Polimorfismos genéticos en pacientes con fisuras labio y/o palatinas no sindrómicos
Resumen
Dentro de los defectos congénitos más frecuentes se encuentran las fisuras labio y/o palatinas (FL/P), presentando una prevalencia de alrededor de 1:1.000 nacimientos vivos. El 70% de FL/P son de tipo no sindrómico, lo cual hace referencia a que se encuentran como un defecto aislado sin anomalías adicionales. Poseen una etiología compleja con un componente tanto ambiental como genético. Con el desarrollo de tecnologías de secuenciación del genoma humano se han identificado variantes polimórficas que pueden estar asociadas al fenotipo de FL/P y por tal motivo pueden contribuir a la etiología multifactorial de éstas. En esta revisión se describen las variantes comúnmente asociadas y su papel en la etiología de las FL/P. Los SNPs localizados en los genes IFR6, MSX1, VAX1, PAX9, CHD1, FGF1, GREM1 y WNT3 se han relacionado significativamente con la presencia de FL/P, y las variantes ubicadas en los genes APC, GSK3, DVL2, BMP4, ABCA4, BHMT, NTN1, TBX1, EPHA3, FAM49A, MGMT, MMP3, TIMP2 y NOG aunque se ha reportado su asociación con la presencia de las fisuras orofaciales aún no es clara su relación con dicho fenotipo. Es importante realizar estudios de identificación de variantes genéticas que involucren poblaciones específicas con el fin de poder comprender la etiología de las FL/P no sindrómicas.
Palabras clave
FL/P, polimorfismos, genes, no-sindrómicas
Referencias
[1] C. Chen, Q. Guo, J. Shi, X. Jiao, K. Lv, X. Liu, et al., "Genetic variants of MGMT, RHPN2, and FAM49A contributed to susceptibility of nonsyndromic orofacial clefts in a Chinese population," J Oral Pathol Med, vol. 47, pp. 796-801, Sep 2018.
[2] M. J. Dixon, M. L. Marazita, T. H. Beaty, and J. C. Murray, "Cleft lip and palate: understanding genetic and environmental influences," Nature Rev Genet, vol. 12, p. 167, 02/18/online 2011.
[3] Y. P. Lu, W. T. Han, Q. Liu, J. X. Li, Z. J. Li, M. Jiang, et al., "Variations in WNT3 gene are associated with incidence of non-syndromic cleft lip with or without cleft palate in a northeast Chinese population," Genet Mol Res, vol. 14, pp. 12646-12653, Oct 19 2015.
[4] Y. Pan, W. Zhang, Y. Du, N. Tong, Y. Han, H. Zhang, et al., "Different roles of two novel susceptibility loci for nonsyndromic orofacial clefts in a Chinese Han population," Am J Med Genet Part A, vol. 155, pp. 2180-2185, 2011/09/01 2011.
[5] V. Vijayan, R. Ummer, R. Weber, R. Silva, and A. Letra, "Association of WNT Pathway Genes With Nonsyndromic Cleft Lip With or Without Cleft Palate," Cleft Palate Craniofac J, vol. 55, pp. 335-341, Mar 2018.
[6] B.-Q. Wang, S.-T. Gao, K. Chen, Z.-Q. Xu, J.-M. Sun, Y. Xia, et al., "Association of the WNT3 polymorphisms and non-syndromic cleft lip with or without cleft palate: evidence from a meta-analysis," Bioscience Rep, vol. 38, p. BSR20181676, 2018.
[7] C. Paz-y-Miño, M. E. Sánchez, M. Del Pozo, R. Burgos, C. Pérez, and P. E. Leone, "Análisis genético de las fisuras faciales humanas. Reevaluación del tipo de herencia: Poligénica o monogénica?," Rev Fac Cs Med, vol. 23, pp. 20-24, Abr 1998.
[8] R. J. Pengelly, L. Arias, J. Martínez, R. Upstill-Goddard, E. G. Seaby, J. Gibson, et al., "Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes," Sci Rep, vol. 6, p. 30457, 07/26/online 2016.
[9] R. J. Pengelly, R. Upstill-Goddard, L. Arias, J. Martinez, J. Gibson, M. Knut, et al., "Resolving clinical diagnoses for syndromic cleft lip and/or palate phenotypes using whole-exome sequencing," Clin Genet, vol. 88, pp. 441-449, 2015/11/01 2015.
[10] S.-J. Zhang, P. Meng, J. Zhang, P. Jia, J. Lin, X. Wang, et al., "Machine Learning Models for Genetic Risk Assessment of Infants with Non-syndromic Orofacial Cleft," Genom Proteom Bioinf, vol. 16, pp. 354-364, 2018.
