Advertisement

Human Genetics

, Volume 135, Issue 12, pp 1355–1364 | Cite as

Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways

  • Erin M. Hagen
  • Robert J. Sicko
  • Denise M. Kay
  • Shannon L. Rigler
  • Aggeliki Dimopoulos
  • Shabbir Ahmad
  • Margaret H. Doleman
  • Ruzong Fan
  • Paul A. Romitti
  • Marilyn L. Browne
  • Michele Caggana
  • Lawrence C. Brody
  • Gary M. Shaw
  • Laura L. Jelliffe-Pawlowski
  • James L. MillsEmail author
Original Investigation

Abstract

Classic heterotaxy consists of congenital heart defects with abnormally positioned thoracic and abdominal organs. We aimed to uncover novel, genomic copy-number variants (CNVs) in classic heterotaxy cases. A microarray containing 2.5 million single-nucleotide polymorphisms (SNPs) was used to genotype 69 infants (cases) with classic heterotaxy identified from California live births from 1998 to 2009. CNVs were identified using the PennCNV software. We identified 56 rare CNVs encompassing genes in the NODAL (NIPBL, TBX6), BMP (PPP4C), and WNT (FZD3) signaling pathways, not previously linked to classic heterotaxy. We also identified a CNV involving FGF12, a gene previously noted in a classic heterotaxy case. CNVs involving RBFOX1 and near MIR302F were detected in multiple cases. Our findings illustrate the importance of body patterning pathways for cardiac development and left/right axes determination. FGF12, RBFOX1, and MIR302F could be important in human heterotaxy, because they were noted in multiple cases. Further investigation into genes involved in the NODAL, BMP, and WNT body patterning pathways and into the dosage effects of FGF12, RBFOX1, and MIR302F is warranted.

Keywords

Primary Ciliary Dyskinesia Rare CNVs Planar Cell Polarity Pathway Nodal Signaling Pathway Nodal Cilium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank the CBDMP and the California Department of Public Health for case identification; Michael Tsai and Natalie Weir at the Minnesota Core Laboratories and the staff at the Biomedical Genomics Center Facility at the University of Minnesota for microarray genotyping; Matthew Shudt and Zhen Zhang at the Wadsworth Center Applied Genomics Technologies Core, New York State Department of Health, for next-generation sequencing; Zoe Edmunds and Katherine Keever at the Wadsworth Center, New York State Department of Health, for technical assistance; and Nathan Pankratz, University of Minnesota, and Karl G. Hill, Social Development Research Group, University of Washington, for generously sharing population B-allele frequency and GC content files for PennCNV software. The California Department of Public Health is not responsible for the results or conclusions drawn by the authors of this publication.

Compliance with ethical standards

Funding

This work was funded by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contracts HHSN275201100001I, HHSN27500005, and N01-DK-73431). Dr. Shaw was partially supported for this work by funds from CDC (5U01DD001033) and NIH (R01HL092330).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

439_2016_1727_MOESM1_ESM.docx (78 kb)
Supplementary material 1 (DOCX 77 kb)

