these disorders. Establishing right genetic diagnosis is crucial for patients' optimal clinical management and family counseling. A nondysmorphic infant reported here developed severe transfusion-dependent anemia and met clinical criteria for diagnosis of Diamond-Blackfan anemia (DBA). However, whole-exome sequencing demonstrated that the child was a compound heterozygote for a paternally inherited pathogenic truncating variant (SPTA1c.4975 C>T) and a novel maternally inherited missense variant of uncertain significance (SPTA1c.5029 G>A) within the spectrin gene, consistent with hereditary hemolytic anemia due to disruption of red blood cell (RBC) cytoskeleton. Ektacytometry demonstrated abnormal membrane flexibility of the child's RBCs. Scanning electron microscopy revealed morphological aberrations of the patient's RBCs. Both parents were found to have mild hereditary elliptocytosis. Importantly, patients with severe RBC membrane defects may be successfully managed with splenectomy to minimize peripheral destruction of misshapen RBCs, whereas patients with DBA require lifelong transfusions, steroid therapy, or hematopoietic stem cell transplantation. As suggested by the WES findings, splenectomy rendered our patient transfusion-independent, improving the family's quality of life and preventing transfusion-related iron overload. This case illustrates the utility of whole-exome sequencing in clinical care of children with genetic disorders of unclear presentation.",
keywords = "anemic pallor, congenital hemolytic anemia, microspherocytosis, reticulocytopenia, unconjugated hyperbilirubinemia",
author = "Monica Khurana and Donna Edwards and Frederick Rescorla and Caroline Miller and Ying He and {Sierra Potchanant}, Elizabeth and Grzegorz Nalepa",
year = "2018",
month = "10",
day = "1",
doi = "10.1101/mcs.a003152",
language = "English (US)",
volume = "4",
journal = "Cold Spring Harbor molecular case studies",
issn = "2373-2873",
publisher = "Cold Spring Harbor Laboratory Press",
number = "5",

}

TY - JOUR

T1 - Whole-exome sequencing enables correct diagnosis and surgical management of rare inherited childhood anemia

AU - Khurana, Monica

AU - Edwards, Donna

AU - Rescorla, Frederick

AU - Miller, Caroline

AU - He, Ying

AU - Sierra Potchanant, Elizabeth

AU - Nalepa, Grzegorz

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Correct diagnosis of inherited bone marrow failure syndromes is a challenge because of the significant overlap in clinical presentation of these disorders. Establishing right genetic diagnosis is crucial for patients' optimal clinical management and family counseling. A nondysmorphic infant reported here developed severe transfusion-dependent anemia and met clinical criteria for diagnosis of Diamond-Blackfan anemia (DBA). However, whole-exome sequencing demonstrated that the child was a compound heterozygote for a paternally inherited pathogenic truncating variant (SPTA1c.4975 C>T) and a novel maternally inherited missense variant of uncertain significance (SPTA1c.5029 G>A) within the spectrin gene, consistent with hereditary hemolytic anemia due to disruption of red blood cell (RBC) cytoskeleton. Ektacytometry demonstrated abnormal membrane flexibility of the child's RBCs. Scanning electron microscopy revealed morphological aberrations of the patient's RBCs. Both parents were found to have mild hereditary elliptocytosis. Importantly, patients with severe RBC membrane defects may be successfully managed with splenectomy to minimize peripheral destruction of misshapen RBCs, whereas patients with DBA require lifelong transfusions, steroid therapy, or hematopoietic stem cell transplantation. As suggested by the WES findings, splenectomy rendered our patient transfusion-independent, improving the family's quality of life and preventing transfusion-related iron overload. This case illustrates the utility of whole-exome sequencing in clinical care of children with genetic disorders of unclear presentation.

AB - Correct diagnosis of inherited bone marrow failure syndromes is a challenge because of the significant overlap in clinical presentation of these disorders. Establishing right genetic diagnosis is crucial for patients' optimal clinical management and family counseling. A nondysmorphic infant reported here developed severe transfusion-dependent anemia and met clinical criteria for diagnosis of Diamond-Blackfan anemia (DBA). However, whole-exome sequencing demonstrated that the child was a compound heterozygote for a paternally inherited pathogenic truncating variant (SPTA1c.4975 C>T) and a novel maternally inherited missense variant of uncertain significance (SPTA1c.5029 G>A) within the spectrin gene, consistent with hereditary hemolytic anemia due to disruption of red blood cell (RBC) cytoskeleton. Ektacytometry demonstrated abnormal membrane flexibility of the child's RBCs. Scanning electron microscopy revealed morphological aberrations of the patient's RBCs. Both parents were found to have mild hereditary elliptocytosis. Importantly, patients with severe RBC membrane defects may be successfully managed with splenectomy to minimize peripheral destruction of misshapen RBCs, whereas patients with DBA require lifelong transfusions, steroid therapy, or hematopoietic stem cell transplantation. As suggested by the WES findings, splenectomy rendered our patient transfusion-independent, improving the family's quality of life and preventing transfusion-related iron overload. This case illustrates the utility of whole-exome sequencing in clinical care of children with genetic disorders of unclear presentation.

KW - anemic pallor

KW - congenital hemolytic anemia

KW - microspherocytosis

KW - reticulocytopenia

KW - unconjugated hyperbilirubinemia

UR - http://www.scopus.com/inward/record.url?scp=85054098106&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054098106&partnerID=8YFLogxK

U2 - 10.1101/mcs.a003152

DO - 10.1101/mcs.a003152

M3 - Article

C2 - 30275003

AN - SCOPUS:85054098106

VL - 4

JO - Cold Spring Harbor molecular case studies

JF - Cold Spring Harbor molecular case studies

SN - 2373-2873

IS - 5

ER -