Araştırma Makalesi


DOI :10.26650/IUITFD.2020.803356   IUP :10.26650/IUITFD.2020.803356    Tam Metin (PDF)

NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ

Güven ToksoyFatih TepgeçTuğba Saraç Sivrikozİbrahim Halil KalelioğluSelma DemirRecep HasAtıl YükselZehra Oya UygunerSeher Başaran

Amaç: Hücre büyüme, farklılaşma, yaşlanma ve siklus düzenlenmesinde önemli rol oynayan RAS-MAPK (Rat-sarcoma-Mitogen-activated-protein-kinase) yolağında bulunan 29 gendeki dominant patojenik varyantların yol açtığı klinik grup “Rasopatiler” olarak adlandırılır. En sık gözleneni Noonan sendromu (NS)’dur. Olguların ~%50’sinde NS ilişkili PTPN11 varyantları saptanır ve bu varyantların %90’ı peptidin N-önündeki ilk SH2 ve C-yönündeki katalitik domainini kodlayan bölgelerde ortaya çıkar. Prenatal evrede artmış nukal kalınlık (NT) ve ayrıca kistik higroma, plevral efüzyon ve asit gibi lenfatik sistem anomalilerinin yanı sıra kardiyak anomaliler, polihidramniyos, ekstremite kısalığı ve makrosefali NS’nin bulguları arasında sayılır. PTPN11 ilişkisi, kromozom anomalisi dışlanmış NT bulgusu olan fetusların %2-3’ünde, ek NS bulgusu olanlarda ise >%10 olarak bildirilmektedir. Gereç ve Yöntem: Çalışmamızda, NS ilişkili Ultrasonografi (USG) bulgusu olan, kromozom anomalisi dışlanmış 246 prenatal olguda, farklı yaklaşımlarla çalışılan PTPN11 gen analiz sonuçları retrospektif olarak değerlendirildi. Olguların 200’ünde genin hedef ekzonları (ekzon 3, 4, 7, 8, 13 ve 14), 46 olguda ise tüm gen Sanger dizileme yöntemi ile incelendi. Bulgular: Genel seride beş olguda (%2) ikisi novel olan (p.P107S ve p.M504T) beş farklı varyant hedeflenmiş ekzonlarda saptandı. Bu beş olgunun ikisinde izole NT ve üçünde çoklu USG bulguları mevcuttu. PTPN11 varyantı saptanmayan altı olguda, Rasopati ilişkili diğer dört genin hedef bölge analizinde, iki olguda SOS1 ve gebelik terminasyonu yapılan üç olgunun birinde hedeflenmiş gen panel testinde RAF1 geninde ilişkili patojenik varyantlar saptandı. NS ilişkili patojenik varyant saptama oranı hem izole NT grubunda hem de çoklu USG bulgulu grupta %2,3 idi. Tartışma: Rasopatilerin %50 sinden sorumlu olan PTPN11 genindeki patojenik varyantların %90’ı hedef ekzonlarda yer almaktadır. Bu nedenle, ilk aşamada PTPN11 hedef ekzon analizi yapılmasının, patogenezin açıklanamadığı olgularda ise genin diğer ekzonlarının ve Rasopati ilişkili diğer genlerin incelenmesinin fayda-maliyet açısından uygun bir yaklaşım olduğu belirlendi. 

DOI :10.26650/IUITFD.2020.803356   IUP :10.26650/IUITFD.2020.803356    Tam Metin (PDF)

THE EFFECTIVENESS OF PTPN11 GENE ANALYSIS IN THE PRENATAL DIAGNOSIS OF NOONAN SYNDROME

Güven ToksoyFatih TepgeçTuğba Saraç Sivrikozİbrahim Halil KalelioğluSelma DemirRecep HasAtıl YükselZehra Oya UygunerSeher Başaran