[11] T. C. Carter, A. M. Molloy, F. Pangilinan, J. F. Troendle, P. N. Kirke, M. R. Conley, et al., "Testing reported associations of genetic risk factors for oral clefts in a large Irish study population," Birth Defects Res A, vol. 88, pp. 84-93, 2010.
[12] N. S. Mohamad Shah, S. Sulong, W. A. Wan Sulaiman, and A. S. Halim, "Two novel genes TOX3 and COL21A1 in large extended Malay families with nonsyndromic cleft lip and/or palate," Mol Genet Genomic Med, vol. 7, pp. e635-e635, 2019.
[13] X. Nie, K. Luukko, and P. Kettunen, "FGF signalling in craniofacial development and developmental disorders," Oral Dis, vol. 12, pp. 102-111, 2006/03/01 2006.
[14] E. Pauws and P. Stanier, "FGF signalling and SUMO modification: new players in the aetiology of cleft lip and/or palate," Trends Genet, vol. 23, pp. 631-640, 2007.
[15] L. M. Escobar, J. Prada, C. Téllez, and J. Castellanos, "Genetic basis of orofacial cleft formation in humans," Rev CES Odontol, vol. 26, pp. 57-67,
2013.
[16] M. Dudas, J. Kim, W.-Y. Li, A. Nagy, J. Larsson, S. Karlsson, et al., "Epithelial and ectomesenchymal role of the type I TGF-β receptor ALK5 during facial morphogenesis and palatal fusion," Dev Biol, vol. 296, pp. 298-314, 2006.
[17] M. Dudas, W.-Y. Li, J. Kim, A. Yang, and V. Kaartinen, "Palatal fusion – Where do the midline cells go?: A review on cleft palate, a major human birth defect," Acta Histochem, vol. 109, pp. 1-14, 2007/03/01/ 2007.
[18] M. A. Montenegro and M. Rojas, "Aspectos Moleculares en la Formación de la Cara y del Paladar," Int J Morphol, vol. 23, pp. 185-194, 2005.
[19] A. K. Hoebel, D. Drichel, M. van de Vorst, A. Böhmer, S. Sivalingam, N. Ishorst, et al., "Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing," J Dent Res, vol. 96, pp. 1314-1321, 2017.
[20] E. Mangold, K. Ludwig, and M. Nöthen, "Breakthroughs in the genetics of orofacial clefting," Trends Mol Med, vol. 17, pp. 725-733, 2011.
[21] F. Rahimov, A. Jugessur, and J. C. Murray, "Genetics of nonsyndromic orofacial clefts," The Cleft palate-craniofacial journal: official publication of the American Cleft Palate-Craniofacial Association vol. 49, pp. 73-91, 2012.
[22] B. Levi, S. Brugman, V. W. Wong, M. Grova, M. T. Longaker, and D. C. Wan, "Palatogenesis: engineering, pathways and pathologies," Organogenesis, vol. 7, pp. 242-254, Oct-Dec 2011.
[23] J. W. Sull, K.-Y. Liang, J. B. Hetmanski, M. D. Fallin, R. G. Ingersoll, J. Park, et al., "Maternal transmission effects of the PAX genes among cleft case-parent trios from four populations," Eur J Hum Genet, vol. 17, pp. 831-839, 2009.
[24] R. J. Richardson, N. L. Hammond, P. A. Coulombe, C. Saloranta, H. O. Nousiainen, R. Salonen, et al., "Periderm prevents pathological epithelial adhesions during embryogenesis," J Clin Invest, vol. 124, pp. 3891-3900, 2014.
[25] M. T. Parada-Sanchez, E. Y. Chu, L. L. Cox, S. S. Undurty, J. M. Standley, J. C. Murray, et al., "Disrupted IRF6-NME1/2 Complexes as a Cause of Cleft Lip/Palate," J Dent Res, vol. 96, pp. 1330-1338, 2017.
[26] Genetic Home Reference. (2019). IRF6 gene: Interferon regulatory factor 6. Available: https://ghr.nlm.nih.gov/gene/IRF6#location
[27] University of California Santa Cruz, "Human Gene IRF6 (ENST00000367021.7) " 2019.
[28] Y. A. Kousa, R. Roushangar, N. Patel, A. Walter, P. Marangoni, R. Krumlauf, et al., "IRF6 and SPRY4 Signaling Interact in Periderm Development," J Dent Res, vol. 96, pp. 1306-1313, 2017.
