Lessons Learned from CNV Analysis of Major Birth Defects
Abstract
:1. Introduction
1.1. Clinical Presentation
1.2. Causes for Congenital Birth Defects
2. Copy-Number Variations (CNVs) and Their Impact on the Expression of Birth Defects
3. Experience of Array-Based Molecular Karyotyping (CNV Analysis) in Larger Cohorts of Individuals with Major Birth Defects
3.1. CNV Analysis in Individuals with the Bladder Exstrophy Epispadias Complex (BEEC)
3.2. CNV Analysis in Individuals with Anorectal Malformations (ARM)
3.3. CNV Analysis in Fetuses with Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT)
3.4. CNV Analysis in Fetuses with Central Nervous System Malformations (CNS Malformations)
3.4.1. CNV Analysis in Fetuses with “Non-Isolated” Brain Malformations
3.4.2. CNV Analysis in Fetuses with “Isolated” Brain Malformations
4. “Sense and Sensibility” for the Diagnostic and Scientific Application of Array-Based Molecular Karyotyping in Individuals with Birth Defects
5. The Dilemma of Causality
5.1. Genotype-Phenotype Correlation Exemplary for the Chromosome 22q Locus
5.2. Genotype-Phenotype Correlation in CNVs Not Comprising Coding Region
6. The Importance of Functional Studies in Cells and Animal Models
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Queisser-Wahrendorf, A.; Stolz, G.; Wiesel, A.; Schlaefer, K.; Spranger, J. Malformations in newborn: Results based on 30,940 infants and fetuses from the Mainz congenital birth defect monitoring system (1990–1998). Arch. Gynecol. Obstet. 2002, 266, 163–167. [Google Scholar] [CrossRef]
- McClellan, J.; King, M.-C. Genetic heterogeneity in human disease. Cell 2010, 141, 210–217. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rasmussen, S.A.; Olney, R.S.; Holmes, L.B.; Lin, A.E.; Keppler-Noreuil, K.M.; Moore, C.A.; the National Birth Defects Prevention Study. Guidelines for case classification for the National Birth Defects Prevention Study. Birth Defects Res. Part A Clin. Mol. Teratol. 2003, 67, 193–201. [Google Scholar] [CrossRef] [PubMed]
- Khoury, M.J.; Moore, C.A.; Evans, J.A. On the use of the term “syndrome” in clinical genetics and birth defects epidemiology. Am. J. Med. Genet. 1994, 49, 26–28. [Google Scholar] [CrossRef] [PubMed]
- Redon, R.; Ishikawa, S.; Fitch, K.R.; Feuk, L.; Perry, G.H.; Andrews, T.D.; Fiegler, H.; Shapero, M.H.; Carson, A.R.; Chen, W.; et al. Global variation in copy number in the human genome. Nature 2006, 444, 444–454. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Choy, K.; Setlur, S.; Lee, C.; Lau, T.K. The impact of human copy number variation on a new era of genetic testing. BJOG 2010, 117, 391–398. [Google Scholar] [CrossRef]
- Weiss, L.A.; Shen, Y.; Korn, J.M.; Arking, D.E.; Miller, D.T.; Fossdal, R.; Saemundsen, E.; Stefansson, H.; Ferreira, M.A.; Green, T.; et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 2008, 358, 667–675. [Google Scholar] [CrossRef] [Green Version]
- Lou, J.; Sun, M.; Zhao, Y.; Fu, Y.; Yuan, H.; Dai, Y.; Liang, F.; He, Y.; Liu, Y. Analysis of tissue from pregnancy loss and aborted fetus with ultrasound anomaly using subtelomeric MLPA and chromosomal array analysis. J. Matern. Neonatal Med. 2020, 1–6. [Google Scholar] [CrossRef]
- Yu, A.; Turbiville, D.; Xu, F.; Ray, J.W.; Britt, A.D.; Lupo, P.J.; Jain, S.K.; Shattuck, K.E.; Robinson, S.S.; Dong, J. Genotypic and phenotypic variability of 22q11.2 microduplications: An institutional experience. Am. J. Med. Genet. Part A 2019, 179, 2178–2189. [Google Scholar] [CrossRef]
