Exome sequencing identifies the first genetic determinants of sirenomelia in humans.
Adaptor Proteins, Signal Transducing
/ genetics
Alleles
Amino Acid Substitution
CDX2 Transcription Factor
/ genetics
Calcium-Binding Proteins
/ genetics
Ectromelia
/ diagnosis
Female
Genetic Association Studies
/ methods
Genetic Predisposition to Disease
Genotype
Humans
Male
Pedigree
Phenotype
Exome Sequencing
CDX2
Sirenomelia
caudal dysgenesis
de novo mutation
exome sequencing
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
05
11
2019
revised:
19
01
2020
accepted:
09
02
2020
pubmed:
15
2
2020
medline:
22
7
2021
entrez:
15
2
2020
Statut:
ppublish
Résumé
Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio-based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2. We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CDX2 Transcription Factor
0
CDX2 protein, human
0
Calcium-Binding Proteins
0
NKD1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
926-933Informations de copyright
© 2020 Wiley Periodicals, Inc.
Références
Angonin, D., & Van Raay, T. J. (2013). Nkd1 functions as a passive antagonist of Wnt signaling. PLoS One, 8(8):e74666. https://doi.org/10.1371/journal.pone.0074666
Backenroth, D., Homsy, J., Murillo, L. R., Glessner, J., Lin, E., Brueckner, M., … Shen, Y. (2014). CANOES: Detecting rare copy number variants from whole exome sequencing data. Nucleic Acids Research, 42(12):e97. https://doi.org/10.1093/nar/gku345
Boer, L. L., Morava, E., Klein, W. M., Schepens-Franke, A. N., & Oostra, R. J. (2017). Sirenomelia: A multisystemic polytopic field defect with ongoing controversies. Birth Defects Research, 109(10), 791-804. https://doi.org/10.1002/bdr2.1049
Castilla, E. E., & Orioli, I. M. (2004). ECLAMC: The Latin-American collaborative study of congenital malformations. Community Genetics, 7(2-3), 76-94. https://doi.org/10.1159/000080776
Castori, M., Silvestri, E., Cappellacci, S., Binni, F., Sforzolini, G. S., & Grammatico, P. (2010). Sirenomelia and VACTERL association in the offspring of a woman with diabetes. American Journal of Medical Genetics, Part A, 152A(7), 1803-1807. https://doi.org/10.1002/ajmg.a.33460
Chandebois, R., & Brunet, C. (1987). Origin of abnormality in a human simelian foetus as elucidated by our knowledge of vertebrate development. Teratology, 36(1), 11-22. https://doi.org/10.1002/tera.1420360104
Chawengsaksophak, K., de Graaff, W., Rossant, J., Deschamps, J., & Beck, F. (2004). Cdx2 is essential for axial elongation in mouse development. Proceedings of the National Academy of Sciences of the United States of America, 101(20), 7641-7645. https://doi.org/10.1073/pnas.0401654101
Chawengsaksophak, K., James, R., Hammond, V. E., Köntgen, F., & Beck, F. (1997). Homeosis and intestinal tumours in Cdx2 mutant mice. Nature, 386(6620), 84-87. https://doi.org/10.1038/386084a0
Collins, R. L., Brand, H., Karczewski, K. J., Zhao, X., Alföldi, J., Francioli, L. C., … Talkowski, M. E. (2019). An open resource of structural variation for medical and population genetics, https://doi.org/578674./578674. [Preprint].
