Clin Genet 2015: 87: 196–198 Printed in Singapore. All rights reserved
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12350
Letter to the Editor
A novel ACAD8 mutation in asymptomatic patients with isobutyryl-CoA dehydrogenase deficiency and a review of the ACAD8 mutation spectrum To the Editor: Isobutyryl-CoA dehydrogenase (IBD) deficiency is a very rare autosomal recessive metabolic disorder that is related to valine catabolism. Inherited metabolic disorders (IMDs) with an increase in C4 acylcarnitine include IBD deficiency, shortchain acyl-CoA dehydrogenase (SCAD) deficiency, ethylmalonic encephalopathy, multiple acyl-CoA dehydrogenase deficiency and formiminoglutamic aciduria. Most Korean newborns are screened by tandem mass spectrometry for differential diagnosis of various IMDs. We identified two Korean patients with IBD deficiency by newborn screening. They were asymptomatic as newborns, but had characteristic findings in acylcarnitines, organic acids, and mutation analyses. Patient 1 showed an elevated C4 acylcarnitine level (1.67 μmol/l, cutoff: A and c.3G>T, have been reported in previous papers (1, 2). The novel mutation, c.1156_1158delCAG, was not found in the single nucleotide polymorphism database (dbSNP; http://www.ncbi.nlm.nih.gov/projects/SNP/) and was not detected in 110 healthy individuals.
196
In addition, we reviewed previous studies of ACAD8 mutations in patients with IBD deficiency. To the best of our knowledge, 20 patients with IBD deficiency have been diagnosed by molecular genetic tests, and 22 ACAD8 mutations have been reported to date (Table 1) (1–7). The nomenclature was updated using Mutalyzer Name Checker (http://www.mutalyzer.nl) based on Human Genome Variation Society nomenclature version 2.0. Among the 22 known ACAD8 mutations, missense mutations are the most common (17/22), and other mutations types include one nonsense, one duplication, one deletion, one initiation codon mutation, and one splicing mutation. The c.455T>C and c.867C>A mutations are frequently observed (10%, 4/40 mutant alleles), 25% of the mutant alleles are located on exon 4, and 80% are located on exons 3, 4, 8, 9, or 10 (Figure 1). In Asia, six patients with IBD deficiency have been reported in the English literature (1, 2, 7). Three of these patients were Korean (including our cases), one was Jordanian, and the other two were East Indian siblings. None of the Asian patients had medical problems, except the Jordanian patient. The initiation codon mutation (c.3G>T, p.Met1Ile) found in the Korean patients affects the start codon, and incomplete transcription and translation might lead to the attenuation of the IBD enzyme (2). It is interesting to note that a small novel deletion of c.1156_1158del (p.Gln386del) was found in two unrelated patients. The glutamine residue at position 386 in the ACAD8 protein is highly conserved across species (http://www.h-invitational.jp/evola/). The activity and the amount of IBD protein may vary according to the ACAD8 mutation, which suggests that the phenotype of IBD deficiency may vary based on the mutation type or locus (6). Two patients with nonsense or frameshift mutations showed clinical manifestations (5, 6), but many cases with missense mutations express no symptoms (1, 2, 5, 6). It is difficult to determine the relationships between missense mutations and phenotypes, and therefore periodic follow-up is necessary
Letter to the Editor Table 1. Genotypes of ACAD8, clinical condition, and ancestry of IBD-deficient cases in the English literature Allele 1 Patient no.
