NOONAN SENDROMU’NUN PRENATAL TANISINDA PTPN11 GEN ANALİZLERİNİN ETKİNLİĞİ

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

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