[29] T. Taniguchi, K. Ogasawara, A. Takaoka, and N. Tanaka, "IRF Family of Transcription Factors as Regulators of Host Defense," Annual Rev Immunol vol. 19, pp. 623-655, 2001/04/01 2001.
[30] Y. Gou, T. Zhang, and J. Xu, "Chapter Fifteen - Transcription Factors in Craniofacial Development: From Receptor Signaling to Transcriptional and Epigenetic Regulation," Curr Topics Dev Biol, vol. 115, Y. Chai, Ed., ed: Academic Press, 2015, pp. 377-410.
[31] V. B. Gurramkonda, A. H. Syed, J. Murthy, and B. Lakkakula, "IRF6 rs2235375 single nucleotide polymorphism is associated with isolated non-syndromic cleft palate but not with cleft lip with or without palate in South Indian population," Braz J Otorhinolaryngol, vol. 84, pp. 473-477, Jul - Aug 2018.
[32] A. Mijiti, W. Ling, Guli, and A. Moming, "Association of single-nucleotide polymorphisms in the IRF6 gene with non-syndromic cleft lip with or without cleft palate in the Xinjiang Uyghur population," Br J Oral Maxillofac Surg, vol. 53, pp. 268-274, Mar 2015.
[33] T. Song, D. Wu, Y. Wang, H. Li, N. Yin, and Z. Zhao, "SNPs and interaction analyses of IRF6, MSX1 and PAX9 genes in patients with nonsyndromic cleft lip with or without palate," Mol Med Rep, vol. 8, pp. 1228-1234, Oct 2013.
[34] J. Shi, T. Song, X. Jiao, C. Qin, and J. Zhou, "Single-nucleotide polymorphisms (SNPs) of the IRF6 and TFAP2A in non-syndromic cleft lip with or without cleft palate (NSCLP) in a northern Chinese population," Biochem Biophys Res Commun, vol. 410, pp. 732-736, Jul 15 2011.
[35] Genetic Home Reference. (2019). MSX1 gene. Available: https://ghr.nlm.nih.gov/gene/MSX1#location
[36] University of California Santa Cruz, "Human Gene MSX1 (ENST00000382723.4) " 2019.
[37] J. Liang, J. Von den Hoff, J. Lange, Y. Ren, Z. Bian, and C. E. L. Carels, "MSX1 mutations and associated disease phenotypes: genotype-phenotype relations," Eur J Hum Genet, vol. 24, pp. 1663-1670, 2016.
[38] A. Paradowska-Stolarz, "MSX1 gene in the etiology orofacial deformities," Postepy Hig Med Dosw, vol. 69, pp. 1499-1504, 2015.
[39] A. Shibata, J. Machida, S. Yamaguchi, M. Kimura, T. Tatematsu, H. Miyachi, et al., "Identification of nuclear localization signals in the human homeoprotein MSX1," Biochem Cell Biol, vol. 96, pp. 483-489, 2018/08/01 2017.
[40] H. Rafighdoost, M. Hashemi, A. Narouei, E. Eskanadri-Nasab, G. Dashti-Khadivaki, and M. Taheri, "Association between CDH1 and MSX1 gene polymorphisms and the risk of nonsyndromic cleft lip and/or cleft palate in a southeast Iranian population," Cleft Palate Craniofac J, vol. 50, pp. e98-e104, Sep 2013.
[41] Genetic Home Reference. (2019). VAX1 gene. Available: https://ghr.nlm.nih.gov/gene/VAX1#location
[42] University of California Santa Cruz. (2019). Human Gene VAX1 Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=vax1
[43] Gene Cards. (2019). VAX1 Gene(Protein Coding). Available: https://www.genecards.org/cgi-bin/carddisp.pl?gene=VAX1&keywords=vax1
[44] D. Li, T. Liu, X. Meng, Q. Guo, J. Shi, Y. Hao, et al., "Polymorphic variants in VAX1 and the risk of nonsyndromic cleft lip with or without cleft palate in a population from northern China," Medicine (Baltimore), vol. 96, p. e6550, Apr 2017.
[45] S. N. de Aquino, A. C. Messetti, E. Bagordakis, H. Martelli-Júnior, M. S. O. Swerts, E. Graner, et al., "Polymorphisms in FGF12, VCL, CX43 and VAX1 in Brazilian patients with nonsyndromic cleft lip with or without cleft palate," BMC Med Genet, vol. 14, pp. 53-53, 2013.