Deciphering Developmental Disorders Study. (2017). Prevalence and architecture of de novo mutations in developmental disorders. Nature, 542(7642), 433-438. https://doi.org/10.1038/nature21062
Di Lorenzo, M., Brandt, M. L., & Veilleux, A. (1991). Sirenomelia in an identical twin: A case report. Journal of Pediatric Surgery, 26(11), 1334-1336. https://doi.org/10.1016/0022-3468(91)90614-Y
Duesterhoeft, S. M., Ernst, L. M., Siebert, J. R., & Kapur, R. P. (2007). Five cases of caudal regression with an aberrant abdominal umbilical artery: Further support for a caudal regression-sirenomelia spectrum. American Journal of Medical Genetics, Part A, 143A(24), 3175-3184. https://doi.org/10.1002/ajmg.a.32028
Etheridge, L. A., Crawford, T. Q., Zhang, S., & Roelink, H. (2010). Evidence for a role of vertebrate Disp1 in long-range Shh signaling. Development (Cambridge, England), 137(1), 133-140. https://doi.org/10.1242/dev.043547
Garrido-Allepuz, C., González-Lamuño, D., & Ros, M. A. (2012). Sirenomelia phenotype in bmp7;shh compound mutants: A novel experimental model for studies of caudal body malformations. PLoS One, 7(9):e44962. https://doi.org/10.1371/journal.pone.0044962
Garrido-Allepuz, C., Haro, E., González-Lamuño, D., Martínez-Frías, M. L., Bertocchini, F., & Ros, M. A. (2011). A clinical and experimental overview of sirenomelia: Insight into the mechanisms of congenital limb malformations. Disease Models & Mechanisms, 4(3), 289-299. https://doi.org/10.1242/dmm.007732
Gerard, M., Layet, V., Costa, T., Roumazeilles, Y., Chenal, P., Cailliez, D., & Gerard, B. (2012). Sirenomelia and caudal malformations in two families. American Journal of Medical Genetics, Part A, 158A(7), 1801-1807. https://doi.org/10.1002/ajmg.a.35408
Greco, T. L., Takada, S., Newhouse, M. M., McMahon, J. A., McMahon, A. P., & Camper, S. A. (1996). Analysis of the vestigial tail mutation demonstrates that Wnt-3a gene dosage regulates mouse axial development. Genes & Development, 10(3), 313-324. https://doi.org/10.1101/gad.10.3.313
Groisman, B., Liascovich, R., Gili, J. A., Barbero, P., & Bidondo, M. P., RENAC Task Force. (2016). Sirenomelia in Argentina: Prevalence, geographic clusters and temporal trends analysis. Birth Defects Research. Part A, Clinical and Molecular Teratology, 106(7), 604-611. https://doi.org/10.1002/bdra.23501
Hikasa, H., & Sokol, S. Y. (2013). Wnt signaling in vertebrate axis specification. Cold Spring Harbor Perspectives in Biology, 5(1), a007955. https://doi.org/10.1101/cshperspect.a007955
Hsu, J. S. J., So, M., Tang, C. S. M., Karim, A., Porsch, R. M., Wong, C., … Garcia-Barcelo, M. -M. (2018). De novo mutations in Caudal Type Homeo Box transcription Factor 2 (CDX2) in patients with persistent cloaca. Human Molecular Genetics, 27(2), 351-358. https://doi.org/10.1093/hmg/ddx406
Ishikawa, A., Kitajima, S., Takahashi, Y., Kokubo, H., Kanno, J., Inoue, T., & Saga, Y. (2004). Mouse Nkd1, a Wnt antagonist, exhibits oscillatory gene expression in the PSM under the control of Notch signaling. Mechanisms of Development, 121(12), 1443-1453. https://doi.org/10.1016/j.mod.2004.08.003
Källén, B., Castilla, E. E., Lancaster, P. A., Mutchinick, O., Knudsen, L. B., Martínez-Frías, M. L., … Robert, E. (1992). The cyclops and the mermaid: An epidemiological study of two types of rare malformation. Journal of Medical Genetics, 29(1), 30-35. https://doi.org/10.1136/jmg.29.1.30
Kjaer, K. W., Keeling, J. W., Opitz, J. M., Gilbert-Barness, E., Hartling, U., Hansen, B. F., & Kjaer, I. (2003). Sirenomelia sequence according to the distance between the first sacral vertebra and the ilia. American Journal of Medical Genetics, Part A, 120A(4), 503-508. https://doi.org/10.1002/ajmg.a.20206
Lynch, S. A., & Wright, C. (1997). Sirenomelia, limb reduction defects, cardiovascular malformation, renal agenesis in an infant born to a diabetic mother. Clinical Dysmorphology, 6(1), 75-80.
