Molecular diagnosis of hereditary spherocytosis by multi-gene target sequencing in Korea: Matching with osmotic fragility test and presence of spherocyte

Hyoung Soo Choi, Qute Choi, Jung Ah Kim, Kyong Ok Im, Si Nae Park, Yoomi Park, Hee Young Shin, Hyoung Jin Kang, Hoon Kook, Seon Young Kim, Soo Jeong Kim, Inho Kim, Ji Yoon Kim, Hawk Kim, Kyung Duk Park, Kyung Bae Park, Meerim Park, Sang Kyu Park, Eun Sil Park, Jeong A. ParkJun Eun Park, Ji Kyoung Park, Hee Jo Baek, Jeong Ho Seo, Ye Jee Shim, Hyo Seop Ahn, Keon Hee Yoo, Hoi Soo Yoon, Young Woong Won, Kun Soo Lee, Kwang Chul Lee, Mee Jeong Lee, Sun Ah Lee, Jun Ah Lee, Jae Min Lee, Jae Hee Lee, Ji Won Lee, Young Tak Lim, Hyun Joo Jung, Hee Won Chueh, Eun Jin Choi, Hye Lim Jung, Ju Han Kim, Dong Soon Lee

Research output: Contribution to journalArticle

Abstract

Background: Current diagnostic tests for hereditary spherocytosis (HS) focus on the detection of hemolysis or indirectly assessing defects of membrane protein, whereas direct methods to detect protein defects are complicated and difficult to implement. In the present study, we investigated the patterns of genetic variation associated with HS among patients clinically diagnosed with HS. Methods: Multi-gene targeted sequencing of 43 genes (17 RBC membrane protein-encoding genes, 20 RBC enzyme-encoding genes, and six additional genes for the differential diagnosis) was performed using the Illumina HiSeq platform. Results: Among 59 patients with HS, 50 (84.7%) had one or more significant variants in a RBC membrane protein-encoding genes. A total of 54 significant variants including 46 novel mutations were detected in six RBC membrane protein-encoding genes, with the highest number of variants found in SPTB (n = 28), and followed by ANK1 (n = 19), SLC4A1 (n = 3), SPTA1 (n = 2), EPB41 (n = 1), and EPB42 (n = 1). Concurrent mutations of genes encoding RBC enzymes (ALDOB, GAPDH, and GSR) were detected in three patients. UGT1A1 mutations were present in 24 patients (40.7%). Positive rate of osmotic fragility test was 86.8% among patients harboring HS-related gene mutations. Conclusions: This constitutes the first large-scaled genetic study of Korean patients with HS. We demonstrated that multi-gene target sequencing is sensitive and feasible that can be used as a powerful tool for diagnosing HS. Considering the discrepancies of clinical and molecular diagnoses of HS, our findings suggest that molecular genetic analysis is required for accurate diagnosis of HS.

Original languageEnglish
Article number114
JournalOrphanet Journal of Rare Diseases
Volume14
Issue number1
DOIs
Publication statusPublished - 2019 May 23

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Spherocytes
Hereditary Spherocytosis
Osmotic Fragility
Korea
Genes
Membrane Proteins
Mutation
Enzymes
Hemolysis
Routine Diagnostic Tests
Molecular Biology