Objective: Dominant pathogenic variants in 29 RAS-MAPK (Rat-sarcoma-Mitogen-activated-protein-kinase) pathway genes, important for the regulation of cell growth, differentiation, aging and cell-cycle, are responsible for RASopathies, Noonan syndrome (NS) is the most common form. PTPN11 variants are detected in 50% of the cases, 90% being identified in the first SH2 and in the catalytic domain at the N- and C-terminals of the peptide, respectively. Increased nuchal translucency (NT), lymphatic system anomalies (cystic hygroma, pleural effusion, ascites), cardiac anomalies, polyhydramnios, short limb and macrocephaly are the NS-associated prenatal findings. PTPN11 association is reported in 2-3% of normal karyotyped fetuses with NT and in >10% when other NS findings are included. Material and Method: PTPN11 analysis with different approaches in 246 normal karyotyped prenatal cases with NS-associated USG findings were retrospectively evaluated. The targeted PTPN11 regions in 200 and the whole gene structure of 46 cases were examined by Sanger sequencing. Results: Pathogenic variants, including two novel variants (p.P107S and p.M504T), were identified in two fetuses with isolated NT and in three fetuses with multiple USG findings, leading to a 2% of detection rate, all found in targeted exons. Two of six cases, further investigated for targets of four Rasopathy genes, had causative genes in SOS1. One of three terminated fetuses, investigated for the targeted-gene panel, had a causative gene in RAF1 genes. Both the isolated NT and multiple USG finding groups revealed an equal detection rate of 2.3%. Discussion: PTPN11 is responsible for 50% of RASopathies and 90% of the pathogenic variants are delineated in the targeted exons. The rational, cost-effective approach for the clarification of the genetic basis of RASopathies is screening the addressed exons of PTPN11 followed by the other exons and other RASopathy related genes. 


