Challenges for CNV interpretation in clinical molecular karyotyping: Lessons learned from a 1001 sample experience

被引：86

作者：

Buysse, Karen ^{[1
]}

Delle Chiaie, Barbara ^{[1
]}

Van Coster, Rudy ^{[2
]}

Loeys, Bart ^{[1
]}

De Paepe, Anne ^{[1
]}

Mortier, Geert ^{[1
]}

Speleman, Frank ^{[1
]}

Menten, Bjoern ^{[1
]}

机构：

[1] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium

[2] Ghent Univ Hosp, Dept Pediat, B-9000 Ghent, Belgium

来源：

EUROPEAN JOURNAL OF MEDICAL GENETICS | 2009年 / 52卷 / 06期

基金：

比利时弗兰德研究基金会;

关键词：

Molecular karyotyping; Array CGH; Copy number variation; Mental retardation; Guidelines; COMPARATIVE GENOMIC HYBRIDIZATION; CONSTITUTIONAL GENETIC DIAGNOSIS; COPY NUMBER VARIATION; MENTAL-RETARDATION; ARRAY-CGH; MICRODELETION SYNDROME; CONGENITAL-ANOMALIES; STRUCTURAL VARIATION; DELETION; MICROARRAYS;

D O I：

10.1016/j.ejmg.2009.09.002

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Molecular karyotyping has moved from bench to bedside for the genetic screening of patients with mental retardation and/or congenital anomalies. The commercial availability of high-resolution microarray platforms has significantly facilitated this process. However, the notion that copy number variants are also abundantly present in the general population challenges the interpretation of the clinical significance of detected copy number variants (CNVs) in these patients. Moreover, the awareness of incomplete penetrance and variable expression, exemplified by the inheritance of causal CNVs from apparently unaffected parents, has further blurred the boundary between benign and pathogenic variation. We analyzed 1001 patients using a large insert clone array (298 patients) and an oligonucleotide-based (703 patients) platform. In this cohort we encountered several examples of causal imbalances that could have been easily interpreted as benign variants when relying on established paradigms. Based on our experience and the pitfalls we encountered, we suggest a decision tree that can be used as a guideline in clinical diagnostics. Using this workflow, we detected 106 clinically significant CNVs in 100 patients, giving a diagnostic yield of at least 10%. Of these imbalances, 58 occurred de nova, 22 were inherited and 26 of unknown inheritance. This underscores that inherited CNVs should not be automatically disregarded as benign variants. Among the clinically relevant CNVs were 11 single-gene aberrations, highlighting the power of high-resolution molecular karyotyping to identify causal genes. (C) 2009 Elsevier Masson SAS. All rights reserved.

引用

页码：398 / 403

页数：6

共 38 条

[11] A tiling resolution DNA microarray with complete coverage of the human genome [J].

Ishkanian, AS ;

Malloff, CA ;

Watson, SK ;

deLeeuw, RJ ;

Chi, B ;

Coe, BP ;

Snijders, A ;

Albertson, DG ;

Pinkel, D ;

Marra, MA ;

Ling, V ;

MacAulay, C ;

Lam, WL .

NATURE GENETICS, 2004, 36 (03) :299-303

[12] Population Analysis of Large Copy Number Variants and Hotspots of Human Genetic Disease [J].

Itsara, Andy ;

Cooper, Gregory M. ;

Baker, Carl ;

Girirajan, Santhosh ;

Li, Jun ;

Absher, Devin ;

Krauss, Ronald M. ;

Myers, Richard M. ;

Ridker, Paul M. ;

Chasman, Daniel I. ;

Mefford, Heather ;

Ying, Phyllis ;

Nickerson, Deborah A. ;

Eichler, Evan E. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2009, 84 (02) :148-161

[13] Population stratification of a common APOBEC gene deletion polymorphism [J].

Kidd, Jeffrey M. ;

Newman, Tera L. ;

Tuzun, Eray ;

Kaul, Rajinder ;

Eichler, Evan E. .

PLOS GENETICS, 2007, 3 (04) :0584-0592

[14] Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome [J].

Kleefstra, Tjitske ;

Brunner, Han G. ;

Amiel, Jeanne ;

Oudakker, Astrid R. ;

Nillesen, Willy M. ;

Magee, Alex ;

Genevieve, David ;

Cormier-Daire, Valerie ;

van Esch, Hilde ;

Fryns, Jean-Pierre ;

Hamel, Ben C. J. ;

Sistermans, Erik A. ;

de Vries, Bert B. A. ;

van Bokhoven, Hans .

AMERICAN JOURNAL OF HUMAN GENETICS, 2006, 79 (02) :370-377

[15] A homozygous deletion of a normal variation locus in a patient with hearing loss from non-consanguineous parents [J].