Location
1
Exon 8
2a 3
Exon 4 Exon 2
4
Exon 4
5
Exon 4
6
Exon 3
7
Exon 4
8
Exon 1
9
Exon 9
10
Exon 3
11b
Exon 8
12b
Exon 8
13
Exon 4
14
Exon 9
15
Exon 6
16
Exon 4
17
Exon 3
18 19
IVS7 Exon 3
20
Exon 1
Allele 2
ACAD8 mutation (protein variation) c.905G>A (p.Arg302Gln) NA (p.Met128Ile) c.162_163dup (p.Phe55Serfs*24) c.409G>A (p.Gly137Arg) c.45T>C (p.Met152Thr) c.348C>A (p.Cys116*) c.400G>T (p.Asp134Tyr) c.3G>T (p.Met1Ile) c.988C>T (p.Arg330Trp) c.289G>A (p.Gly97Arg) c.867C>A (p.His289Gln) c.867C>A (p.His289Gln) c.443C>T (p.Pro148Leu) c.958G>A (p.Ala320Thr) c.687T>G (p.Phe229Leu) c.455T>C (p.Met152Thr) c.233T>C (p.Met78Thr) c.841+3G>C c.289G>A (p.Gly97Arg) c.3G>T (p.Met1Ile)
Location Exon 8 Exon 4 Exon 6 Exon 9 Exon 10 Exon 9 Exon 4 Exon 9 Exon 9 Exon 4 Exon 8 Exon 8 Exon 4 Exon 10 Exon 10 Exon 5 Exon 3 IVS7 Exon 10 Exon 10
ACAD8 mutation (protein variation)
Type of mutation
Clinical symptom
Ancestry
Reference
c.905G>A (p.Arg302Gln) NA (p.Met128Ile) c.607G>A (p.Val203Ile) c.958G>A (p.Ala320Thr) c.1154A>G (p.Gln385Arg) c.1000C>T (p.Arg334Cys) c.400G>T (p.Asp134Tyr) c.1000C>T (p.Arg334Cys) c.988C>T (p.Arg330Trp) c.455T>C (p.Met152Thr) c.867C>A (p.His289Gln) c.867C>A (p.His289Gln) c.455T>C (p.Met152Thr) c.1129G>A (p.Gly377Ser) c.1129G>A (p.Gly377Ser) c.512C>G (p.Ser171Cys) c.233T>C (p.Met78Thr) c.841+3G>C c.1156_1158delCAG (p.Gln386del) c.1156_1158delCAG (p.Gln386del)
MIS/MIS
+
Hispanic
MIS/MIS DUP/MIS
− +
Turkish German
Roe et al. (3) and Nguyen et al. (4) Sass et al. (5) Sass et al. (5)
MIS/MIS
−
Danish
Pedersen et al. (6)
MIS/MIS
+
Native American
Pedersen et al. (6)
NON/MIS
+
Caucasian
Pedersen et al. (6)
MIS/MIS
+
Native American
Pedersen et al. (6)
INI/MIS
−
Korean
Yoo et al. (2)
MIS/MIS
+
North African
Oglesbee et al. (1)
MIS/MIS
−
European
Oglesbee et al. (1)
MIS/MIS
−
East Indian
Oglesbee et al. (1)
MIS/MIS
−
East Indian
Oglesbee et al. (1)
MIS/MIS
−
European
Oglesbee et al. (1)
MIS/MIS
NA
European
Oglesbee et al. (1)
MIS/MIS
−
Hispanic
Oglesbee et al. (1)
MIS/MIS
−
European
Oglesbee et al. (1)
MIS/MIS
−
Hispanic
Oglesbee et al. (1)
SP/SP MIS/DEL
+ −
Jordan Korean
Popek et al. (7) This report
INI/DEL
−
Korean
This report
DEL, deletion mutation; DUP, duplication mutation; IBD, isobutyryl-CoA dehydrogenase; INI, initiation codon mutation; MIS, missense mutation; NA, not available; NON, nonsense mutation; SCAD, short-chain acyl-CoA dehydrogenase; SP, splicing mutation. a Mutation data in patient 2 are available only at the amino acid level. b Patients 11 and 12 are siblings.