References

  1. Campos CM, Zanardo EA, Dutra RL, Kulikowski LD, Kim CA (2015) Investigation of copy number variation in children with conotruncal heart defects. Arq Bras Cardiol 104:24–31. doi: 10.5935/abc.20140169 PubMedPubMedCentralGoogle Scholar
  2. Cohen PT, Philp A, Vazquez-Martin C (2005) Protein phosphatase 4–from obscurity to vital functions. FEBS Lett 579:3278–3286. doi: 10.1016/j.febslet.2005.04.070 CrossRefPubMedGoogle Scholar
  3. Croen LA, Shaw GM, Jensvold NG, Harris JA (1991) Birth defects monitoring in California: a resource for epidemiological research. Paediatr Perinat Epidemiol 5:423–427. doi: 10.1111/j.1365-3016.1991.tb00728.x CrossRefPubMedGoogle Scholar
  4. Fakhro KA, Choi M, Ware SM, Belmont JW, Towbin JA, Lifton RP, Khokha MK, Brueckner M (2011) Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. Proc Natl Acad Sci 108:2915–2920. doi: 10.1073/pnas.1019645108 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Feng Y, Wu H, Xu Y, Zhang Z, Liu T, Lin X, Feng XH (2014) Zinc finger protein 451 is a novel Smad corepressor in transforming growth factor-beta signaling. J Biol Chem 289:2072–2083. doi: 10.1074/jbc.M113.526905 CrossRefPubMedGoogle Scholar
  6. Ferencz C, Loffredo CA, Correa-Villaseñor A, Wilson PD (1997) Genetic and environmental risk factors of major cardiovascular malformations. In: The Baltimore-Washington infant study 1981–1989, perspectives in pediatric cardiology, vol V. Futura Publishing, ArmonkGoogle Scholar
  7. Gallagher TL, Arribere JA, Geurts PA, Exner CR, McDonald KL, Dill KK, Marr HL, Adkar SS, Garnett AT, Amacher SL, Conboy JG (2011) Rbfox-regulated alternative splicing is critical for zebrafish cardiac and skeletal muscle functions. Dev Biol 359:251–261. doi: 10.1016/j.ydbio.2011.08.025 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Geng J, Picker J, Zheng Z, Zhang X, Wang J, Hisama F, Brown DW, Mullen MP, Harris D, Stoler J, Seman A, Miller DT, Fu Q, Roberts AE, Shen Y (2014) Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield. BMC Genom 15:1127. doi: 10.1186/1471-2164-15-1127 CrossRefGoogle Scholar
  9. Ghebranious N, Giampietro PF, Wesbrook FP, Rezkalla SH (2007) A novel microdeletion at 16p11.2 harbors candidate genes for aortic valve development, seizure disorder, and mild mental retardation. Am J Med Genet A 143A:1462–1471. doi: 10.1002/ajmg.a.31837 CrossRefPubMedGoogle Scholar
  10. Hadjantonakis AK, Pisano E, Papaioannou VE (2008) Tbx6 regulates left/right patterning in mouse embryos through effects on nodal cilia and perinodal signaling. PLoS One 3:e2511. doi: 10.1371/journal.pone.0002511 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Hartung H, Feldman B, Lovec H, Coulier F, Birnbaum D, Goldfarb M (1997) Murine FGF-12 and FGF-13: expression in embryonic nervous system, connective tissue and heart. Mech Dev 64:31–39. doi: 10.1016/S0925-4773(97)00042-7 CrossRefPubMedGoogle Scholar
  12. Jia S, Dai F, Wu D, Lin X, Xing C, Xue Y, Wang Y, Xiao M, Wu W, Feng XH, Meng A (2012) Protein phosphatase 4 cooperates with Smads to promote BMP signaling in dorsoventral patterning of zebrafish embryos. Dev Cell 22:1065–1078. doi: 10.1016/j.devcel.2012.03.001 CrossRefPubMedGoogle Scholar
  13. Kennedy MP, Omran H, Leigh MW, Dell S, Morgan L, Molina PL, Robinson BV, Minnix SL, Olbrich H, Severin T, Ahrens P, Lange L, Morillas HN, Noone PG, Zariwala MA, Knowles MR (2007) Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation 115:2814–2821. doi: 10.1161/circulationaha.106.649038 CrossRefPubMedGoogle Scholar
  14. Komatsu Y, Mishina Y (2013) Establishment of left-right asymmetry in vertebrate development: the node in mouse embryos. Cell Mol Life Sci 70:4659–4666. doi: 10.1007/s00018-013-1399-9 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Kurkowiak M, Ziętkiewicz E, Witt M (2015) Recent advances in primary ciliary dyskinesia genetics. J Med Genet 52(1):1–9. doi: 10.1136/jmedgenet-2014-102755
  16. Kuroyanagi H (2009) Fox-1 family of RNA-binding proteins. Cell Mol Life Sci 66:3895–3907. doi: 10.1007/s00018-009-0120-5 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Lale S, Yu S, Ahmed A (2011) Complex congenital heart defects in association with maternal diabetes and partial deletion of the A2BP1 gene. Fetal Pediatr Pathol 30:161–166. doi: 10.3109/15513815.2010.547555 CrossRefPubMedGoogle Scholar
  18. Li D, Tekin M, Buch M, Fan YS (2012) Co-existence of other copy number variations with 22q11.2 deletion or duplication: a modifier for variable phenotypes of the syndrome? Mol Cytogenet 5:18. doi: 10.1186/1755-8166-5-18 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Li Y, Yagi H, Onuoha EO, Damerla RR, Francis R, Furutani Y, Tariq M, King SM, Hendricks G, Cui C, Saydmohammed M, Lee DM, Zahid M, Sami I, Leatherbury L, Pazour GJ, Ware SM, Nakanishi T, Goldmuntz E, Tsang M, Lo CW (2016) DNAH6 and its interactions with PCD genes in heterotaxy and primary ciliary dyskinesia. PLoS Genet 12(2). doi: 10.1371/journal.pgen.1005821