[46] University of California Santa Cruz. (2019). Human Gene PAX9 (ENST00000402703.6). Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=pax9
[47] Genetic Home Reference. (2019). PAX9 gene. Available: https://ghr.nlm.nih.gov/gene/PAX9#location
[48] V. Tallón-Walton, M.-C. Manzanares-Céspedes, P. Carvalho-Lobato, I. Valdivia-Gandur, S. Arte, and P. Nieminen, "Exclusion of PAX9 and MSX1 mutation in six families affected by tooth agenesis. A genetic study and literature review," Med Oral Patol Oral Cir Bucal, vol. 19, pp. e248-e254, 2013.
[49] O. Bonczek, V. Balcar, and O. Serý, "PAX9 gene mutations and tooth agenesis: A review," Clin Genet, vol. 92, pp. 467-476, 2017.
[50] W. Zhang, H. C. Qu, and Y. Zhang, "PAX-9 polymorphism may be a risk factor for hypodontia: a meta-analysis," Genet Mol Res, vol. 13, pp. 9997-10006, Nov 28 2014.
[51] E. Isman, S. Nergiz, H. Acar, and Z. Sari, "PAX9 polymorphisms and susceptibility with sporadic tooth agenesis in Turkish populations: a case-control study," BMC Genomics, vol. 14, pp. 733-733, 2013.
[52] University of California Santa Cruz. (2019). Human Gene CDH1 (ENST00000261769.9) Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=cdh1
[53] G. H. Reference. (2019). CDH1 gene. Available: https://ghr.nlm.nih.gov/gene/CDH1#
[54] G. Liu, "CDH1 promoter methylation in patients with cervical carcinoma: a systematic meta-analysis with trial sequential analysis," Future Oncol vol. 14, pp. 51-63, 2018/01/01 2017.
[55] T. Gall and A. Frampton, "Gene of the month: E-cadherin (CDH1)," J Clin Pathol, vol. 66, pp. 928-932, 2013.
[56] H. Song, X. Wang, J. Yan, N. Mi, X. Jiao, Y. Hao, et al., "Association of single-nucleotide polymorphisms of CDH1 with nonsyndromic cleft lip with or without cleft palate in a northern Chinese Han population," Medicine (Baltimore), vol. 96, p. e5574, Feb 2017.
[57] I. Prudovsky, D. Kacer, J. Davis, V. Shah, S. Jayanthi, I. Huber, et al., "Folding of Fibroblast Growth Factor 1 Is Critical for Its Nonclassical Release," Biochemistry, vol. 55, pp. 1159-1167, 2016.
[58] M. Li, P. Page-McCaw, and W. Chen, "FGF1 Mediates Overnutrition-Induced Compensatory β-Cell Differentiation," Diabetes, vol. 65, pp. 96-109, 2016.
[59] University of California Santa Cruz. (2019). Human Gene FGF1 (ENST00000621536.4). Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=FGF1
[60] National Center for Biotechnology Information. (2019). FGF1 fibroblast growth factor 1 [ Homo sapiens (human) ]. Available: https://www.ncbi.nlm.nih.gov/gene/2246
[61] Z. Rafiqdoost, A. Rafiqdoost, H. Rafiqdoost, M. Hashemi, J. Khayatzadeh, and E. Eskandari-Nasab, "Investigation of FGF1 and FGFR gene polymorphisms in a group of Iranian patients with nonsyndromic cleft lip with or without cleft palate," Int J Pediatr Otorhinolaryngol, vol. 78, pp. 731-
736, May 2014.
[62] Y. Hanada, Y. Nakamura, Y. Ozono, Y. Ishida, Y. Takimoto, M. Taniguchi, et al., "Fibroblast growth factor 12 is expressed in spiral and vestibular ganglia and necessary for auditory and equilibrium function," Sci Rep, vol. 8, pp. 11491-11491, 2018.
[63] I. Guella, L. Huh, M. B. McKenzie, E. B. Toyota, E. M. Bebin, M. L. Thompson, et al., "De novo FGF12 mutation in 2 patients with neonatal-onset epilepsy," Neurology Genetics, vol. 2, pp. e120, 2016.
[64] F. Nakayama, T. Yasuda, S. Umeda, M. Asada, T. Imamura, V. Meineke, et al., "Fibroblast growth factor-12 (FGF12) translocation into intestinal epithelial cells is dependent on a novel cell-penetrating peptide domain: involvement of internalization in the in vivo role of exogenous FGF12," J Biol Chem, vol. 286, pp. 25823-25834, 2011.