- Zhao, Y.; Diacou, A.; Johnston, H.R.; Musfee, F.I.; McDonald-McGinn, D.M.; McGinn, D.; Crowley, T.B.; Repetto, G.M.; Swillen, A.; Breckpot, J.; et al. Complete Sequence of the 22q11.2 Allele in 1053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects. Am. J. Hum. Genet. 2020, 106, 26–40. [Google Scholar] [CrossRef]
- Draaken, M.; Reutter, H.; Schramm, C.; Bartels, E.; Boemers, T.M.; Ebert, A.-K.; Rösch, W.; Schröder, A.; Stein, R.; Moebus, S.; et al. Microduplications at 22q11.21 are associated with non-syndromic classic bladder exstrophy. Eur. J. Med. Genet. 2010, 53, 55–60. [Google Scholar] [CrossRef]
- Lundin, J.; Söderhäll, C.; Lundén, L.; Hammarsjö, A.; White, I.; Schoumans, J.; Läckgren, G.; Kockum, C.C.; Nordenskjöld, A. 22q11.2 microduplication in two patients with bladder exstrophy and hearing impairment. Eur. J. Med. Genet. 2010, 53, 61–65. [Google Scholar] [CrossRef]
- Draaken, M.; Baudisch, F.; Timmermann, B.; Kuhl, H.; Kerick, M.; Proske, J.; Wittler, L.; Pennimpede, T.; Ebert, A.-K.; Rösch, W.; et al. Classic bladder exstrophy: Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region. Birth Defects Res. Part A Clin. Mol. Teratol. 2014, 100, 512–517. [Google Scholar] [CrossRef] [Green Version]
- Draaken, M.; Mughal, S.S.; Pennimpede, T.; Wolter, S.; Wittler, L.; Ebert, A.-K.; Rösch, W.; Stein, R.; Bartels, E.; Schmidt, D.; et al. Isolated bladder exstrophy associated with a de novo 0.9 Mb microduplication on chromosome 19p13.12. Birth Defects Res. Part A Clin. Mol. Teratol. 2013, 97, 133–139. [Google Scholar] [CrossRef] [Green Version]
- Von Lowtzow, C.; Hofmann, A.; Zhang, R.; Marsch, F.; Ebert, A.-K.; Rösch, W.; Stein, R.; Boemers, T.M.; Hirsch, K.; Marcelis, C.; et al. CNV analysis in 169 patients with bladder exstrophy-epispadias complex. BMC Med. Genet. 2016, 17, 35. [Google Scholar] [CrossRef] [Green Version]
- Bartels, E.; Draaken, M.; Kazmierczak, B.; Spranger, S.; Schramm, C.; Baudisch, F.; Nöthen, M.M.; Schmiedeke, E.; Ludwig, M.; Reutter, H. De novo partial trisomy 18p and partial monosomy 18q in a patient with anorectal malformation. Cytogenet. Genome Res. 2011, 134, 243–248. [Google Scholar] [CrossRef]
- Dworschak, G.C.; Draaken, M.; Marcelis, C.; De Blaauw, I.; Pfundt, R.; Van Rooij, I.A.; Bartels, E.; Hilger, A.; Jenetzky, E.; Schmiedeke, E.; et al. De novo 13q deletions in two patients with mild anorectal malformations as part of VATER/VACTERL and VATER/VACTERL-like association and analysis of EFNB2 in patients with anorectal malformations. Am. J. Med. Genet. Part A 2013, 161, 3035–3041. [Google Scholar] [CrossRef]
- Dworschak, G.C.; Draaken, M.; Hilger, A.C.; Schramm, C.; Bartels, E.; Schmiedeke, E.; Grasshoff-Derr, S.; Märzheuser, S.; Holland-Cunz, S.; Lacher, M.; et al. Genome-wide mapping of copy number variations in patients with both anorectal malformations and central nervous system abnormalities. Birth Defects Res. Part A Clin. Mol. Teratol. 2014, 103, 235–242. [Google Scholar] [CrossRef]
- Dworschak, G.; Crétolle, C.; Hilger, A.; Engels, H.; Korsch, E.; Reutter, H.; Ludwig, M. Comprehensive review of the duplication 3q syndrome and report of a patient with Currarino syndrome and de novo duplication 3q26.32-q27.2. Clin. Genet. 2016, 91, 661–671. [Google Scholar] [CrossRef]