Knijnenburg, J. ;

Oberstein, S. A. J. Lesnik ;

Frei, K. ;

Lucas, T. ;

Gijsbers, A. C. J. ;

Ruivenkamp, C. A. L. ;

Tanke, H. J. ;

Szuhai, K. .

JOURNAL OF MEDICAL GENETICS, 2009, 46 (06) :412-417

[16] Genomic Microarrays in Mental Retardation: A Practical Workflow for Diagnostic Applications [J].

Koolen, David A. ;

Pfundt, Rolph ;

de Leeuw, Nicole ;

Hehir-Kwa, Jayne Y. ;

Nillesen, Willy M. ;

Neefs, Ineke ;

Scheltinga, Ine ;

Sistermans, Erik ;

Smeets, Dominique ;

Brunner, Han G. ;

van Kessel, Ad Geurts ;

Veltman, Joris A. ;

de Vries, Bert B. A. .

HUMAN MUTATION, 2009, 30 (03) :283-292

[17] Molecular Karyotyping of Patients with Unexplained Mental Retardation by SNP Arrays: A Multicenter Study [J].

McMullan, Dominic J. ;

Bonin, Michael ;

Hehir-Kwa, Jayne Y. ;

de Vries, Bert B. A. ;

Dufke, Andreas ;

Rattenberry, Eleanor ;

Steehouwer, Marloes ;

Moruz, Luminita ;

Pfundt, Rolph ;

de Leeuw, Nicole ;

Riess, Angelika ;

Altug-Teber, Ozge ;

Enders, Herbert ;

Singer, Sylke ;

Grasshoff, Ute ;

Walter, Michael ;

Walker, Judith M. ;

Lamb, Catherine V. ;

Davison, E. Val ;

Brueton, Louise ;

Riess, Olaf ;

Veltman, Joris A. .

HUMAN MUTATION, 2009, 30 (07) :1082-1092

[18] Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes [J].

Mefford, Heather C. ;

Sharp, Andrew J. ;

Baker, Carl ;

Itsara, Andy ;

Jiang, Zhaoshi ;

Buysse, Karen ;

Huang, Shuwen ;

Maloney, Viv K. ;

Crolla, John A. ;

Baralle, Diana ;

Collins, Amanda ;

Mercer, Catherine ;

Norga, Koen ;

de Ravel, Thomy ;

Devriendt, Koen ;

Bongers, Ernie M. H. F. ;

de Leeuw, Nicole ;

Reardon, William ;

Gimelli, Stefania ;

Bena, Frederique ;

Hennekam, Raoul C. ;

Male, Alison ;

Gaunt, Lorraine ;

Clayton-Smith, Jill ;

Simonic, Ingrid ;

Park, Soo Mi ;

Mehta, Sarju G. ;

Nik-Zainal, Serena ;

Woods, C. Geoffrey ;

Firth, Helen V. ;

Parkin, Georgina ;

Fichera, Marco ;

Reitano, Santina ;

Lo Giudice, Mariangela ;

Li, Kelly E. ;

Casuga, Iris ;

Broomer, Adam ;

Conrad, Bernard ;

Schwerzmann, Markus ;

Raber, Lorenz ;

Gallati, Sabina ;

Striano, Pasquale ;

Coppola, Antonietta ;

Tolmie, John L. ;

Tobias, Edward S. ;

Lilley, Chris ;

Armengol, Lluis ;

Spysschaert, Yves ;

Verloo, Patrick ;

De Coene, Anja .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 359 (16) :1685-U130

[19] Private inherited microdeletion/microduplications: Implications in clinical practice [J].

Mencarelli, Maria Antonietta ;

Katzaki, Eleni ;

Papa, Filomena Tiziana ;

Sampieri, Katia ;

Caselli, Rossella ;

Uliana, Vera ;

Pollazzon, Marzia ;

Canitano, Roberto ;

Mostardini, Rosa ;

Grosso, Salvatore ;

Longo, Ilaria ;

Ariani, Francesca ;

Meloni, Ilaria ;

Hayek, Josef ;

Balestri, Paolo ;

Mari, Francesca ;

Renieri, Alessandra .

EUROPEAN JOURNAL OF MEDICAL GENETICS, 2008, 51 (05) :409-416

[20] Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports [J].

Menten, B. ;

Maas, N. ;

Thienpont, B. ;

Buysse, K. ;

Vandesompele, J. ;

Melotte, C. ;

de Ravel, T. ;

Van Vooren, S. ;

Balikova, I. ;

Backx, L. ;

Janssens, S. ;

De Paepe, A. ;

De Moor, B. ;

Moreau, Y. ;

Marynen, P. ;

Fryns, J-P ;

Mortier, G. ;

Devriendt, K. ;

Speleman, F. ;

Vermeesch, J. R. .

JOURNAL OF MEDICAL GENETICS, 2006, 43 (08) :625-633

← 1 2 3 4 →