  20. Lin AE, Krikov S, Riehle-Colarusso T, Frias JL, Belmont J, Anderka M, Geva T, Getz KD, Botto LD (2014) Laterality defects in the national birth defects prevention study (1998–2007): birth prevalence and descriptive epidemiology. Am J Med Genet A 164A:2581–2591. doi: 10.1002/ajmg.a.36695 CrossRefPubMedGoogle Scholar
  21. Lobo J, Zariwala MA, Noone PG (2015) Primary ciliary dyskinesia. Semin Respir Crit Care Med 36(2):169–179. doi: 10.1055/s-0035-1546748
  22. Mizoguchi T, Izawa T, Kuroiwa A, Kikuchi Y (2006) Fgf signaling negatively regulates Nodal-dependent endoderm induction in zebrafish. Dev Biol 300:612–622. doi: 10.1016/j.ydbio.2006.08.073 CrossRefPubMedGoogle Scholar
  23. Mohapatra B, Casey B, Li H, Ho-Dawson T, Smith L, Fernbach SD, Molinari L, Niesh SR, Jefferies JL, Craigen WJ, Towbin JA, Belmont JW, Ware SM (2009) Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. Hum Mol Genet 18:861–871. doi: 10.1093/hmg/ddn411 PubMedGoogle Scholar
  24. Muto A, Calof AL, Lander AD, Schilling TF (2011) Multifactorial origins of heart and gut defects in nipbl-deficient zebrafish, a model of Cornelia de Lange Syndrome. PLoS Biol 9:e1001181. doi: 10.1371/journal.pbio.1001181 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Nakano N, Maeyama K, Sakata N, Itoh F, Akatsu R, Nakata M, Katsu Y, Ikeno S, Togawa Y, Vo Nguyen TT, Watanabe Y, Kato M, Itoh S (2014) C18 ORF1, a novel negative regulator of transforming growth factor-beta signaling. J Biol Chem 289:12680–12692. doi: 10.1074/jbc.M114.558981 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Nakhleh N, Francis R, Giese RA, Tian X, Li Y, Zariwala MA, Yagi H, Khalifa O, Kureshi S, Chatterjee B, Sabol SL, Swisher M, Connelly PS, Daniels MP, Srinivasan A, Kuehl K, Kravitz N, Burns K, Sami I, Omran H, Barmada M, Olivier K, Chawla KK, Leigh M, Jonas R, Knowles M, Leatherbury L, Lo CW (2012) High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation 125(18):2232–2242. doi: 10.1161/CIRCULATIONAHA.111.079780
  27. Neugebauer JM, Amack JD, Peterson AG, Bisgrove BW, Yost HJ (2009) FGF signalling during embryo development regulates cilia length in diverse epithelia. Nature 458:651–654. doi: 10.1038/nature07753 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Rigler SL, Kay DM, Sicko RJ, Fan R, Liu A, Caggana M, Browne ML, Druschel CM, Romitti PA, Brody LC, Mills JL (2015) Novel copy-number variants in a population-based investigation of classic heterotaxy. Genet Med 17:348–357. doi: 10.1038/gim.2014.112 CrossRefPubMedGoogle Scholar
  29. Rochais F, Mesbah K, Kelly RG (2009) Signaling pathways controlling second heart field development. Circ Res 104:933–942. doi: 10.1161/circresaha.109.194464 CrossRefPubMedGoogle Scholar
  30. Rosa A, Spagnoli FM, Brivanlou AH (2009) The miR-430/427/302 family controls mesendodermal fate specification via species-specific target selection. Dev Cell 16:517–527. doi: 10.1016/j.devcel.2009.02.007 CrossRefPubMedGoogle Scholar
  31. Schulman J, Hahn JA (1993) Quality control of birth defect registry data: a case study. Public Health Rep 108:91–98PubMedPubMedCentralGoogle Scholar
  32. Shen MM (2007) Nodal signaling: developmental roles and regulation. Development 134:1023–1034. doi: 10.1242/dev.000166 CrossRefPubMedGoogle Scholar
  33. Shiraishi I, Ichikawa H (2012) Human heterotaxy syndrome—from molecular genetics to clinical features, management, and prognosis. Circ J 76:2066–2075. doi: 10.1253/circj.CJ-12-0957 CrossRefPubMedGoogle Scholar
  34. Smith KA, Noel E, Thurlings I, Rehmann H, Chocron S, Bakkers J (2011) Bmp and nodal independently regulate lefty1 expression to maintain unilateral nodal activity during left-right axis specification in zebrafish. PLoS Genet 7:e1002289. doi: 10.1371/journal.pgen.1002289 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Srivastava D, Olson EN (2000) A genetic blueprint for cardiac development. Nature 407:221–226. doi: 10.1038/35025190 CrossRefPubMedGoogle Scholar
  36. Sutherland MJ, Ware SM (2009) Disorders of left-right asymmetry: heterotaxy and situs inversus. Am J Med Genet C Semin Med Genet 151C:307–317. doi: 10.1002/ajmg.c.30228 CrossRefPubMedGoogle Scholar
  37. Vladar EK, Antic D, Axelrod JD (2009) Planar cell polarity signaling: the developing cell’s compass. Cold Spring Harb Perspect Biol 1:a002964. doi: 10.1101/cshperspect.a002964 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, Ichida F, Joo K, Kimura M, Imamura S, Kamatani N, Momma K, Takao A, Nakazawa M, Shimizu N, Matsuoka R (2003) Role of TBX1 in human del22q11.2 syndrome. Lancet 362:1366–1373. doi: 10.1016/S0140-6736(03)14632-6 CrossRefPubMedGoogle Scholar
  39. Zhu L, Belmont JW, Ware SM (2006) Genetics of human heterotaxias. Eur J Hum Genet 14:17–25. doi: 10.1038/sj.ejhg.5201506 PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2016