- Hilger, A.; Schramm, C.; Pennimpede, T.; Wittler, L.; Dworschak, G.C.; Bartels, E.; Engels, H.; Zink, A.M.; Degenhardt, F.; Müller, A.M.; et al. De novo microduplications at 1q41, 2q37.3, and 8q24.3 in patients with VATER/VACTERL association. Eur. J. Hum. Genet. 2013, 21, 1377–1382. [Google Scholar] [CrossRef] [Green Version]
- Schramm, C.; Draaken, M.; Bartels, E.; Boemers, T.M.; Schmiedeke, E.; Grasshoff-Derr, S.; Märzheuser, S.; Hosie, S.; Holland-Cunz, S.; Baudisch, F.; et al. De novo duplication of 18p11.21-18q12.1 in a female with anorectal malformation. Am. J. Med. Genet. Part A 2011, 155, 445–449. [Google Scholar] [CrossRef]
- Schramm, C.; Draaken, M.; Bartels, E.; Boemers, T.M.; Aretz, S.; Brockschmidt, F.F.; Nöthen, M.M.; Ludwig, M.; Reutter, H.M. De novo microduplication at 22q11.21 in a patient with VACTERL association. Eur. J. Med. Genet. 2011, 54, 9–13. [Google Scholar] [CrossRef]
- Zhang, R.; Marsch, F.; Kause, F.; Degenhardt, F.; Schmiedeke, E.; Märzheuser, S.; Hoppe, B.; Bachour, H.; Boemers, T.M.; Schäfer, M.; et al. Array-based molecular karyotyping in 115 VATER/VACTERL and VATER/VACTERL-like patients identifies disease-causing copy number variations. Birth Defects Res. 2017, 109, 1063–1069. [Google Scholar] [CrossRef]
- Digilio, M.C.; Marino, B.; Bagolan, P.; Giannotti, A.; Dallapiccola, B. Microdeletion 22q11 and oesophageal atresia. J. Med. Genet. 1999, 36, 137–139. [Google Scholar]
- Worthington, S.; Colley, A.; Fagan, K.; Dai, K.; Lipson, A.H. Anal anomalies: An uncommon feature of velocardiofacial (Shprintzen) syndrome? J. Med. Genet. 1997, 34, 79–82. [Google Scholar] [CrossRef]
- Verbitsky, M.; Westland, R.; Perez, A.; Kiryluk, K.; Liu, Q.; Krithivasan, P.; Mitrotti, A.; Fasel, D.A.; Batourina, E.; Sampson, M.G.; et al. The copy number variation landscape of congenital anomalies of the kidney and urinary tract. Nat. Genet. 2019, 51, 764. [Google Scholar] [CrossRef] [Green Version]
- Krutzke, S.K.; Engels, H.; Hofmann, A.; Schumann, M.M.; Cremer, K.; Zink, A.M.; Hilger, A.; Ludwig, M.; Gembruch, U.; Reutter, H.; et al. Array-based molecular karyotyping in fetal brain malformations: Identification of novel candidate genes and chromosomal regions. Birth Defects Res. Part A Clin. Mol. Teratol. 2015, 106, 16–26. [Google Scholar] [CrossRef] [PubMed]
- Schumann, M.; Hofmann, A.; Krutzke, S.K.; Hilger, A.C.; Marsch, F.; Stienen, D.; Gembruch, U.; Ludwig, M.; Merz, W.M.; Reutter, H. Array-based molecular karyotyping in fetuses with isolated brain malformations identifies disease-causing CNVs. J. Neurodev. Disord. 2016, 8, 1–11. [Google Scholar] [CrossRef] [Green Version]
- Reutter, H.M.; Boyadjiev, S.A.; Gambhir, L.; Ebert, A.-K.; Rösch, W.H.; Stein, R.; Schröder, A.; Boemers, T.M.; Bartels, E.; Vogt, H.; et al. Phenotype severity in the bladder exstrophy-epispadias complex: Analysis of genetic and nongenetic contributing factors in 441 families from North America and Europe. J. Pediatr. 2011, 159, 825–831.e1. [Google Scholar] [CrossRef] [Green Version]
- Romie, S.S.; Hartsfield, J.K.; Sutcliffe, M.J.; Dumont, D.P.; Kousseff, B.G. Monosomy 6q1: Syndrome delineation. Am. J. Med. Genet. 1996, 62, 105–108. [Google Scholar] [CrossRef]
- Conley, M.; Beckwith, J.; Mancer, J.; Tenckhoff, L. The spectrum of the DiGeorge syndrome. J. Pediatr. 1979, 94, 883–890. [Google Scholar] [CrossRef]