[65] Genetic Home Reference. (2019). FGF12 gene, fibroblast growth factor 12. Available: https://ghr.nlm.nih.gov/gene/FGF12#location
[66] University of California Santa Cruz. (2019). Human Gene FGF12 (ENST00000454309.6). Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=FGF12
[67] Genetic Home Reference. (2019). Gen GREM1, Gremlin 1, antagonista BMP de la familia DAN. Available: https://ghr.nlm.nih.gov/gene/GREM1#normalfunction
[68] University of California Santa Cruz. (2019). Human Gene GREM1 (ENST00000622074.1) Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=GREM1
[69] I. J. H. van Vlodrop, M. M. L. Baldewijns, K. M. Smits, L. J. Schouten, L. van Neste, W. van Criekinge, et al., "Prognostic significance of Gremlin1 (GREM1) promoter CpG island hypermethylation in clear cell renal cell carcinoma," Am J Pathol, vol. 176, pp. 575-584, 2010.
[70] D. B. McKenna, J. Van Den Akker, A. Y. Zhou, L. Ryan, A. Leon, R. O’Connor, et al., "Identification of a novel GREM1 duplication in a patient with multiple colon polyps," Fam Cancer, vol. 18, pp. 63-66, 2019/01/01 2019.
[71] A. Mostowska, K. K. Hozyasz, P. Wójcicki, K. Żukowski, A. Dąbrowska, A. Lasota, et al., "Association between polymorphisms at the GREM1 locus
and the risk of nonsyndromic cleft lip with or without cleft palate in the Polish population," Birth Defects Res A, vol. 103, pp. 847-856, 2015.
[72] X. Wang, H. Song, X. Jiao, Y. Hao, W. Zhang, Y. Gao, et al., "Association between a single-nucleotide polymorphism in the GREM1 gene and non-syndromic orofacial cleft in the Chinese population," J Oral Pathol Med, vol. 47, pp. 206-210, Feb 2018.
[73] P. A. Andrade Filho, A. Letra, A. Cramer, J. L. Prasad, G. P. Garlet, A. R. Vieira, et al., "Insights from studies with oral cleft genes suggest associations between WNT-pathway genes and risk of oral cancer," J Dental Res, vol. 90, pp. 740-746, 2011.
[74] Genetic Home Reference. (2019). WNT3 gene, Wnt family member 3. Available: https://ghr.nlm.nih.gov/gene/WNT3
[75] University of California Santa Cruz. (2019). Human Gene WNT3 (ENST00000225512.5). Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=WNT3
[76] A. Mostowska, K. K. Hozyasz, B. Biedziak, P. Wojcicki, M. Lianeri, and P. P. Jagodzinski, "Genotype and haplotype analysis of WNT genes in non-syndromic cleft lip with or without cleft palate," Eur J Oral Sci, vol. 120, pp. 1-8, 2012.
[77] Genetic Home Reference. (2019). APC gene, WNT signaling pathway regulator. Available: https://ghr.nlm.nih.gov/gene/APC#location
[78] University of California Santa Cruz. (2019). Human Gene APC (ENST00000257430.8) Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=apc
[79] J. Borowsky, T. Dumenil, M. Bettington, S. Pearson, C. Bond, L. Fennell, et al., "The role of APC in WNT pathway activation in serrated neoplasia," Mod Pathol, vol. 31, pp. 495-504, 2017.
[80] C. Galli, M. Piemontese, S. Lumetti, E. Manfredi, G. Macaluso, and G. Passeri, "GSK3b-inhibitor lithium chloride enhances activation of Wnt canonical signaling and osteoblast differentiation on hydrophilic titanium surfaces," Clin Oral Implants Res, vol. 24, pp. 921-927, 2012.
[81] National Center for Biotechnology Information. (2019). GSK3B glycogen synthase kinase 3 beta [ Homo sapiens (human) ]. Available: https://www.ncbi.nlm.nih.gov/gene/2932
[82] P. De Marco, E. Merello, A. Consales, G. Piatelli, A. Cama, Z. Kibar, et al., "Genetic analysis of disheveled 2 and disheveled 3 in human neural tube defects," J Mol Neurosci, vol. 49, pp. 582-588, 2013.
[83] University of California Santa Cruz. (2019). Human Gene DVL2 (ENST00000005340.9) Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=DVL2
[84] National Center for Biotechnology Information. (2019). DVL2 dishevelled segment polarity protein 2 [ Homo sapiens (human) ]. Available: https://www.ncbi.nlm.nih.gov/gene/1856
[85] S. Modica and C. Wolfrum, "The dual role of BMP4 in adipogenesis and metabolism," Adipocyte, vol. 6, pp. 141-146, 2017.
[86] M. Yu, H. Wang, Z. Fan, C. Xie, H. Liu, Y. Liu, et al., "BMP4 mutations in tooth agenesis and low bone mass," Arch Oral Biol, vol. 103, pp. 40-46, 2019/07/01/ 2019.