c.841+3G>C (2) c.348C>A (1) c.289G>A (2) c.233T>C (2)
c.3G>T (2)
1 5’-UTR Exon 1 ~ 109bp
c.1000C>T (2) c.988C>T (2) c.958G>A (2)
c.512C>G (1)
Exon 2
Exon 3
Exon 4
Exon 5
Exon 6
Exon 7
Exon 8
Exon 9
Exon 10
110 ~ 210bp
211 ~ 380bp
381 ~ 490bp
491 ~ 567bp
568 ~ 705bp
706 ~ 841bp
842 ~ 939bp
940 ~ 1092bp
1093 ~ 1195bp
c.162_163dup (1)
c.400G>T (2) c.409G>A (1) c.443C>T (1) c.455T>C (4) p.Met128Ile (2)
c.687T>G (1) c.607G>A (1)
c.867C>A (4) c.905G>A (2)
Exon 11 3’-UTR
1196 ~ 1248bp
c.1129G>A (2) c.1154A>G (1) c.1156_1158del (2)
Fig. 1. The locations, types, and frequencies of ACAD8 mutations reported in the literature. Of the 22 mutations, including the cases of this study, there were 17 missense, 1 nonsense, 1 deletion, 1 duplication with frameshift, 1 initiation codon, and 1 splicing mutation. , initiation codon mutation; , duplication mutation; , deletion mutation; , missense mutation; , nonsense mutation; , splicing mutation; , reported in amino acid level; numbers inside parenthesis, frequencies of mutations found in isobutyryl-CoA dehydrogenase (IBD) patients.
197
Letter to the Editor for patients who display developmental delays or metabolic derangements in early childhood. In summary, we discovered a novel c.1156_1158delCAG mutation in ACAD8 in patients with IBD deficiency, and investigated the mutation spectrum of ACAD8 . We expect that our findings will be helpful for understanding the genetic backgrounds of patients with IBD deficiency. Acknowledgements This study was supported by a grant from the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A120030).
J.W. Yuna K.I. Job H.I. Wooa S.-Y. Leea C.-S. Kia J.-W. Kima J. Songc D.H. Leed Y.-W. Leeb* H.-D. Parka* a Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea b Department of Laboratory Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea c Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea, and d Department of Pediatrics, Soonchunhyang University College of Medicine, Soonchunhyang University Hospital, Seoul, Republic of Korea References 1. Oglesbee D, He M, Majumder N et al. Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency. Genet Med 2007: 9: 108–116.
198
2. Yoo EH, Cho HJ, Ki CS, Lee SY. Isobutyryl-CoA dehydrogenase deficiency with a novel ACAD8 gene mutation detected by tandem mass spectrometry newborn screening. Clin Chem Lab Med 2007: 45: 1495–1497. 3. Roe CR, Cederbaum SD, Roe DS, Mardach R, Galindo A, Sweetman L. Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism. Mol Genet Metab 1998: 65: 264–271. 4. Nguyen TV, Andresen BS, Corydon TJ et al. Identification of isobutyrylCoA dehydrogenase and its deficiency in humans. Mol Genet Metab 2002: 77: 68–79. 5. Sass JO, Sander S, Zschocke J. Isobutyryl-CoA dehydrogenase deficiency: isobutyrylglycinuria and ACAD8 gene mutations in two infants. J Inherit Metab Dis 2004: 27: 741–745. 6. Pedersen CB, Bischoff C, Christensen E et al. Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening. Pediatr Res 2006: 60: 315–320. 7. Popek M, Walter M, Fernando M, Lindner M, Schwab KO, Sass JO. Two inborn errors of metabolism in a newborn: glutaric aciduria type I combined with isobutyrylglycinuria. Clin Chim Acta 2010: 411: 2087–2091.