- Schulze, B.R.B.; Tariverdian, G.; Komposch, G.; Stellzig, A. Misclassification risk of patients with bilateral cleft lip and palate and manifestations of median facial dysplasia: A new variant of del(22q11.2) syndrome? Am. J. Med. Genet. 2001, 99, 280–285. [Google Scholar] [CrossRef]
- I Wilson, D.; Burn, J.; Scambler, P.; Goodship, J. DiGeorge syndrome: Part of CATCH 22. J. Med. Genet. 1993, 30, 852–856. [Google Scholar] [CrossRef] [Green Version]
- Yamagishi, H.; Ishii, C.; Maeda, J.; Kojima, Y.; Matsuoka, R.; Kimura, M.; Takao, A.; Momma, K.; Matsuo, N. Phenotypic discordance in monozygotic twins with 22q11.2 deletion. Am. J. Med. Genet. 1998, 78, 319–321. [Google Scholar] [CrossRef]
- Holschneider, A.; Hutson, J.; Peña, A.; Beket, E.; Chatterjee, S.; Coran, A.; Davies, M.; Georgeson, K.; Grosfeld, J.; Gupta, D.; et al. Preliminary report on the International Conference for the Development of Standards for the Treatment of Anorectal Malformations. J. Pediatr. Surg. 2005, 40, 1521–1526. [Google Scholar] [CrossRef]
- Ebert, A.K.; Reutter, H.; Ludwig, M.; Rösch, W.H.; Orphanet, J. The exstrophy-epispadias complex. Rare Dis. 2009, 30, 23. [Google Scholar] [CrossRef] [Green Version]
- McDonald-McGinn, D.M.; Sullivan, K.E. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine 2011, 90, 1–18. [Google Scholar] [CrossRef]
- Saitta, S.C.; Harris, S.E.; Gaeth, A.P.; Driscoll, D.A.; McDonald-McGinn, D.M.; Maisenbacher, M.K.; Yersak, J.M.; Chakraborty, P.K.; Hacker, A.M.; Zackai, E.H.; et al. Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum. Mol. Genet. 2003, 13, 417–428. [Google Scholar] [CrossRef]
- Vergaelen, E.; Swillen, A.; Van Esch, H.; Claes, S.; Van Goethem, G.; Devriendt, K. 3 generation pedigree with paternal transmission of the 22q11.2 deletion syndrome: Intrafamilial phenotypic variability. Eur. J. Med. Genet. 2015, 58, 244–248. [Google Scholar] [CrossRef] [Green Version]
- De La Chapelle, A.; Herva, R.; Koivisto, M.; Aula, P. A deletion in chromosome 22 can cause DiGeorge syndrome. Qual. Life Res. 1981, 57, 253–256. [Google Scholar] [CrossRef]
- Yagi, H.; Furutani, Y.; Hamada, H.; Sasaki, T.; Asakawa, S.; Minoshima, S.; Ichida, F.; Joo, K.; Kimura, M.; Imamura, S.-I.; et al. Role of TBX1 in human del22q11.2 syndrome. Lancet 2003, 362, 1366–1373. [Google Scholar] [CrossRef]
- Lopez-Rivera, E.; Liu, Y.P.; Verbitsky, M.; Anderson, B.R.; Capone, V.P.; Otto, E.A.; Yan, Z.; Mitrotti, A.; Martino, J.; Steers, N.J.; et al. Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N. Engl. J. Med. 2017, 376, 742–754. [Google Scholar] [CrossRef] [Green Version]
- Fudenberg, G.; Pollard, K.S. Chromatin features constrain structural variation across evolutionary timescales. Proc. Natl. Acad. Sci. USA 2019, 116, 2175–2180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lupiáñez, D.G.; Kraft, K.; Heinrich, V.; Krawitz, P.; Brancati, F.; Klopocki, E.; Horn, D.; Kayserili, H.; Opitz, J.M.; Laxova, R.; et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 2015, 161, 1012–1025. [Google Scholar] [CrossRef] [Green Version]
- Zhilian, J.; Shou, J.; Guo, Y.; Tang, Y.; Wu, Y.; Jia, Z.; Zhai, Y.; Chen, Z.; Xu, Q.; Wu, Q. Efficient inversions and duplications of mammalian regulatory DNA elements and gene clusters by CRISPR/Cas9. J. Mol. Cell Biol. 2015, 7, 284–298. [Google Scholar] [CrossRef] [Green Version]