[87] University of California Santa Cruz. (2019). Human Gene BMP4 (ENST00000559087.5) Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=BMP4
[88] Genetic Home Reference. (2019). BMP4 gene, bone morphogenetic protein 4. Available: https://ghr.nlm.nih.gov/gene/BMP4#location
[89] I. Kempa, L. Ambrozaitytė, J. Stavusis, I. Akota, B. Barkane, A. Krumina, et al., "Association of BMP4 polymorphisms with non-syndromic cleft lip with or without cleft palate and isolated cleft in Latvian and Lithuanian populations," Stomatologija, vol. 16, pp. 94-101, 2014.
[90] H. Rafighdoost, M. Hashemi, H. Danesh, F. Bizhani, G. Bahari, and M. Taheri, "Association of single nucleotide polymorphisms in AXIN2, BMP4, and IRF6 with Non-Syndromic Cleft Lip with or without Cleft Palate in a sample of the southeast Iranian population," J Appl Oral Sci, vol. 25, pp. 650-656, Nov-Dec 2017.
[91] J. Zernant, Y. A. Xie, C. Ayuso, R. Riveiro-Alvarez, M.-A. Lopez-Martinez, F. Simonelli, et al., "Analysis of the ABCA4 genomic locus in Stargardt disease," Hum Mol Genet, vol. 23, pp. 6797-6806, 2014.
[92] M. V. Salles, F. L. Motta, R. Martin, R. Filippelli-Silva, E. Dias da Silva, P. Varela, et al., "Variants in the ABCA4 gene in a Brazilian population with Stargardt disease," Mol Vis, vol. 24, pp. 546-559, 2018.
[93] A. Auricchio, I. Trapani, and R. Allikmets, "Gene Therapy of ABCA4-Associated Diseases," Cold Spring Harbor perspectives in medicine, vol. 5, pp. a017301-a017301, 2015.
[94] Genetic Home Reference. (2019). ABCA4 gene, ATP binding cassette subfamily A member 4. Available: https://ghr.nlm.nih.gov/gene/ABCA4#normalfunction
[95] University of California Santa Cruz. (2019). Human Gene ABCA4 (ENST00000370225.3). Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=ABCA4
[96] V. Babu Gurramkonda, A. Hussain Syed, J. Murthy, G. Chaubey, and V. K. Bhaskar Lakkakula, "Polymorphic variants near 1p22 and 20q11.2 loci and the risk of non-syndromic cleft lip and palate in South Indian population," Int J Pediatr Otorhinolaryngol, vol. 79, pp. 2389-2393, Dec 2015.
[97] N. Mi, Y. Hao, X. Jiao, X. Zheng, J. Shi, and Y. Chen, "A polymorphic marker associated with non-syndromic cleft lip with or without cleft palate in a population in Heilongjiang Province, northern China," Arch Oral Biol, vol. 60, pp. 357-361, Feb 2015.
[98] Y. Hu, E. Chen, Y. Mu, J. Li, and R. Chen, "BHMT Gene Polymorphisms as Risk Factors for Cleft Lip and Cleft Palate in a Chinese Population," Biomed Environ Sci, vol. 24, pp. 89-93, 2011/04/01/ 2011.
[99] R. Bellampalli, M. Vohra, K. Sharma, N. Bhaskaranand, K. Bhat, K. Prasad, et al., "Acute lymphoblastic leukemia and genetic variations in BHMT gene: Case-control study and computational characterization," Cancer Biomark, vol. 19, pp. 393-401, 2017.
[100] National Center for Biotechnology Information. (2019). BHMT betaine--homocysteine S-methyltransferase Available: https://www.ncbi.nlm.nih.gov/gene/635
[101] University of California Santa Cruz. (2019). Human Gene BHMT (ENST00000274353.9) Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=BHMT
[102] A. Méneret, E. A. Franz, O. Trouillard, T. C. Oliver, Y. Zagar, S. P. Robertson, et al., "Mutations in the netrin-1 gene cause congenital mirror movements," J Clin Invest, vol. 127, pp. 3923-3936, 2017.
[103] S. Jiang, J. Y. Shi, Y. S. Lin, S. J. Duan, X. Chen, J. J. Jiao, et al., "NTN1 gene was risk to NSCLO among Han Chinese Population," Oral Dis, vol. 25, pp. 535-542, 2018.
