Öz
Amaç: PTPN11 geninde hastalık yapıcı varyant saptanan sekiz olgunun genotip/fenotip ilişkisini tartışmak.
Gereç ve Yöntem: Karadeniz Teknik Üniversitesi Tıp Fakültesi ve Trabzon Kanuni Eğitim ve Araştırma Hastanesi Tıbbi Genetik Anabilim Dalları’nda,
2017-2019 yılları arasında Noonan Sendromu ön tanısı ile PTPN11 geni dizi analizi yapılan sekiz olgu retrospektif olarak incelendi.
Bulgular: PTPN11 geni patojenik varyantı saptanan sekiz olguda en sık gözlenen bulgular kalp defekti (%87,5), boy kısalığı (%87,5) ve düşük
yerleşimli ve arkaya dönük kulaklar (%87,5) iken en sık rastlanan kalp defekti pulmoner stenozdu (%62,5). Olguların klinik özellikleri ise Noonan
sendromu (%87,5) ve multipl lentijinli Noonan sendromu (%12,5) ile uyumlu bulundu. Çalışmada en sık rastlanan mutasyon (%25) NM_002834.5:
PTPN11; c.922A>G; p.Asn308Asp idi.
Sonuç: Çalışma sonucu bulunan tüm hastalık yapıcı varyantların neden olduğu fenotipler güncel veriler ile uyumlu bulunmuştur. RASopatilerin
%50’sinde PTPN11 geni patojenik varyantlarının sorumlu olduğu bilinmektedir ve kromozom analizi normal olan, klinik bulgular ile Noonan
Sendromu skorlamasını karşılayan hastalarda PTPN11 dizi analizi yapılması maliyet-etkin bir yöntemdir.
Anahtar Kelimeler
Noonan Sendromu PTPN11 Multipl Lentijinli Noonan Sendromu Genotip/Fenotip İlişkisi
Etik Beyan
Bu çalışma için etik kurul onayı Sağlık Bilimleri Üniversitesi Kanuni Eğitim ve Araştırma Hastanesi Klinik Araştırmalar Etik Kurulu’ndan alınmıştır (protokol no: 2019/23, tarih: 25.04.2019).
Destekleyen Kurum
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Proje Numarası
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Teşekkür
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Kaynakça
- 1. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-369.
- 2. Riller Q, Rieux-Laucat F. RASopathies: From germline mutations to somatic and multigenic diseases. Biomed J. 2021;44:422-432.
- 3. Jongmans M, Otten B, Noordam K, et al. Genetics and variation in phenotype in Noonan syndrome. Horm Res. 2004;62 Suppl 3:56-9.
- 4. van der Burgt I. Noonan syndrome. Orphanet J Rare Dis. 2007;2:4.
- 5. Stenson PD, Mort M, Ball EV, et al. 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.
- 6. Landrum MJ, Lee JM, Benson M, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46:D1062-D1067.
- 7. Firth HV, Richards SM, Bevan AP, et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009;84:524-533.
- 8. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013;Chapter 7:Unit7.20.
- 9. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding nonsynonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073-1081.
- 10. Schwarz JM, Cooper DN, Schuelke M, et al. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361-362.
- 11. Richards S, Aziz N, Bale S, 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;17:405-424.
- 12. Neel BG, Gu H, Pao L. The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28:284-293.
- 13. 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.
- 14. Sarkozy A, Conti E, Seripa D, et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet. 2003;40:704-708.
- 15. 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.
- 16. 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.
- 17. Allen MJ, Sharma S. Noonan Syndrome. StatPearls. 2021, StatPearls Publishing.
- 18. Uludağ Alkaya D, Lissewski C, Yeşil G, et al. Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1. Am J Med Genet A. 2021;185:3623-3633.
- 19. Şimşek-Kiper PÖ, Alanay Y, Gülhan B, et al. Clinical and molecular analysis of RASopathies in a group of Turkish patients. Clin Genet. 2013;83:181-186.
Öz
Objectives: To discuss the genotype/phenotype correlation of eight cases with pathogenic variant in the PTPN11 gene.
Materials and Methods: Eight cases with a prediagnosis of Noonan Syndrome, in which the PTPN11 gene sequence analysis was performed
between 2017 and 2019 at Karadeniz Technical University Faculty of Medicine and Trabzon Kanuni Training and Research Hospital, Department of
Medical Genetics were retrospectively evaluated in the study.
Results: The most common findings in the eight cases with pathogenic variant in the PTPN11 gene were heart defect (87.5%), short stature (87.5%),
and low-set posteriorly rotated ears (87.5%) and the most common heart defect was pulmonary stenosis (62.5%). The clinical diagnoses of those
cases were Noonan Syndrome (87.5%) and Noonan syndrome with multiple lentigines (12.5%). NM_002834.5: PTPN11; c.922A>G; p.Asn308Asp
mutation was the most commonly (25%) detected mutation.
Conclusion: The phenotypes caused by all disease-causing variants found in this study were detected to be compatible with the current knowledge.
Pathogenic variants of PTPN11 are responsible for 50% of RASopathies, and PTPN11 sequence analysis is a cost-effective method in patients with
normal karyotyping, meeting the scoring system for Noonan Syndrome with clinical findings
Anahtar Kelimeler
Noonan Syndrome PTPN11 Noonan Syndrome with Multiple Lentigines Genotype/Phenotype Correlation
Etik Beyan
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Destekleyen Kurum
-
Proje Numarası
-
Teşekkür
-
Kaynakça
- 1. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-369.
- 2. Riller Q, Rieux-Laucat F. RASopathies: From germline mutations to somatic and multigenic diseases. Biomed J. 2021;44:422-432.
- 3. Jongmans M, Otten B, Noordam K, et al. Genetics and variation in phenotype in Noonan syndrome. Horm Res. 2004;62 Suppl 3:56-9.
- 4. van der Burgt I. Noonan syndrome. Orphanet J Rare Dis. 2007;2:4.
- 5. Stenson PD, Mort M, Ball EV, et al. 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.
- 6. Landrum MJ, Lee JM, Benson M, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46:D1062-D1067.
- 7. Firth HV, Richards SM, Bevan AP, et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009;84:524-533.
- 8. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013;Chapter 7:Unit7.20.
- 9. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding nonsynonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073-1081.
- 10. Schwarz JM, Cooper DN, Schuelke M, et al. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361-362.
- 11. Richards S, Aziz N, Bale S, 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;17:405-424.
- 12. Neel BG, Gu H, Pao L. The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28:284-293.
- 13. 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.
- 14. Sarkozy A, Conti E, Seripa D, et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet. 2003;40:704-708.
- 15. 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.
- 16. 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.
- 17. Allen MJ, Sharma S. Noonan Syndrome. StatPearls. 2021, StatPearls Publishing.
- 18. Uludağ Alkaya D, Lissewski C, Yeşil G, et al. Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1. Am J Med Genet A. 2021;185:3623-3633.
- 19. Şimşek-Kiper PÖ, Alanay Y, Gülhan B, et al. Clinical and molecular analysis of RASopathies in a group of Turkish patients. Clin Genet. 2013;83:181-186.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Tıbbi Genetik (Kanser Genetiği hariç) |
| Bölüm | Makaleler |
| Yazarlar | |
| Proje Numarası | - |
| Yayımlanma Tarihi | 18 Ekim 2022 |
| Yayımlandığı Sayı | Yıl 2022 Cilt: 75 Sayı: 3 |
