Determination of Copy Number Variations in Non-Syndromic Congenital Cleft Palate - Lip Patients

Yıl 2021, , 462 - 470, 13.09.2021

Emine İkbal Atlı , Engin Atlı Sinem Yalçıntepe , Selma Demir , Yasemin Özten Hakan Gurkan

https://doi.org/10.20515/otd.910654

Öz

Cleft lip and palate is the most common craniofacial anomaly. There is no concomitant anomaly in 70% of the cases and it is called non-syndromic cleft lip and palate. Molecular and quantitative developments in the science of genetics suggest that genetic mechanisms may play a role in both syndromic and non-syndromic types of this pathology. Non-syndromic cleft lip / palate is a common developmental abnormality that occurs during the embryonic period. This study aims to define genetic abnormalities due to copy number changes in cleft lip / palate pathogenesis. Our study, using the CytoScan 180K sequence targeted to detect genome-wide copy number variations, was performed with a sample of 17 patients with cleft lip and palate aged 1-15 years. Seven significant copy number changes were detected. These changes consisted of duplications (9p23-p24, 18q12.1, Xp22.12, Xp22.31, Yq11.21 / 16q24.1) and deletions (5q21.3 and 6p22.3-23) in patients with cleft lip and palate. It has also been shown in our study that genetic factors play a role in non-syndromic cases. Larger scale genome screening studies continue in different populations as well. The important point to be kept in mind in prospective patient management is this; If there is a cleft lip and palate in the family and relatives, the risk of cleft lip and palate increases in the next child. Even in sporadic cases where parents are not affected, it should be kept in mind that the risk of oral cleft in the next child is increased and the family should be informed about the next pregnancy.

Anahtar Kelimeler

Nonsyndromic cleft lip and palate, genetic diagnosis, a-CGH, copy number variations

Sendromik Olmayan Konjenital Yarık Damak-Dudak Bulunan Hastalarda Kopya Sayısı Varyasyonlarının Belirlenmesi

Öz

Dudak damak yarığı en sık görülen kraniyofasiyal anomalidir. Olguların %70 inde eşlik eden anomali bulunmaz ve non sendromik dudak damak yarığı olarak adlandırılır. Genetik biliminde moleküler ve kantitatif olarak meydana gelen gelişmeler bu patolojinin sendromik ve sendromik olmayan her iki tipinde de genetik mekanizmalarının rol oynuyor olabileceğini düşündürmektedir. Sendromik olmayan yarık dudak/damak, embriyonik dönemde gerçekleşen yaygın bir gelişimsel anormalliktir. Bu çalışma, yarık dudak/damak patogenezinde yer alan kopya sayısı değişimlerine bağlı genetik anormallikleri tanımlamak amacı taşımaktadır. Genom çapında kopya sayısı varyasyonlarını saptama hedefli CytoScan 180K dizisi kullanılarak yaptığımız çalışma, 1-15 yaşları arasındaki 17 yarık damak dudak olan hasta örneği ile gerçekleştirilmiştir. Yedi önemli kopya sayısı değişimi saptanmıştır. Bu değişimler yarık damak dudak hastalarında, duplikasyonlardan (9p23-p24, 18q12.1, Xp22.12, Xp22.31, Yq11.21/16q24.1) ve delesyonlardan (5q21.3 ve 6p22.3-23) oluşuyordu. Genetik faktörlerin sendromik olmayan vakalarda da rol oynadığı çalışmamız ile de gösterilmiştir. Daha geniş ölçekli genom tarama çalışmaları farklı populasyonlarda da devam etmektedir. İleriye yönelik hasta yönetiminde göz önünde tutulması gereken; aile ve akrabalarda yarık dudak ve damak bulunması halinde sonraki çocukta yarık damak dudak görülme riskinin arttığıdır. Anne babanın etkilenmediği sporadik vakalarda dahi, bir sonraki çocukta oral yarık riskinin arttığı göz önünde tutulmalı ve aile, sonraki gebelik için mutlaka bilgilendirilmelidir.