[104] University of California Santa Cruz. (2019). Human Gene NTN1 (ENST00000173229.6). Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=ntn1
[105] Genetic Home Reference. (2019). NTN1 gene, netrin 1. Available: https://ghr.nlm.nih.gov/gene/NTN1#location
[106] Q. Guo, D. Li, X. Meng, T. Liu, J. Shi, Y. Hao, et al., "Association between PAX7 and NTN1 gene polymorphisms and nonsyndromic orofacial clefts in a northern Chinese population," Medicine (Baltimore), vol. 96, p. e6724, May 2017.
[107] C. K. Huertas-Rodríguez, C. Payán-Gómez, and R. M. Forero-Castro, "El síndrome 22q11.2D<span class="elsevierStyleHsp" style=""></span>S como un subtipo genético de esquizofrenia," Rev Colomb Psiquiatr, vol. 44, pp. 50-60, 2015.
[108] S. Gao, X. Li, and B. A. Amendt, "Understanding the role of Tbx1 as a candidate gene for 22q11.2 deletion syndrome," Curr Allergy Asthma Rep vol. 13, pp. 613-621, 2013.
[109] N. Funato, M. Nakamura, J. A. Richardson, D. Srivastava, and H. Yanagisawa, "Tbx1 regulates oral epithelial adhesion and palatal development," Hum Mol Genet, vol. 21, pp. 2524-2537, 2012.
[110] University of California Santa Cruz. (2019). Human Gene TBX1 (ENST00000332710.8) Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=tbx1
[111] Genetic Home Reference. (2019). TBX1 gene, T-box 1. Available: https://ghr.nlm.nih.gov/gene/TBX1#location
[112] L. M. Paranaiba, S. N. de Aquino, A. Bufalino, H. Martelli-Junior, E. Graner, L. A. Brito, et al., "Contribution of polymorphisms in genes associated with craniofacial development to the risk of nonsyndromic cleft lip and/or palate in the Brazilian population," Med Oral Patol Oral Cir Bucal, vol. 18, pp. e414-420, May 1 2013.
[113] J. Dulak, "Many roles for Pax7," Cell cycle (Georgetown, Tex.), vol. 16, pp. 21-22, 2017.
[114] Genetic Home Reference. (2019). PAX7 gene, paired box 7. Available: https://ghr.nlm.nih.gov/gene/PAX7#location
[115] U. o. C. S. Cruz. (2019). Human Gene PAX7 (ENST00000420770.6) Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=PAX7
[116] R. Zhou, M. Wang, W. Li, S. Wang, Z. Zhou, J. Li, et al., "Gene-Gene Interactions among SPRYs for Nonsyndromic Cleft Lip/Palate," J Dental Res vol. 98, pp. 180-185, 2019/02/01 2018.
[117] University of California Santa Cruz. (2019). Human Gene SPRY2 (ENST00000377104.3). Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=SPRY2
[118] genetic Home Reference. (2019). Gen SPRY2, antagonista de señalización RTK sprouty 2. Available: https://ghr.nlm.nih.gov/gene/SPRY2#location
[119] T. Song, J. Shi, Q. Guo, K. Lv, X. Jiao, T. Hu, et al., "Association between NOGGIN and SPRY2 polymorphisms and nonsyndromic cleft lip with or without cleft palate," Am J Med Genet A, vol. 167A, pp. 137-141, Jan 2015.
[120] T. Fukunaga, W. Zou, J. T. Warren, and S. L. Teitelbaum, "Vinculin regulates osteoclast function," The J Biol Chem vol. 289, pp. 13554-13564, 2014.
[121] Genetic Home Reference. (2019). VCL gene, vinculin. Available: https://ghr.nlm.nih.gov/gene/VCL#location
[122] University of California Santa Cruz. (2019). Human Gene VCL (ENST00000211998.9) Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=VCL
[123] J. Ming, Y. Zhou, J. Du, S. Fan, B. Pan, Y. Wang, et al., "miR-381 suppresses C/EBPα-dependent Cx43 expression in breast cancer cells," Biosci Rep, vol. 35, p. e00266, 2015.
[124] M. Busby, M. T. Hallett, and I. Plante, "The Complex Subtype-Dependent Role of Connexin 43 (GJA1) in Breast Cancer," Int J Mol Sci vol. 19, p. 693, 2018.
[125] R. Gu, J. Xu, Y. Lin, W. Sheng, D. Ma, X. Ma, et al., "The role of histone modification and a regulatory single-nucleotide polymorphism (rs2071166) in the Cx43 promoter in patients with TOF," Sci Rep vol. 7, pp. 10435-10435, 2017.
[126] University of California Santa Cruz. (2019). Human Gene GJA1 (ENST00000649132.1). Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=GJA1
[127] Genetic Home Reference, "GJA1 gene, gap junction protein alpha 1," 2019.