Keywords

  • Hereditary spherocytosis
  • Molecular diagnosis
  • RBC membrane disorder

ASJC Scopus subject areas

  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Molecular diagnosis of hereditary spherocytosis by multi-gene target sequencing in Korea : Matching with osmotic fragility test and presence of spherocyte. / Choi, Hyoung Soo; Choi, Qute; Kim, Jung Ah; Im, Kyong Ok; Park, Si Nae; Park, Yoomi; Shin, Hee Young; Kang, Hyoung Jin; Kook, Hoon; Kim, Seon Young; Kim, Soo Jeong; Kim, Inho; Kim, Ji Yoon; Kim, Hawk; Park, Kyung Duk; Park, Kyung Bae; Park, Meerim; Park, Sang Kyu; Park, Eun Sil; Park, Jeong A.; Park, Jun Eun; Park, Ji Kyoung; Baek, Hee Jo; Seo, Jeong Ho; Shim, Ye Jee; Ahn, Hyo Seop; Yoo, Keon Hee; Yoon, Hoi Soo; Won, Young Woong; Lee, Kun Soo; Lee, Kwang Chul; Lee, Mee Jeong; Lee, Sun Ah; Lee, Jun Ah; Lee, Jae Min; Lee, Jae Hee; Lee, Ji Won; Lim, Young Tak; Jung, Hyun Joo; Chueh, Hee Won; Choi, Eun Jin; Jung, Hye Lim; Kim, Ju Han; Lee, Dong Soon.

In: Orphanet Journal of Rare Diseases, Vol. 14, No. 1, 114, 23.05.2019.

Research output: Contribution to journalArticle

Choi, HS, Choi, Q, Kim, JA, Im, KO, Park, SN, Park, Y, Shin, HY, Kang, HJ, Kook, H, Kim, SY, Kim, SJ, Kim, I, Kim, JY, Kim, H, Park, KD, Park, KB, Park, M, Park, SK, Park, ES, Park, JA, Park, JE, Park, JK, Baek, HJ, Seo, JH, Shim, YJ, Ahn, HS, Yoo, KH, Yoon, HS, Won, YW, Lee, KS, Lee, KC, Lee, MJ, Lee, SA, Lee, JA, Lee, JM, Lee, JH, Lee, JW, Lim, YT, Jung, HJ, Chueh, HW, Choi, EJ, Jung, HL, Kim, JH & Lee, DS 2019, 'Molecular diagnosis of hereditary spherocytosis by multi-gene target sequencing in Korea: Matching with osmotic fragility test and presence of spherocyte', Orphanet Journal of Rare Diseases, vol. 14, no. 1, 114. https://doi.org/10.1186/s13023-019-1070-0
Choi, Hyoung Soo ; Choi, Qute ; Kim, Jung Ah ; Im, Kyong Ok ; Park, Si Nae ; Park, Yoomi ; Shin, Hee Young ; Kang, Hyoung Jin ; Kook, Hoon ; Kim, Seon Young ; Kim, Soo Jeong ; Kim, Inho ; Kim, Ji Yoon ; Kim, Hawk ; Park, Kyung Duk ; Park, Kyung Bae ; Park, Meerim ; Park, Sang Kyu ; Park, Eun Sil ; Park, Jeong A. ; Park, Jun Eun ; Park, Ji Kyoung ; Baek, Hee Jo ; Seo, Jeong Ho ; Shim, Ye Jee ; Ahn, Hyo Seop ; Yoo, Keon Hee ; Yoon, Hoi Soo ; Won, Young Woong ; Lee, Kun Soo ; Lee, Kwang Chul ; Lee, Mee Jeong ; Lee, Sun Ah ; Lee, Jun Ah ; Lee, Jae Min ; Lee, Jae Hee ; Lee, Ji Won ; Lim, Young Tak ; Jung, Hyun Joo ; Chueh, Hee Won ; Choi, Eun Jin ; Jung, Hye Lim ; Kim, Ju Han ; Lee, Dong Soon. / Molecular diagnosis of hereditary spherocytosis by multi-gene target sequencing in Korea : Matching with osmotic fragility test and presence of spherocyte. In: Orphanet Journal of Rare Diseases. 2019 ; Vol. 14, No. 1.
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title = "Molecular diagnosis of hereditary spherocytosis by multi-gene target sequencing in Korea: Matching with osmotic fragility test and presence of spherocyte",