Correspondence: Hyung-Doo Park, MD, PhD Department of Laboratory Medicine and Genetics Samsung Medical Center Sungkyunkwan University School of Medicine 81 Irwon-ro, Gangnam-gu Seoul 135-710 Republic of Korea Tel.: +82 2 3410 0290 fax: +82 2 3410 2719 e-mail: [email protected] and Yong-Wha Lee, MD, PhD Department of Laboratory Medicine and Genetics Soonchunhyang University College of Medicine Soonchunhyang University Bucheon Hospital 170 Jomaru-ro, Wonmi-gu Bucheon 420–767 Republic of Korea Tel: +82 32 621 5943 fax: +82 32 621 5944 e-mail: [email protected]
Copyright of Clinical Genetics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12350
Letter to the Editor
A novel ACAD8 mutation in asymptomatic patients with isobutyryl-CoA dehydrogenase deficiency and a review of the ACAD8 mutation spectrum To the Editor: Isobutyryl-CoA dehydrogenase (IBD) deficiency is a very rare autosomal recessive metabolic disorder that is related to valine catabolism. Inherited metabolic disorders (IMDs) with an increase in C4 acylcarnitine include IBD deficiency, shortchain acyl-CoA dehydrogenase (SCAD) deficiency, ethylmalonic encephalopathy, multiple acyl-CoA dehydrogenase deficiency and formiminoglutamic aciduria. Most Korean newborns are screened by tandem mass spectrometry for differential diagnosis of various IMDs. We identified two Korean patients with IBD deficiency by newborn screening. They were asymptomatic as newborns, but had characteristic findings in acylcarnitines, organic acids, and mutation analyses. Patient 1 showed an elevated C4 acylcarnitine level (1.67 μmol/l, cutoff: A and c.3G>T, have been reported in previous papers (1, 2). The novel mutation, c.1156_1158delCAG, was not found in the single nucleotide polymorphism database (dbSNP; http://www.ncbi.nlm.nih.gov/projects/SNP/) and was not detected in 110 healthy individuals.
196
In addition, we reviewed previous studies of ACAD8 mutations in patients with IBD deficiency. To the best of our knowledge, 20 patients with IBD deficiency have been diagnosed by molecular genetic tests, and 22 ACAD8 mutations have been reported to date (Table 1) (1–7). The nomenclature was updated using Mutalyzer Name Checker (http://www.mutalyzer.nl) based on Human Genome Variation Society nomenclature version 2.0. Among the 22 known ACAD8 mutations, missense mutations are the most common (17/22), and other mutations types include one nonsense, one duplication, one deletion, one initiation codon mutation, and one splicing mutation. The c.455T>C and c.867C>A mutations are frequently observed (10%, 4/40 mutant alleles), 25% of the mutant alleles are located on exon 4, and 80% are located on exons 3, 4, 8, 9, or 10 (Figure 1). In Asia, six patients with IBD deficiency have been reported in the English literature (1, 2, 7). Three of these patients were Korean (including our cases), one was Jordanian, and the other two were East Indian siblings. None of the Asian patients had medical problems, except the Jordanian patient. The initiation codon mutation (c.3G>T, p.Met1Ile) found in the Korean patients affects the start codon, and incomplete transcription and translation might lead to the attenuation of the IBD enzyme (2). It is interesting to note that a small novel deletion of c.1156_1158del (p.Gln386del) was found in two unrelated patients. The glutamine residue at position 386 in the ACAD8 protein is highly conserved across species (http://www.h-invitational.jp/evola/). The activity and the amount of IBD protein may vary according to the ACAD8 mutation, which suggests that the phenotype of IBD deficiency may vary based on the mutation type or locus (6). Two patients with nonsense or frameshift mutations showed clinical manifestations (5, 6), but many cases with missense mutations express no symptoms (1, 2, 5, 6). It is difficult to determine the relationships between missense mutations and phenotypes, and therefore periodic follow-up is necessary
Letter to the Editor Table 1. Genotypes of ACAD8, clinical condition, and ancestry of IBD-deficient cases in the English literature Allele 1 Patient no.
