Noonan syndrome: molecular and clinical findings in individuals with PTPN11 pathogenic variants

Yıl 2024, Cilt: 17 Sayı: 3, 542 - 548, 05.07.2024

Derya Karaer , Taner Durak , Kadri Karaer

https://doi.org/10.31362/patd.1438458

Öz

Purpose: RASopathies encompass a spectrum of disorders resulting from pathogenic variants in genes associated with the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway, critical for cellular functions like proliferation, differentiation and survival. Noonan syndrome (NS), the most prevalent form of RASopathies, presents with a myriad of clinical features including characteristic facial dysmorphisms, congenital heart defects, and developmental delays. Despite its clinical recognition, molecular confirmation remains elusive in a notable percentage of cases. In this study, we aimed to investigate the clinical and molecular profiles of six patients diagnosed with NS, focusing on the role of PTPN11 gene mutations.
Materials and methods: Molecular evaluation was performed using PTPN11 gene sequence analysis and whole gene sequencing methods in six patients who were thought to have typical NS phenotypes based on clinical evaluations.
Results: Molecular screening in patients identified four different pathogenic variants in the PTPN11 gene. These variants, all heterozygous, were classified as pathogenic according to established criteria.
Conclusion: Our findings contribute to understanding the genetic landscape of NS and underscore the significance of molecular analysis in confirming diagnoses.

Anahtar Kelimeler

Noonan syndrome, PTPN11, pathogenic variant, SHP2

Noonan sendromu: PTPN11 patojenik varyantları olan bireylerde moleküler ve klinik bulgular

Öz

Amaç: RASopatiler, çoğalma, farklılaşma ve hayatta kalma gibi hücresel işlevler için kritik olan, Ras/mitojenle aktifleştirilen protein kinaz (RAS/MAPK) yolu ile ilişkili genlerdeki patojenik varyantlardan kaynaklanan, bir dizi bozukluğu kapsar. RASopatilerin en yaygın şekli olan Noonan sendromu (NS), karakteristik yüz dismorfizmleri, konjenital kalp defektleri ve gelişimsel gecikmeler dahil olmak üzere sayısız klinik özellik ile ortaya çıkar. Klinik olarak tanınmasına rağmen, vakaların kayda değer bir yüzdesinde moleküler doğrulama hala belirsizliğini korumaktadır. Bu çalışmada PTPN11 gen mutasyonu bulunan NS tanısı alan altı hastanın klinik ve moleküler profillerini araştırmayı amaçladık.
Gereç ve yöntem: Klinik değerlendirmelere göre tipik NS fenotipine sahip olduğu düşünülen altı hastada PTPN11 gen dizi analizi ve tam gen dizileme yöntemleri kullanılarak moleküler değerlendirme yapıldı.
Bulgular: Hastalarda yapılan moleküler taramada PTPN11 geninde dört farklı patojenik varyant tespit edildi. Tamamı heterozigot olan bu varyantlar, belirlenen kriterlere göre patojenik olarak sınıflandırıldı.
Sonuç: Bulgularımız NS'nin genetik yapısının anlaşılmasına katkıda bulunmakta ve tanıların doğrulanmasında moleküler analizin öneminin altını çizmektedir.

Anahtar Kelimeler

Noonan sendromu, PTPN11, patojenik varyant, SHP2

Kaynakça

• 1. Tajan M, Paccoud R, Branka S, Edouard T, Yart A. The RASopathy family: consequences of germline activation of the RAS/MAPK pathway. Endocr Rev 2018;39:676-700. https://doi.org/10.1210/er.2017-00232
• 2. Tidyman WE, Rauen KA. Expansion of the RASopathies. Curr Genet Med Rep 2016;4:57-64. https://doi.org/10.1007/s40142-016-0100-7
• 3. Liao J, Mehta L. Molecular genetics of Noonan syndrome and RASopathies. Pediatr Endocrinol Rev 2019;16:435-446. https://doi.org/10.17458/per. vol16.2019.lm.molecularnoonan
• 4. Riller Q, Rieux Laucat F. RASopathies: from germline mutations to somatic and multigenic diseases. Biomed J 2021;44:422-432. https://doi.org/10.1016/j.bj.2021.06.004
• 5. Tartaglia M, Mehler EL, Goldberg R, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 2001;29:465-468. https://doi.org/10.1038/ng772
• 6. Sznajer Y, Keren B, Baumann C, et al. The spectrum of cardiac anomalies in Noonan syndrome as a result of mutations in the PTPN11 gene. Pediatrics 2007;119:1325-1331. http://dx.doi.org/10.1542/peds.2006-0211
• 7. Roberts AE, Araki T, Swanson KD, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 2007;39:70-74. https://doi.org/10.1038/ng1926
• 8. Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab 2011;25:161-179. https://doi.org/10.1016/j.beem.2010.09.002
• 9. Allanson JE, Roberts AE. Noonan syndrome. Gene-Tests: Reviews. National Center for Biotechnology Information. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1124. Accessed December 23, 2023
• 10. Van der Burgt I. Noonan syndrome. Orphanet J Rare Dis 2007;2:4. https://doi.org/10.1186/1750-1172-2-4 11. Yart A, Edouard T. Noonan syndrome: an update on growth and development. Curr Opin Endocrinol Diabetes Obes 2018;25:67-73. https://doi.org/10.1097/ MED.0000000000000380
• 12. Allanson JE, Bohring A, Dörr HG, et al. The face of Noonan syndrome: does phenotype predict genotype. Am J Med Genet A 2010;152:1960-1966. https://doi.org/10.1002/ajmg.a.33518
• 13. Zenker M, Edouard T, Blair JC, Cappa M. Noonan syndrome: improving recognition and diagnosis. Arch Dis Child 2022;107:1073-1078. https://doi.org/10.1136/archdischild-2021-322858
• 14. Richards S, Aziz N, Bale S, et al. ACMG Laboratory Quality Assurance Committee. 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;17:405-424. https://doi.org/10.1038/gim.2015.30
• 15. 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;133:1-9. https://doi.org/10.1007/s00439-013-1358-4
• 16. Landrum MJ, Lee JM, Benson M, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 2018;46:1062-1067. https://doi.org/10.1093/nar/gkx1153
• 17. Athota JP, Bhat M, Nampoothiri S, et al. Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations. BMC Med Genet 2020;21:50. https://doi.org/10.1186/s12881-020-0986-5
• 18. Musante L, Kehl HG, Majewski F, et al. Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. Eur J Hum Genet 2003;11:201-206. https://doi.org/10.1038/sj.ejhg.5200935
• 19. Atik T, Aykut A, Hazan F, et al. Mutation spectrum and phenotypic features in Noonan syndrome with PTPN11 mutations: definition of two novel mutations. Indian J Pediatr 2016;83:517-521. https://doi.org/10.1007/s12098-015-1998-6
• 20. Altıner S, Çebi AH, Celik S, Gökcü M. Genotype/phenotype correlation of cases with PTPN11 gene mutation: eastern black sea experience. J Ankara University School Med 2022;75:368-372. https://doi.org/10.4274/atfm.galenos.2022.06978
• 21. Noonan JA. Noonan syndrome. An update and review for the primary pediatrician. Clin Pediatr 1994;33:548-555. https://doi.org/10.1177/000992289403300907
• 22. Menashe M, Arbel R, Raveh D, Achiron R, Yagel S. Poor prenatal detection rate of cardiac anomalies in Noonan syndrome. Ultrasound Obstet Gynecol 2002;19:51-55. https://doi.org/10.1046/j.0960-7692.2001.00485.x