Authors and Affiliations

  • Erin M. Hagen
    • 1
  • Robert J. Sicko
    • 2
  • Denise M. Kay
    • 2
  • Shannon L. Rigler
    • 1
  • Aggeliki Dimopoulos
    • 1
  • Shabbir Ahmad
    • 3
  • Margaret H. Doleman
    • 3
  • Ruzong Fan
    • 1
  • Paul A. Romitti
    • 4
  • Marilyn L. Browne
    • 5
    • 6
  • Michele Caggana
    • 2
  • Lawrence C. Brody
    • 7
  • Gary M. Shaw
    • 8
  • Laura L. Jelliffe-Pawlowski
    • 9
  • James L. Mills
    • 1
    Email author
  1. 1.Division of Intramural Population Health ResearchEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthBethesdaUSA
  2. 2.Wadsworth Center, New York State Department of HealthAlbanyUSA
  3. 3.California Birth Defects Monitoring Program, California Department of Public HealthSacramentoUSA
  4. 4.Department of EpidemiologyCollege of Public Health, The University of IowaIowa CityUSA
  5. 5.Congenital Malformations Registry, New York State Department of HealthAlbanyUSA
  6. 6.University at Albany School of Public HealthAlbanyUSA
  7. 7.Genome Technology BranchNational Human Genome Research Institute, National Institutes of HealthBethesdaUSA
  8. 8.Department of PediatricsStanford University School of MedicineStanfordUSA
  9. 9.Department of Epidemiology and BiostatisticsUniversity of California San Francisco School of MedicineSan FranciscoUSA

Personalised recommendations