[128] A. Sasnauskiene, V. Jonusiene, A. Krikštaponienė, S. Butkyte, D. Dabkevičienė, D. Kanopiene, et al., "NOTCH1, NOTCH3, NOTCH4, and JAG2 protein levels in human endometrial cancer," Medicine (Kaunas), vol. 50, pp. 14-18, 2014.
[129] N. Nowwarote and T. Osathanon, "Dysregulation of Notch signaling related genes in oral lichen planus," Asian Pac J Trop Biomed, vol. 7, pp. 666-669, 2017.
[130] D. Chiron, M. Sophie, G. Descamps, M. Philippe, S. Le Gouill, S. Marionneau, et al., "Critical role of the NOTCH ligand JAG2 in self-renewal of myeloma cells," Blood Cells Mol Dis, vol. 48, pp. 247-253, 2012.
[131] University of California Santa Cruz. (2019). Human Gene JAG2 (ENST00000331782.7). Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=JAG2
[132] National Center for Biotechnology Information. (2019). JAG2 jagged canonical Notch ligand 2 [ Homo sapiens (human) ]. Available: https://www.ncbi.nlm.nih.gov/gene/3714
[133] Y. Chen, A. B. Rabson, and D. H. Gorski, "MEOX2 regulates nuclear factor-kappaB activity in vascular endothelial cells through interactions with p65 and IkappaBbeta," Cardiovasc Res, vol. 87, pp. 723-731, 2010.
[134] L. Tian, Z. Z. Tao, H. P. Ye, G. Y. Li, Z. F. Zhan, and H. W. Tuo, "Over-expression of MEOX2 promotes apoptosis through inhibiting PI3K/Akt pathway in laryngeal cancer cells," Neoplasma, vol. 65, pp. 745-752, 2018.
[135] University of California Santa Cruz. (2019). Human Gene MEOX2 (ENST00000262041.5). Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=MEOX2
[136] National Center for Biotechnology Information. (2019). MEOX2 mesenchyme homeobox 2 [ Homo sapiens (human) ]. Available: https://www.ncbi.nlm.nih.gov/gene/4223
[137] D. L. Tran, H. Imura, A. Mori, S. Suzuki, T. Niimi, M. Ono, et al., "Association of MEOX2 polymorphism with nonsyndromic cleft palate only in a Vietnamese population," Congenit Anom (Kyoto), vol. 58, pp. 124-129, Jul 2018.
[138] S. Y. Shu, M. J. Zhang, H. Q. Cheng, S. J. Tang, W. L. Chen, S. R. Wu, et al., "Mutation analysis of PVRL1 in patients with non-syndromic cleft of the lip and/or palate in Guangdong," Genet Mol Res, vol. 14, pp. 3400-3408, 2015.
[139] D. Aşlar and H. Taştan, ""Identification of Novel Variants in the PVRL1 Gene in Patients With Nonsyndromic Cleft Lip With or Without Cleft Palate," Genet Test Mol Biomarkers, vol. 20, pp. 269-272, 2016.
[140] University of California Santa Cruz. (2019). Human Gene NECTIN1 (ENST00000264025.7). Available: https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_gene=PVRL1
[141] Genetic Home Reference. (2019). NECTIN1 gene, nectin cell adhesion molecule 1. Available: https://ghr.nlm.nih.gov/gene/NECTIN1#location
[142] J. Yan, H. Song, N. Mi, X. Jiao, and Y. Hao, "Nucleotide variants of the NAT2 and EGF61 genes in patients in Northern China with nonsyndromic
cleft lip with or without cleft palate," Medicine (Baltimore), vol. 96, p. e7973, Sep 2017.
[143] A. Letra, R. M. Silva, L. G. Motta, S. H. Blanton, J. T. Hecht, J. M. Granjeirol, et al., "Association of MMP3 and TIMP2 promoter polymorphisms with nonsyndromic oral clefts," Birth Defects Res A, vol. 94, pp. 540-548, Jul 2012.
[144] X. Yin, L. Ma, Y. Li, M. Xu, W. Wang, H. Wang, et al., "Genetic variants of 20q12 contributed to non-syndromic orofacial clefts susceptibility," Oral Dis, vol. 23, pp. 50-54, Jan 2017.
[145] Y. An, W. Duan, G. Huang, X. Chen, L. Li, C. Nie, et al., "Genome-wide copy number variant analysis for congenital ventricular septal defects in Chinese Han population," BMC Med Genomics, vol. 9, p. 2, Jan 8 2016.