abstract = "Background: Current diagnostic tests for hereditary spherocytosis (HS) focus on the detection of hemolysis or indirectly assessing defects of membrane protein, whereas direct methods to detect protein defects are complicated and difficult to implement. In the present study, we investigated the patterns of genetic variation associated with HS among patients clinically diagnosed with HS. Methods: Multi-gene targeted sequencing of 43 genes (17 RBC membrane protein-encoding genes, 20 RBC enzyme-encoding genes, and six additional genes for the differential diagnosis) was performed using the Illumina HiSeq platform. Results: Among 59 patients with HS, 50 (84.7{\%}) had one or more significant variants in a RBC membrane protein-encoding genes. A total of 54 significant variants including 46 novel mutations were detected in six RBC membrane protein-encoding genes, with the highest number of variants found in SPTB (n = 28), and followed by ANK1 (n = 19), SLC4A1 (n = 3), SPTA1 (n = 2), EPB41 (n = 1), and EPB42 (n = 1). Concurrent mutations of genes encoding RBC enzymes (ALDOB, GAPDH, and GSR) were detected in three patients. UGT1A1 mutations were present in 24 patients (40.7{\%}). Positive rate of osmotic fragility test was 86.8{\%} among patients harboring HS-related gene mutations. Conclusions: This constitutes the first large-scaled genetic study of Korean patients with HS. We demonstrated that multi-gene target sequencing is sensitive and feasible that can be used as a powerful tool for diagnosing HS. Considering the discrepancies of clinical and molecular diagnoses of HS, our findings suggest that molecular genetic analysis is required for accurate diagnosis of HS.",
keywords = "Hereditary spherocytosis, Molecular diagnosis, RBC membrane disorder",
author = "Choi, {Hyoung Soo} and Qute Choi and Kim, {Jung Ah} and Im, {Kyong Ok} and Park, {Si Nae} and Yoomi Park and Shin, {Hee Young} and Kang, {Hyoung Jin} and Hoon Kook and Kim, {Seon Young} and Kim, {Soo Jeong} and Inho Kim and Kim, {Ji Yoon} and Hawk Kim and Park, {Kyung Duk} and Park, {Kyung Bae} and Meerim Park and Park, {Sang Kyu} and Park, {Eun Sil} and Park, {Jeong A.} and Park, {Jun Eun} and Park, {Ji Kyoung} and Baek, {Hee Jo} and Seo, {Jeong Ho} and Shim, {Ye Jee} and Ahn, {Hyo Seop} and Yoo, {Keon Hee} and Yoon, {Hoi Soo} and Won, {Young Woong} and Lee, {Kun Soo} and Lee, {Kwang Chul} and Lee, {Mee Jeong} and Lee, {Sun Ah} and Lee, {Jun Ah} and Lee, {Jae Min} and Lee, {Jae Hee} and Lee, {Ji Won} and Lim, {Young Tak} and Jung, {Hyun Joo} and Chueh, {Hee Won} and Choi, {Eun Jin} and Jung, {Hye Lim} and Kim, {Ju Han} and Lee, {Dong Soon}",
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T1 - Molecular diagnosis of hereditary spherocytosis by multi-gene target sequencing in Korea