PDF Görünüm

Referanslar

  • 1. Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y. The RAS/ MAPK syndromes: Novel roles of the RAS pathway in human genetic disorders. Hum Mutat 2008;29(8):992-1006. [CrossRef] google scholar
  • 2. Rauen KA. The RASopathies. Annu Rev Genom Hum G. 2013;14:355-69. [CrossRef] google scholar
  • 3. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 2001;29(4):465-8. [CrossRef] google scholar
  • 4. Jindal GA, Goyal Y, Burdine RD, Rauen KA, Shvartsman SY. RASopathies: unraveling mechanisms with animal models. Dis Model Mech 2015;8(8):769-82. [CrossRef] google scholar
  • 5. Lin AE, O’Brien B, Demmer LA, Almeda KK, Blanco CL, Glasow PF, et al. Prenatal features of Costello syndrome: ultrasonographic findings and atrial tachycardia. Prenat Diagn 2009;29(7):682-90. [CrossRef] google scholar
  • 6. Hakami F, Dillon MW, Lebo M, Mason-Suares H. Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder. Prenat Diagn 2016;36(5):418-23. [CrossRef] google scholar
  • 7. Renna MD, Pisani P, Conversano F, Perrone E, Casciaro E, Renzo GC, et al. Sonographic markers for early diagnosis of fetal malformations. World J Radiol 2013;5(10):356-71. [CrossRef] google scholar
  • 8. Jackson M, Rose NC. Diagnosis and management of fetal nuchal translucency. Semin Roentgenol 1998;33(4):333-8. [CrossRef] google scholar
  • 9. Hyett J, Thilaganathan B. First trimester screening for fetal abnormalities. Curr Opin Obstet Gynecol 1999;11(6):563-9. [CrossRef] google scholar
  • 10. Hung CS, Lin JL, Lee YJ, Lin SP, Chao MC, Lo FS. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc 2007;106(2):169- 72. [CrossRef] google scholar
  • 11. Athota JP, Bhat M, Nampoothiri S, Gowrishankar K, Narayanachar SG, Puttamallesh V, et al. Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations. BMC Med Genet 2020;21(1):50. [CrossRef] google scholar
  • 12. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 2014;133(1):1-9. [CrossRef] google scholar
  • 13. Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002;70(6):1555-63. [CrossRef] google scholar
  • 14. Musante L, Kehl HG, Majewski F, Meinecke P, Schweiger S, Gillessen-Kaesbach G, et al. Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-faciocutaneous syndrome. Eur J Hum Genet 2003;11(2):201-6. [CrossRef] google scholar
  • 15. Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, et al. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet 2004;41(11):e117. [CrossRef] google scholar
  • 16. Baldassarre G, Mussa A, Dotta A, Banaudi E, Forzano S, Marinosci A, et al. Prenatal features of Noonan syndrome: prevalence and prognostic value. Prenat Diagn 2011;31(10):949-54. [CrossRef] 1 google scholar
  • 7. Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat 2011;32(7):760-72. [CrossRef] google scholar
  • 18. Croonen EA, Nillesen WM, Stuurman KE, Oudesluijs G, van de Laar IM, Martens L, et al. Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings. Eur J Hum Genet 2013;21(9):936-42. [CrossRef] google scholar
  • 19. Schluter G, Steckel M, Schiffmann H, Harms K, Viereck V, Emons G, et al. Prenatal DNA diagnosis of Noonan syndrome in a fetus with massive hygroma colli, pleural effusion and ascites. Prenat Diagn 2005;25(7):574-6. [CrossRef] google scholar
  • 20. Lee KA, Williams B, Roza K, Ferguson H, David K, Eddleman K, et al. PTPN11 analysis for the prenatal diagnosis of Noonan syndrome in fetuses with abnormal ultrasound findings. Clin Genet 2009;75(2):190-4. [CrossRef] google scholar
  • 21. Myers A, Bernstein JA, Brennan ML, Curry C, Esplin ED, Fisher J, et al. Perinatal features of the RASopathies: Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome. Am J Med Genet A 2014;164A(11):2814- 21. [CrossRef] google scholar
  • 22. Leach NT, Wilson Mathews DR, Rosenblum LS, Zhou Z, Zhu H, Heim RA. Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. Genet Med 2019;21(2):417-25. [CrossRef] google scholar
  • 23. Sarkozy A, Conti E, Seripa D, Digilio MC, Grifone N, Tandoi C, et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet 2003;40(9):704-8. [CrossRef] google scholar
  • 24. Narayanan DL, Pandey H, Moirangthem A, Mandal K, Gupta R, Puri RD, et al. Hotspots in PTPN11 Gene Among Indian Children With Noonan Syndrome. Indian Pediatr 2017;54(8):638-43. [CrossRef] google scholar
  • 25. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405-24. [CrossRef] google scholar
  • 26. Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Bioinformatics 2019;35(11):1978-80. [CrossRef] google scholar
  • 27. Kosaki K, Suzuki T, Muroya K, Hasegawa T, Sato S, Matsuo N, et al. PTPN11 (protein-tyrosine phosphatase, nonreceptortype 11) mutations in seven Japanese patients with Noonan syndrome. J Clin Endocrinol Metab 2002;87(8):3529-33. [CrossRef] google scholar
  • 28. Zenker M, Voss E, Reis A. Mild variable Noonan syndrome in a family with a novel PTPN11 mutation. Eur J Med Genet 2007;50(1):43-7. [CrossRef] google scholar
  • 29. Blom N, Gammeltoft S, Brunak S. Sequence and structurebased prediction of eukaryotic protein phosphorylation sites. J Mol Biol 1999;294(5):1351-62. [CrossRef] google scholar
  • 30. Blom N, Sicheritz-Ponten T, Gupta R, Gammeltoft S, Brunak S. Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics 2004;4(6):1633-49. [CrossRef] google scholar
  • 31. Bertelloni S, Baroncelli GI, Dati E, Ghione S, Baldinotti F, Toschi B, et al. IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens) 2013;12(1):86-92. [CrossRef] google scholar
  • 32. Ezquieta B, Santome JL, Carcavilla A, Guillen-Navarro E, Perez-Aytes A, Sanchez del Pozo J, et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed) 2012;65(5):447- 55. [CrossRef] google scholar
  • 33. Tajan M, de Rocca Serra A, Valet P, Edouard T, Yart A. SHP2 sails from physiology to pathology. Eur J Med Genet 2015;58(10):509-25. [CrossRef] google scholar

Atıflar

Biçimlendirilmiş bir atıfı kopyalayıp yapıştırın veya seçtiğiniz biçimde dışa aktarmak için seçeneklerden birini kullanın


DIŞA AKTAR



APA

Toksoy, G., Tepgeç, F., Saraç Sivrikoz, T., Kalelioğlu, İ.H., Demir, S., Has, R., Yüksel, A., Uyguner, Z.O., & Başaran, S. (2021). NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ. İstanbul Tıp Fakültesi Dergisi, 84(1), 34-39. https://doi.org/10.26650/IUITFD.2020.803356


AMA

Toksoy G, Tepgeç F, Saraç Sivrikoz T, Kalelioğlu İ H, Demir S, Has R, Yüksel A, Uyguner Z O, Başaran S. NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ. İstanbul Tıp Fakültesi Dergisi. 2021;84(1):34-39. https://doi.org/10.26650/IUITFD.2020.803356


ABNT

Toksoy, G.; Tepgeç, F.; Saraç Sivrikoz, T.; Kalelioğlu, İ.H.; Demir, S.; Has, R.; Yüksel, A.; Uyguner, Z.O.; Başaran, S. NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ. İstanbul Tıp Fakültesi Dergisi, [Publisher Location], v. 84, n. 1, p. 34-39, 2021.


