NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ

Yıl 2021, , 34 - 39, 15.01.2021

Güven Toksoy , Fatih Tepgeç Tuğba Saraç İbrahim Kalelioğlu , Selma Demir , Recep Has , Atıl Yüksel Zehra Oya Uyguner Seher Başaran

https://doi.org/10.26650/IUITFD.2020.803356

Öz

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.

Anahtar Kelimeler

PTPN11, Noonan sendromu, artmış nukal kalınlık, kistik higroma, plevral efüzyon

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

Öz

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.

Anahtar Kelimeler

PTPN11, Noonan syndrome, increased nuchai translucency, cystic hygroma, , pleural effusion

Kaynakça

• 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]
• 2. Rauen KA. The RASopathies. Annu Rev Genom Hum G. 2013;14:355-69. [CrossRef]
• 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]
• 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]
• 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]
• 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]
• 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]
• 8. Jackson M, Rose NC. Diagnosis and management of fetal nuchal translucency. Semin Roentgenol 1998;33(4):333-8. [CrossRef]
• 9. Hyett J, Thilaganathan B. First trimester screening for fetal abnormalities. Curr Opin Obstet Gynecol 1999;11(6):563-9. [CrossRef]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 17. 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]