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Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia

Whole-exome sequencing (WES) has been increasingly useful for the diagnosis of patients with rare causes of anemia, particularly when there is an atypical clinical presentation or targeted genotyping approaches are inconclusive. Here, we describe a 20-yr-old man with a lifelong moderate-to-severe an...

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Autores principales: Steinberg-Shemer, Orna, Ulirsch, Jacob C., Noy-Lotan, Sharon, Krasnov, Tanya, Attias, Dina, Dgany, Orly, Laor, Ruth, Sankaran, Vijay G., Tamary, Hannah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701307/
https://www.ncbi.nlm.nih.gov/pubmed/28667000
http://dx.doi.org/10.1101/mcs.a001941
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author Steinberg-Shemer, Orna
Ulirsch, Jacob C.
Noy-Lotan, Sharon
Krasnov, Tanya
Attias, Dina
Dgany, Orly
Laor, Ruth
Sankaran, Vijay G.
Tamary, Hannah
author_facet Steinberg-Shemer, Orna
Ulirsch, Jacob C.
Noy-Lotan, Sharon
Krasnov, Tanya
Attias, Dina
Dgany, Orly
Laor, Ruth
Sankaran, Vijay G.
Tamary, Hannah
author_sort Steinberg-Shemer, Orna
collection PubMed
description Whole-exome sequencing (WES) has been increasingly useful for the diagnosis of patients with rare causes of anemia, particularly when there is an atypical clinical presentation or targeted genotyping approaches are inconclusive. Here, we describe a 20-yr-old man with a lifelong moderate-to-severe anemia with accompanying splenomegaly who lacked a definitive diagnosis. After a thorough clinical workup and targeted genetic sequencing, we identified a paternally inherited β-globin mutation (HBB:c.93-21G>A, IVS-I-110:G>A), a known cause of β-thalassemia minor. As this mutation alone was inconsistent with the severity of the anemia, we performed WES. Although we could not identify any relevant pathogenic single-nucleotide variants (SNVs) or small indels, copy-number variant (CNV) analyses revealed a likely triplication of the entire α-globin cluster, which was subsequently confirmed by multiplex ligation-dependent probe amplification. Treatment and follow-up was redefined according to the diagnosis of β-thalassemia intermedia resulting from a single β-thalassemia mutation in combination with an α-globin cluster triplication. Thus, we describe a case where the typical WES-based analysis of SNVs and small indels was unrevealing, but WES-based CNV analysis resulted in a definitive diagnosis that informed clinical decision-making. More generally, this case illustrates the value of performing CNV analysis when WES is otherwise unable to elucidate a clear genetic diagnosis.
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spelling pubmed-57013072017-12-04 Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia Steinberg-Shemer, Orna Ulirsch, Jacob C. Noy-Lotan, Sharon Krasnov, Tanya Attias, Dina Dgany, Orly Laor, Ruth Sankaran, Vijay G. Tamary, Hannah Cold Spring Harb Mol Case Stud Research Report Whole-exome sequencing (WES) has been increasingly useful for the diagnosis of patients with rare causes of anemia, particularly when there is an atypical clinical presentation or targeted genotyping approaches are inconclusive. Here, we describe a 20-yr-old man with a lifelong moderate-to-severe anemia with accompanying splenomegaly who lacked a definitive diagnosis. After a thorough clinical workup and targeted genetic sequencing, we identified a paternally inherited β-globin mutation (HBB:c.93-21G>A, IVS-I-110:G>A), a known cause of β-thalassemia minor. As this mutation alone was inconsistent with the severity of the anemia, we performed WES. Although we could not identify any relevant pathogenic single-nucleotide variants (SNVs) or small indels, copy-number variant (CNV) analyses revealed a likely triplication of the entire α-globin cluster, which was subsequently confirmed by multiplex ligation-dependent probe amplification. Treatment and follow-up was redefined according to the diagnosis of β-thalassemia intermedia resulting from a single β-thalassemia mutation in combination with an α-globin cluster triplication. Thus, we describe a case where the typical WES-based analysis of SNVs and small indels was unrevealing, but WES-based CNV analysis resulted in a definitive diagnosis that informed clinical decision-making. More generally, this case illustrates the value of performing CNV analysis when WES is otherwise unable to elucidate a clear genetic diagnosis. Cold Spring Harbor Laboratory Press 2017-11 /pmc/articles/PMC5701307/ /pubmed/28667000 http://dx.doi.org/10.1101/mcs.a001941 Text en © 2017 Steinberg-Shemer et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Steinberg-Shemer, Orna
Ulirsch, Jacob C.
Noy-Lotan, Sharon
Krasnov, Tanya
Attias, Dina
Dgany, Orly
Laor, Ruth
Sankaran, Vijay G.
Tamary, Hannah
Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia
title Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia
title_full Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia
title_fullStr Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia
title_full_unstemmed Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia
title_short Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia
title_sort whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701307/
https://www.ncbi.nlm.nih.gov/pubmed/28667000
http://dx.doi.org/10.1101/mcs.a001941
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