Chicago: Author-Date Style

Toksoy, Güven, and Fatih Tepgeç and Tuğba Saraç Sivrikoz and İbrahim Halil Kalelioğlu and Selma Demir and Recep Has and Atıl Yüksel and Zehra Oya Uyguner and Seher Başaran. 2021. “NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ.” İstanbul Tıp Fakültesi Dergisi 84, no. 1: 34-39. https://doi.org/10.26650/IUITFD.2020.803356


Chicago: Humanities Style

Toksoy, Güven, and Fatih Tepgeç and Tuğba Saraç Sivrikoz and İbrahim Halil Kalelioğlu and Selma Demir and Recep Has and Atıl Yüksel and Zehra Oya Uyguner and Seher Başaran. NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ.” İstanbul Tıp Fakültesi Dergisi 84, no. 1 (Jul. 2024): 34-39. https://doi.org/10.26650/IUITFD.2020.803356


Harvard: Australian Style

Toksoy, G & Tepgeç, F & Saraç Sivrikoz, T & Kalelioğlu, İH & Demir, S & Has, R & Yüksel, A & Uyguner, ZO & Başaran, S 2021, 'NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ', İstanbul Tıp Fakültesi Dergisi, vol. 84, no. 1, pp. 34-39, viewed 21 Jul. 2024, https://doi.org/10.26650/IUITFD.2020.803356


Harvard: Author-Date Style

Toksoy, G. and Tepgeç, F. and Saraç Sivrikoz, T. and Kalelioğlu, İ.H. and Demir, S. and Has, R. and Yüksel, A. and Uyguner, Z.O. and Başaran, S. (2021) ‘NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ’, İstanbul Tıp Fakültesi Dergisi, 84(1), pp. 34-39. https://doi.org/10.26650/IUITFD.2020.803356 (21 Jul. 2024).


MLA

Toksoy, Güven, and Fatih Tepgeç and Tuğba Saraç Sivrikoz and İbrahim Halil Kalelioğlu and Selma Demir and Recep Has and Atıl Yüksel and Zehra Oya Uyguner and Seher Başaran. NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ.” İstanbul Tıp Fakültesi Dergisi, vol. 84, no. 1, 2021, pp. 34-39. [Database Container], https://doi.org/10.26650/IUITFD.2020.803356


Vancouver

Toksoy G, Tepgeç F, Saraç Sivrikoz T, Kalelioğlu İH, Demir S, Has R, Yüksel A, Uyguner ZO, Başaran S. NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ. İstanbul Tıp Fakültesi Dergisi [Internet]. 21 Jul. 2024 [cited 21 Jul. 2024];84(1):34-39. Available from: https://doi.org/10.26650/IUITFD.2020.803356 doi: 10.26650/IUITFD.2020.803356


ISNAD

Toksoy, Güven - Tepgeç, Fatih - Saraç Sivrikoz, Tuğba - Kalelioğlu, İbrahimHalil - Demir, Selma - Has, Recep - Yüksel, Atıl - Uyguner, ZehraOya - Başaran, Seher. NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ”. İstanbul Tıp Fakültesi Dergisi 84/1 (Jul. 2024): 34-39. https://doi.org/10.26650/IUITFD.2020.803356



ZAMAN ÇİZELGESİ


Gönderim06.10.2020
Kabul08.12.2020
Çevrimiçi Yayınlanma28.01.2021

LİSANS


Attribution-NonCommercial (CC BY-NC)

This license lets others remix, tweak, and build upon your work non-commercially, and although their new works must also acknowledge you and be non-commercial, they don’t have to license their derivative works on the same terms.


PAYLAŞ




İstanbul Üniversitesi Yayınları, uluslararası yayıncılık standartları ve etiğine uygun olarak, yüksek kalitede bilimsel dergi ve kitapların yayınlanmasıyla giderek artan bilimsel bilginin yayılmasına katkıda bulunmayı amaçlamaktadır. İstanbul Üniversitesi Yayınları açık erişimli, ticari olmayan, bilimsel yayıncılığı takip etmektedir.