Location
1
Exon 8
2a 3
Exon 4 Exon 2
4
Exon 4
5
Exon 4
6
Exon 3
7
Exon 4
8
Exon 1
9
Exon 9
10
Exon 3
11b
Exon 8
12b
Exon 8
13
Exon 4
14
Exon 9
15
Exon 6
16
Exon 4
17
Exon 3
18 19
IVS7 Exon 3
20
Exon 1
Allele 2
ACAD8 mutation (protein variation) c.905G>A (p.Arg302Gln) NA (p.Met128Ile) c.162_163dup (p.Phe55Serfs*24) c.409G>A (p.Gly137Arg) c.45T>C (p.Met152Thr) c.348C>A (p.Cys116*) c.400G>T (p.Asp134Tyr) c.3G>T (p.Met1Ile) c.988C>T (p.Arg330Trp) c.289G>A (p.Gly97Arg) c.867C>A (p.His289Gln) c.867C>A (p.His289Gln) c.443C>T (p.Pro148Leu) c.958G>A (p.Ala320Thr) c.687T>G (p.Phe229Leu) c.455T>C (p.Met152Thr) c.233T>C (p.Met78Thr) c.841+3G>C c.289G>A (p.Gly97Arg) c.3G>T (p.Met1Ile)
Location Exon 8 Exon 4 Exon 6 Exon 9 Exon 10 Exon 9 Exon 4 Exon 9 Exon 9 Exon 4 Exon 8 Exon 8 Exon 4 Exon 10 Exon 10 Exon 5 Exon 3 IVS7 Exon 10 Exon 10
ACAD8 mutation (protein variation)
Type of mutation
Clinical symptom
Ancestry
Reference
c.905G>A (p.Arg302Gln) NA (p.Met128Ile) c.607G>A (p.Val203Ile) c.958G>A (p.Ala320Thr) c.1154A>G (p.Gln385Arg) c.1000C>T (p.Arg334Cys) c.400G>T (p.Asp134Tyr) c.1000C>T (p.Arg334Cys) c.988C>T (p.Arg330Trp) c.455T>C (p.Met152Thr) c.867C>A (p.His289Gln) c.867C>A (p.His289Gln) c.455T>C (p.Met152Thr) c.1129G>A (p.Gly377Ser) c.1129G>A (p.Gly377Ser) c.512C>G (p.Ser171Cys) c.233T>C (p.Met78Thr) c.841+3G>C c.1156_1158delCAG (p.Gln386del) c.1156_1158delCAG (p.Gln386del)
MIS/MIS
+
Hispanic
MIS/MIS DUP/MIS
− +
Turkish German
Roe et al. (3) and Nguyen et al. (4) Sass et al. (5) Sass et al. (5)
MIS/MIS
−
Danish
Pedersen et al. (6)
MIS/MIS
+
Native American
Pedersen et al. (6)
NON/MIS
+
Caucasian
Pedersen et al. (6)
MIS/MIS
+
Native American
Pedersen et al. (6)
INI/MIS
−
Korean
Yoo et al. (2)
MIS/MIS
+
North African
Oglesbee et al. (1)
MIS/MIS
−
European
Oglesbee et al. (1)
MIS/MIS
−
East Indian
Oglesbee et al. (1)
MIS/MIS
−
East Indian
Oglesbee et al. (1)
MIS/MIS
−
European
Oglesbee et al. (1)
MIS/MIS
NA
European
Oglesbee et al. (1)
MIS/MIS
−
Hispanic
Oglesbee et al. (1)
MIS/MIS
−
European
Oglesbee et al. (1)
MIS/MIS
−
Hispanic
Oglesbee et al. (1)
SP/SP MIS/DEL
+ −
Jordan Korean
Popek et al. (7) This report
INI/DEL
−
Korean
This report
DEL, deletion mutation; DUP, duplication mutation; IBD, isobutyryl-CoA dehydrogenase; INI, initiation codon mutation; MIS, missense mutation; NA, not available; NON, nonsense mutation; SCAD, short-chain acyl-CoA dehydrogenase; SP, splicing mutation. a Mutation data in patient 2 are available only at the amino acid level. b Patients 11 and 12 are siblings.