T2 - Matching with osmotic fragility test and presence of spherocyte

AU - Choi, Hyoung Soo

AU - Choi, Qute

AU - Kim, Jung Ah

AU - Im, Kyong Ok

AU - Park, Si Nae

AU - Park, Yoomi

AU - Shin, Hee Young

AU - Kang, Hyoung Jin

AU - Kook, Hoon

AU - Kim, Seon Young

AU - Kim, Soo Jeong

AU - Kim, Inho

AU - Kim, Ji Yoon

AU - Kim, Hawk

AU - Park, Kyung Duk

AU - Park, Kyung Bae

AU - Park, Meerim

AU - Park, Sang Kyu

AU - Park, Eun Sil

AU - Park, Jeong A.

AU - Park, Jun Eun

AU - Park, Ji Kyoung

AU - Baek, Hee Jo

AU - Seo, Jeong Ho

AU - Shim, Ye Jee

AU - Ahn, Hyo Seop

AU - Yoo, Keon Hee

AU - Yoon, Hoi Soo

AU - Won, Young Woong

AU - Lee, Kun Soo

AU - Lee, Kwang Chul

AU - Lee, Mee Jeong

AU - Lee, Sun Ah

AU - Lee, Jun Ah

AU - Lee, Jae Min

AU - Lee, Jae Hee

AU - Lee, Ji Won

AU - Lim, Young Tak

AU - Jung, Hyun Joo

AU - Chueh, Hee Won

AU - Choi, Eun Jin

AU - Jung, Hye Lim

AU - Kim, Ju Han

AU - Lee, Dong Soon

PY - 2019/5/23

Y1 - 2019/5/23

N2 - Background: Current diagnostic tests for hereditary spherocytosis (HS) focus on the detection of hemolysis or indirectly assessing defects of membrane protein, whereas direct methods to detect protein defects are complicated and difficult to implement. In the present study, we investigated the patterns of genetic variation associated with HS among patients clinically diagnosed with HS. Methods: Multi-gene targeted sequencing of 43 genes (17 RBC membrane protein-encoding genes, 20 RBC enzyme-encoding genes, and six additional genes for the differential diagnosis) was performed using the Illumina HiSeq platform. Results: Among 59 patients with HS, 50 (84.7%) had one or more significant variants in a RBC membrane protein-encoding genes. A total of 54 significant variants including 46 novel mutations were detected in six RBC membrane protein-encoding genes, with the highest number of variants found in SPTB (n = 28), and followed by ANK1 (n = 19), SLC4A1 (n = 3), SPTA1 (n = 2), EPB41 (n = 1), and EPB42 (n = 1). Concurrent mutations of genes encoding RBC enzymes (ALDOB, GAPDH, and GSR) were detected in three patients. UGT1A1 mutations were present in 24 patients (40.7%). Positive rate of osmotic fragility test was 86.8% among patients harboring HS-related gene mutations. Conclusions: This constitutes the first large-scaled genetic study of Korean patients with HS. We demonstrated that multi-gene target sequencing is sensitive and feasible that can be used as a powerful tool for diagnosing HS. Considering the discrepancies of clinical and molecular diagnoses of HS, our findings suggest that molecular genetic analysis is required for accurate diagnosis of HS.

AB - Background: Current diagnostic tests for hereditary spherocytosis (HS) focus on the detection of hemolysis or indirectly assessing defects of membrane protein, whereas direct methods to detect protein defects are complicated and difficult to implement. In the present study, we investigated the patterns of genetic variation associated with HS among patients clinically diagnosed with HS. Methods: Multi-gene targeted sequencing of 43 genes (17 RBC membrane protein-encoding genes, 20 RBC enzyme-encoding genes, and six additional genes for the differential diagnosis) was performed using the Illumina HiSeq platform. Results: Among 59 patients with HS, 50 (84.7%) had one or more significant variants in a RBC membrane protein-encoding genes. A total of 54 significant variants including 46 novel mutations were detected in six RBC membrane protein-encoding genes, with the highest number of variants found in SPTB (n = 28), and followed by ANK1 (n = 19), SLC4A1 (n = 3), SPTA1 (n = 2), EPB41 (n = 1), and EPB42 (n = 1). Concurrent mutations of genes encoding RBC enzymes (ALDOB, GAPDH, and GSR) were detected in three patients. UGT1A1 mutations were present in 24 patients (40.7%). Positive rate of osmotic fragility test was 86.8% among patients harboring HS-related gene mutations. Conclusions: This constitutes the first large-scaled genetic study of Korean patients with HS. We demonstrated that multi-gene target sequencing is sensitive and feasible that can be used as a powerful tool for diagnosing HS. Considering the discrepancies of clinical and molecular diagnoses of HS, our findings suggest that molecular genetic analysis is required for accurate diagnosis of HS.

KW - Hereditary spherocytosis

KW - Molecular diagnosis

KW - RBC membrane disorder

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U2 - 10.1186/s13023-019-1070-0

DO - 10.1186/s13023-019-1070-0

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JO - Orphanet Journal of Rare Diseases

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