Anahtar Kelimeler

Nonsendromik yarık damak ve dudak, genetik tanı, a-CGH, kopya sayısı değişimleri

Kaynakça

• 1. Nazer J, Ramirez MC, Cifuentes L. Evolution of prevalence rates of orofacial clefts in a maternity of a Chilean clinical hospital. Rev Med Chil. 2010;138(5): 567–72.
• 2. Rahimov F, Jugessur A, Murray JC. Genetics of nonsyndromic orofacial clefts. Cleft Palate Craniofacial Journal. 2012; 49(1):73–91.
• 3. Christensen K, Juel K, Herskind AM et al. Long term follow up study of survival associated with cleft lip and palate at birth. BMJ. 2004; 328(7453):1405.
• 4. Menezes R, Marazita ML, Goldstein McHenry T et al. AXIS inhibition protein 2, orofacial clefts and a family history of cancer. J Am Dent Assoc. 2009; 140(1):80–84.
• 5. Dietz A, Pedersen DA, Jacobsen R et al. Risk of breast cancer in families with cleft lip and palate. Ann Epidemiol. 2012; 22(1):37–42.
• 6. Tunçbilek G, Özgür F, Balcı S. 1229 yarık dudak ve damak hastasında görülen ek malformasyon ve sendromlar. Çocuk Sağlığı ve Hastalıkları Dergisi, 2004; 47: 172-6.
• 7. Jugessur A, Farlie PG, Kilpatrick N. The genetics of isolated orofacial clefts: from genotypes to subphenotypes. Oral Dis. 2009a; 15(7):437–453.
• 8. Jensen BL, Kreiborg S, Dahl E et al. Cleft lip and palate in Denmark, 1976–1981: epidemiology, variability, and early somatic development. Cleft Palate J. 1988; 25(3):258–269.
• 9. Mossey PA, Little J, Munger RG et al. Cleft lip and palate. Lancet. 2009; 374(9703): 1773–1785.
• 10. Gundlach KK, Maus C. Epidemiological studies on the frequency of clefts in Europe and world-wide. J Craniomaxillofac Surg. 2006; 34(Suppl 2):1–2.
• 11. Dixon MJ, Marazita ML, Beaty TH et al. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet. 2011; 12(3):167–178.
• 12. Tomatır AG, Demirhan H, Sorkun HÇ et al. Major congenital anomalies: a five year retrospective regional study in Turkey. Genet Mol Res 2009;8(1):19-27.
• 13. Sivertsen A, Wilcox AJ, Skjaerven R et al. Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives. BMJ. 2008; 336(7641):432–434.
• 14. Marazita ML. The Evolution of Human Genetic Studies of Cleft Lip and Cleft Palate. Annu Rev Genomics Hum Genet. 2012;13:263-83.
• 15. Marazita ML, Murray JC, Lidral AC et al. Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32–35. Am J Hum Genet. 2004; 75(2):161–173.
• 16. Letra A, Menezes R, Govil M et al. Follow-up association studies of chromosome region 9q and nonsyndromic cleft lip/palate. Am J Med Genet A. 2010; 152A(7):1701–1710.
• 17. Beaty TH, Ruczinski I, Murray JC et al. Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate. Genet Epidemiol. 2011; 35(6): 469–478.
• 18. Birnbaum S, Ludwig KU, Reutter H et al. Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat Genet. 2009; 41(4):473–477.
• 19. Grant SF, Wang K, Zhang H et al. A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24. J Pediatr. 2009; 155(6):909–913.
• 20. Ludwig KU, Mangold E, Herms S et al. Genomewide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci. Nat Genet. 2012 Sep;44(9):968-71
• 21. Mangold E, Ludwig KU, Birnbaum S et al. Genomewide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat Genet. 2010; 42(1):24–26.
• 22. Collins A, Arias L, Pengelly R et al. The potential for next generation sequencing to characterise the genetic variation underlying nonsyndromic cleft lip and palate phenotypes. OA Genet 2013; 1: 10.
• 23. Zucchero TM, Cooper ME, Maher BS et al. Interferon Regulatory Factor 6 (IRF6) Gene Variants and the Risk of Isolated Cleft Lip or Palate. N Engl J Med 2004; 351: 769-80.
• 24. Lidral AC, Romitti PA, Basart AM et al. Association of MSX1 and TGFB3 with Nonsyndromic Clefting in Humans. Am J Hum Genet 1998; 63: 557-68.
• 25. Van Den Boogaard MJH, Dorland M, Beemer FA et al. MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet 2000; 24: 342-3.
• 26. Leslie EJ, Marazita ML. Genetics of cleft lip and cleft palate. Am J Med Genet Part C Semin Med Genet 2013; 163: 246-58.
• 27. Eiberg H, D Bixler, LS Nielsen, et al. Suggestion of linkage of a major locus for nonsyndromic orofacial cleft with F13A and tentative assignment to chromosome 6. Clin Genet 32(2): 129-132.
• 28. Marazita ML, JC Murray, AC Lidral et al. Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35. Am J Hum Genet. 2004 Aug;75(2):161-73.
• 29. Carinci F, Pezzetti F, Scapoli L et al. Nonsyndromic cleft lip and palate: evidence of linkage to a microsatellite marker on 6p23 Am J Hum Genet. 1995 Jan;56(1):337-9.
• 30. Ann LL. "The role of structural variation in cleft lip and palate." PhD (Doctor of Philosophy) thesis, University of Iowa, 2018.
• 31. Turleau C, Chavin-Colin F, Narbouton R et al. Trisomy 18q-: trisomy mapping of chromosome 18 revisited. Clin Genet.1980;18: 20-26
• 32. Mewar R, Kline AD, Harrison W et al. Clinical and molecular evaluation of four patients with partial duplications of the long arm of chromosome 18. Am J Hum Genet. 1993 Dec;53(6):1269-78.
• 33. Lei TY, Wang HT, Li F et al. Application of high resolution SNP arrays in patients with congenital oral clefts in south China. J Genet. 2016 Dec;95(4):801-809.
• 34. Lintas C, Picinelli C, Piras IS et al. Xp22.33p22.12 Duplication in a Patient with Intellectual Disability and Dysmorphic Facial Features. Mol Syndromol. 2016 Feb;6(5):236-41.
• 35. Liu P, Erez A, Nagamani SC et al. Copy number gain at Xp22.31 includes complex duplication rearrangements and recurrent triplications. Hum Mol Genet. 2011 May 15;20(10):1975-88.
• 36. Buniello A, MacArthur JAL, Cerezo M et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Research, 2019, Vol. 47 (Database issue): D1005-D1012.
• 37. Kasajima R, Yamaguchi R, Shimizu E et al. Variant analysis of prostate cancer in Japanese patients and a new attempt to predict related biological pathways. Oncol Rep. 2020 Mar;43(3):943-952.