- Klopocki, E.; Lohan, S.; Brancati, F.; Koll, R.; Brehm, A.; Seemann, P.; Dathe, K.; Stricker, S.; Hecht, J.; Bosse, K.; et al. Copy-number variations involving the IHH locus are associated with syndactyly and craniosynostosis. Am. J. Hum. Genet. 2011, 88, 70–75. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Will, A.J.; Cova, G.; Osterwalder, M.; Chan, W.-L.; Wittler, L.; Brieske, N.; Heinrich, V.; De Villartay, J.-P.; Vingron, M.; Klopocki, E.; et al. Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog). Nat. Genet. 2017, 49, 1539–1545. [Google Scholar] [CrossRef] [PubMed]
- Laugsch, M.; Bartusel, M.; Rehimi, R.; Alirzayeva, H.; Karaolidou, A.; Crispatzu, G.; Zentis, P.; Nikolic, M.; Bleckwehl, T.; Kolovos, P.; et al. Modeling the Pathological Long-Range Regulatory Effects of Human Structural Variation with Patient-Specific hiPSCs. Cell Stem Cell 2019, 24, 736–752. [Google Scholar] [CrossRef]
- Kim, D.S.; Kim, J.H.; Burt, A.A.; Crosslin, D.R.; Burnham, N.; Kim, C.E.; McDonald-McGinn, D.M.; Zackai, E.H.; Nicolson, S.C.; Spray, T.L.; et al. Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival. J. Thorac. Cardiovasc. Surg. 2016, 151, 1147–1151. [Google Scholar] [CrossRef] [Green Version]
- Wapner, R.J.; Martin, C.L.; Levy, B.; Ballif, B.C.; Eng, C.M.; Zachary, J.M.; Savage, M.; Platt, L.D.; Saltzman, D.; Grobman, W.A.; et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N. Engl. J. Med. 2012, 367, 2175–2184. [Google Scholar] [CrossRef] [Green Version]
Phenotype | Study | Individuals | Disease-Causing CNVs |
---|---|---|---|
BEEC | Draaken et al., 2010, 2013, 2014 | N = 295 (295 isolated) | dup19p13.12 7 × dup22q11.21 |
Total Number | N = 420 | Disease-causing CNVs n = 8 | |
Cases solved 2% |
Phenotype | Study | Individuals | Disease-Causing CNVs |
---|---|---|---|
ARM | Schramm et al., 2011a, Schramm et al., 2011b | n = 16 (5 isolated/11 non-isolated) | dup18p11.21–18q12 |
ARM and CNS | Dworschak et al., 2015 | n = 32 (32 non-isolated) | del6q14.3q16.3, del14q32.2, del17q12q21.2, 2 × del22q11.21 |
ARM in the context of the VATER/VACTERL Association | Schramm et al., 2011b, Hilger et al., 2013, Dworschak et al., 2013, Zhang et al., 2017a | n = 176 (176 non-isolated) | dup1q41, dup2q37.3, dup8q24.3, del13q31.2-qter, del17q12, del22q11.21, dup22q11.21 |
Total Number | n = 224 | Disease-causing CNVs n = 13 | |
Cases solved 6% |
Phenotype | Study | Individuals | Disease-Causing CNVs |
---|---|---|---|
Central Nervous System Malformations | Krutzke et al., 2015, Schumann et al., 2016 | n = 68 (35 isolated) | del1q25.1, del3p26.3, dup5q35.1, del6p25.1-6p25.3, del6q25.3-qter, del6q27, dup9p23, dup11p14.3, del15q11.2-q13.1, del16p12.2, dup17p11.2-17p12, dup18q21.1, delXp22.2-Xp22.32 |
Total Number | n = 420 | Disease-causing CNVs n = 15 | |
Cases solved 22% |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Hilger, A.C.; Dworschak, G.C.; Reutter, H.M. Lessons Learned from CNV Analysis of Major Birth Defects. Int. J. Mol. Sci. 2020, 21, 8247. https://doi.org/10.3390/ijms21218247
Hilger AC, Dworschak GC, Reutter HM. Lessons Learned from CNV Analysis of Major Birth Defects. International Journal of Molecular Sciences. 2020; 21(21):8247. https://doi.org/10.3390/ijms21218247
Chicago/Turabian StyleHilger, Alina Christine, Gabriel Clemens Dworschak, and Heiko Martin Reutter. 2020. "Lessons Learned from CNV Analysis of Major Birth Defects" International Journal of Molecular Sciences 21, no. 21: 8247. https://doi.org/10.3390/ijms21218247