Meagher, M. J., & Braun, R. E. (2001). Requirement for the murine zinc finger protein ZFR in perigastrulation growth and survival. Molecular and Cellular Biology, 21(8), 2880-2890. https://doi.org/10.1128/MCB.21.8.2880-2890.2001
Opitz, J. M., Zanni, G., Reynolds, J. F., & Gilbert-Barness, E. (2002). Defects of blastogenesis. American Journal of Medical Genetics, 115(4), 269-286. https://doi.org/10.1002/ajmg.10983
Orioli, I. M., Amar, E., Arteaga-Vazquez, J., Bakker, M. K., Bianca, S., Botto, L. D., … Castilla, E. E. (2011). Sirenomelia: An epidemiologic study in a large dataset from the International Clearinghouse of Birth Defects Surveillance and Research, and literature review. American Journal of Medical Genetics, Part C: Seminars in Medical Genetics, 157C(4), 358-373. https://doi.org/10.1002/ajmg.c.30324
Ozturk, M. A., Bastug, O., Halis, H., Korkmaz, L., Memur, S., Sarici, D., & Kara, A. (2014). A rare association: Sirenomelia with adrenalomegaly in an infant of diabetic mother. Journal of Neonatal-Perinatal Medicine, 7(3), 253-256. https://doi.org/10.3233/NPM-1476813
Pallares, L. F., Carbonetto, P., Gopalakrishnan, S., Parker, C. C., Ackert-Bicknell, C. L., Palmer, A. A., & Tautz, D. (2015). Mapping of craniofacial traits in outbred mice identifies major developmental genes involved in shape determination. PLoS Genetics, 11(11):e1005607. https://doi.org/10.1371/journal.pgen.1005607
Quenez, O., Cassinari, K., Coutant, S., Lecoquierre, F., Le Guennec, K., Rousseau, S., … Nicolas, G. (2019). Detection of copy number variations from NGS data using read depth information: A diagnostic performance evaluation. https://hal.archives-ouvertes.fr/hal-02317979v2. Consulté à l'adresse https://hal-normandie-univ.archives-ouvertes.fr/hal-02317979
Savory, J. G. A., Bouchard, N., Pierre, V., Rijli, F. M., De Repentigny, Y., Kothary, R., & Lohnes, D. (2009). Cdx2 regulation of posterior development through non-Hox targets. Development, 136(24), 4099-4110. https://doi.org/10.1242/dev.041582
Seidahmed, M. Z., Abdelbasit, O. B., Alhussein, K. A., Miqdad, A. M., Khalil, M. I., & Salih, M. A. (2014). Sirenomelia and severe caudal regression syndrome. Saudi Medical Journal, 35(Suppl 1), S36-S43.
Stocker, J. T., & Heifetz, S. A. (1987). Sirenomelia. A morphological study of 33 cases and review of the literature. Perspectives in Pediatric Pathology, 10, 7-50.
Thottungal, A. D., Charles, A. K., Dickinson, J. E., & Bower, C. (2010). Caudal dysgenesis and sirenomelia-single centre experience suggests common pathogenic basis. American Journal of Medical Genetics, Part A, 152A(10), 2578-2587. https://doi.org/10.1002/ajmg.a.33599
van de Ven, C., Bialecka, M., Neijts, R., Young, T., Rowland, J. E., Stringer, E. J., … Deschamps, J. (2011). Concerted involvement of Cdx/Hox genes and Wnt signaling in morphogenesis of the caudal neural tube and cloacal derivatives from the posterior growth zone. Development, 138(16), 3451-3462. https://doi.org/10.1242/dev.066118
Wansleeben, C., van Gurp, L., Feitsma, H., Kroon, C., Rieter, E., Verberne, M., … Meijlink, F. (2011). An ENU-mutagenesis screen in the mouse: Identification of novel developmental gene functions. PLoS One, 6(4):e19357. https://doi.org/10.1371/journal.pone.0019357
Zakin, L., Reversade, B., Kuroda, H., Lyons, K. M., & De Robertis, E. M. (2005). Sirenomelia in Bmp7 and Tsg compound mutant mice: Requirement for Bmp signaling in the development of ventral posterior mesoderm. Development, 132(10), 2489-2499. https://doi.org/10.1242/dev.01822
Zheng, W., Zhang, C., Bell, E. W., & Zhang, Y. (2019). I-TASSER gateway: A protein structure and function prediction server powered by XSEDE. Future Generations Computer Systems: FGCS, 99, 73-85. https://doi.org/10.1016/j.future.2019.04.011