c.841+3G>C (2) c.348C>A (1) c.289G>A (2) c.233T>C (2)
c.3G>T (2)
1 5’-UTR Exon 1 ~ 109bp
c.1000C>T (2) c.988C>T (2) c.958G>A (2)
c.512C>G (1)
Exon 2
Exon 3
Exon 4
Exon 5
Exon 6
Exon 7
Exon 8
Exon 9
Exon 10
110 ~ 210bp
211 ~ 380bp
381 ~ 490bp
491 ~ 567bp
568 ~ 705bp
706 ~ 841bp
842 ~ 939bp
940 ~ 1092bp
1093 ~ 1195bp
c.162_163dup (1)
c.400G>T (2) c.409G>A (1) c.443C>T (1) c.455T>C (4) p.Met128Ile (2)
c.687T>G (1) c.607G>A (1)
c.867C>A (4) c.905G>A (2)
Exon 11 3’-UTR
1196 ~ 1248bp
c.1129G>A (2) c.1154A>G (1) c.1156_1158del (2)
Fig. 1. The locations, types, and frequencies of ACAD8 mutations reported in the literature. Of the 22 mutations, including the cases of this study, there were 17 missense, 1 nonsense, 1 deletion, 1 duplication with frameshift, 1 initiation codon, and 1 splicing mutation. , initiation codon mutation; , duplication mutation; , deletion mutation; , missense mutation; , nonsense mutation; , splicing mutation; , reported in amino acid level; numbers inside parenthesis, frequencies of mutations found in isobutyryl-CoA dehydrogenase (IBD) patients.
197
Letter to the Editor for patients who display developmental delays or metabolic derangements in early childhood. In summary, we discovered a novel c.1156_1158delCAG mutation in ACAD8 in patients with IBD deficiency, and investigated the mutation spectrum of ACAD8 . We expect that our findings will be helpful for understanding the genetic backgrounds of patients with IBD deficiency. Acknowledgements This study was supported by a grant from the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A120030).
J.W. Yuna K.I. Job H.I. Wooa S.-Y. Leea C.-S. Kia J.-W. Kima J. Songc D.H. Leed Y.-W. Leeb* H.-D. Parka* a Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea b Department of Laboratory Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea c Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea, and d Department of Pediatrics, Soonchunhyang University College of Medicine, Soonchunhyang University Hospital, Seoul, Republic of Korea References 1. Oglesbee D, He M, Majumder N et al. Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency. Genet Med 2007: 9: 108–116.
198
2. Yoo EH, Cho HJ, Ki CS, Lee SY. Isobutyryl-CoA dehydrogenase deficiency with a novel ACAD8 gene mutation detected by tandem mass spectrometry newborn screening. Clin Chem Lab Med 2007: 45: 1495–1497. 3. Roe CR, Cederbaum SD, Roe DS, Mardach R, Galindo A, Sweetman L. Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism. Mol Genet Metab 1998: 65: 264–271. 4. Nguyen TV, Andresen BS, Corydon TJ et al. Identification of isobutyrylCoA dehydrogenase and its deficiency in humans. Mol Genet Metab 2002: 77: 68–79. 5. Sass JO, Sander S, Zschocke J. Isobutyryl-CoA dehydrogenase deficiency: isobutyrylglycinuria and ACAD8 gene mutations in two infants. J Inherit Metab Dis 2004: 27: 741–745. 6. Pedersen CB, Bischoff C, Christensen E et al. Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening. Pediatr Res 2006: 60: 315–320. 7. Popek M, Walter M, Fernando M, Lindner M, Schwab KO, Sass JO. Two inborn errors of metabolism in a newborn: glutaric aciduria type I combined with isobutyrylglycinuria. Clin Chim Acta 2010: 411: 2087–2091.
Correspondence: Hyung-Doo Park, MD, PhD Department of Laboratory Medicine and Genetics Samsung Medical Center Sungkyunkwan University School of Medicine 81 Irwon-ro, Gangnam-gu Seoul 135-710 Republic of Korea Tel.: +82 2 3410 0290 fax: +82 2 3410 2719 e-mail: [email protected] and Yong-Wha Lee, MD, PhD Department of Laboratory Medicine and Genetics Soonchunhyang University College of Medicine Soonchunhyang University Bucheon Hospital 170 Jomaru-ro, Wonmi-gu Bucheon 420–767 Republic of Korea Tel: +82 32 621 5943 fax: +82 32 621 5944 e-mail: [email protected]
Copyright of Clinical Genetics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
