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Human Genetics

, Volume 135, Issue 2, pp 209–222 | Cite as

Spectrum of mutations and genotype–phenotype analysis in Noonan syndrome patients with RIT1 mutations

  • Masako Yaoita
  • Tetsuya Niihori
  • Seiji Mizuno
  • Nobuhiko Okamoto
  • Shion Hayashi
  • Atsushi Watanabe
  • Masato Yokozawa
  • Hiroshi Suzumura
  • Akihiko Nakahara
  • Yusuke Nakano
  • Tatsunori Hokosaki
  • Ayumi Ohmori
  • Hirofumi Sawada
  • Ohsuke Migita
  • Aya Mima
  • Pablo Lapunzina
  • Fernando Santos-Simarro
  • Sixto García-Miñaúr
  • Tsutomu Ogata
  • Hiroshi Kawame
  • Kenji Kurosawa
  • Hirofumi Ohashi
  • Shin-ichi Inoue
  • Yoichi Matsubara
  • Shigeo Kure
  • Yoko AokiEmail author
Original Investigation

Abstract

RASopathies are autosomal dominant disorders caused by mutations in more than 10 known genes that regulate the RAS/MAPK pathway. Noonan syndrome (NS) is a RASopathy characterized by a distinctive facial appearance, musculoskeletal abnormalities, and congenital heart defects. We have recently identified mutations in RIT1 in patients with NS. To delineate the clinical manifestations in RIT1 mutation-positive patients, we further performed a RIT1 analysis in RASopathy patients and identified 7 RIT1 mutations, including two novel mutations, p.A77S and p.A77T, in 14 of 186 patients. Perinatal abnormalities, including nuchal translucency, fetal hydrops, pleural effusion, or chylothorax and congenital heart defects, are observed in all RIT1 mutation-positive patients. Luciferase assays in NIH 3T3 cells demonstrated that the newly identified RIT1 mutants, including p.A77S and p.A77T, and the previously identified p.F82V, p.T83P, p.Y89H, and p.M90I, enhanced Elk1 transactivation. Genotype–phenotype correlation analyses of previously reported NS patients harboring RIT1, PTPN11, SOS1, RAF1, and KRAS revealed that hypertrophic cardiomyopathy (56 %) was more frequent in patients harboring a RIT1 mutation than in patients harboring PTPN11 (9 %) and SOS1 mutations (10 %). The rates of hypertrophic cardiomyopathy were similar between patients harboring RIT1 mutations and patients harboring RAF1 mutations (75 %). Short stature (52 %) was less prevalent in patients harboring RIT1 mutations than in patients harboring PTPN11 (71 %) and RAF1 (83 %) mutations. These results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature.

Keywords

Intellectual Disability Atrial Septal Defect Hypertrophic Cardiomyopathy Hypoplastic Left Heart Syndrome Tolvaptan 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors thank the patients, their families, and the doctors who participated in this study. We are grateful to Jun-ichi Miyazaki of Osaka University for supplying the pCAGGS expression vector. We thank Rumiko Izumi, Daiju Oba, Ayumi Nishiyama and Shingo Takahara, who contributed to the routine diagnostic work, and Yoko Tateda, Kumi Kato, and Riyo Takahashi for their technical assistance. This work was supported by the Funding Program for the Next Generation of World-Leading Researchers (NEXT Program) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (LS004) to YA. This work was supported by grants from the Ministry of Health, Labor and Welfare of Japan, the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and development, AMED, and the Japan Society for the Promotion of Science [a Grant-in-Aid for Scientific Research (B), Grant-in-Aid for Exploratory Research] to YA. This work was also supported in part by the Japanese Foundation for Pediatric Research.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Masako Yaoita
    • 1
  • Tetsuya Niihori
    • 1
  • Seiji Mizuno
    • 2
  • Nobuhiko Okamoto
    • 3
  • Shion Hayashi
    • 4
  • Atsushi Watanabe
    • 5
  • Masato Yokozawa
    • 6
  • Hiroshi Suzumura
    • 7
  • Akihiko Nakahara
    • 8
  • Yusuke Nakano
    • 9
  • Tatsunori Hokosaki
    • 10
  • Ayumi Ohmori
    • 11
  • Hirofumi Sawada
    • 11
  • Ohsuke Migita
    • 12
  • Aya Mima
    • 13
  • Pablo Lapunzina
    • 14
  • Fernando Santos-Simarro
    • 14
  • Sixto García-Miñaúr
    • 14
  • Tsutomu Ogata
    • 15
  • Hiroshi Kawame
    • 16
  • Kenji Kurosawa
    • 17
  • Hirofumi Ohashi
    • 18
  • Shin-ichi Inoue
    • 1
  • Yoichi Matsubara
    • 19
  • Shigeo Kure
    • 20
  • Yoko Aoki
    • 1
    Email author
  1. 1.Department of Medical GeneticsTohoku University School of MedicineSendaiJapan
  2. 2.Department of PediatricsCentral Hospital, Aichi Human Service CenterKasugaiJapan
  3. 3.Department of Medical GeneticsOsaka Medical Center, Research Institute for Maternal and Child HealthIzumiJapan
  4. 4.Department of NeonatologyThe Jikei University HospitalTokyoJapan
  5. 5.Division of Clinical GeneticsNippon Medical School HospitalTokyoJapan
  6. 6.Department of Pediatric CardiologyHokkaido Medical Center for Child Health and RehabilitationSapporoJapan
  7. 7.Department of PediatricsDokkyo Medical UniversityTochigiJapan
  8. 8.Department of Pediatrics, Faculty of MedicineUniversity of MiyazakiMiyazakiJapan
  9. 9.Department of CardiologyNagano Children’s HospitalNaganoJapan
  10. 10.Department of PediatricsYokohama City University HospitalYokohamaJapan
  11. 11.Department of PediatricsMie UniversityTsuJapan
  12. 12.Department of PediatricsSt. Marianna University School of MedicineKawasakiJapan
  13. 13.Department of PediatricsYodogawa Christian HospitalOsakaJapan
  14. 14.Institute of Medical and Molecular Genetics (INGEMM)La Paz University HospitalMadridSpain
  15. 15.Department of PediatricsHamamatsu University School of MedicineHamamatsuJapan
  16. 16.Division of Genomic Medicine Support and Genetic CounselingTohoku Medical Megabank Organization, Tohoku UniversitySendaiJapan
  17. 17.Division of Medical GeneticsKanagawa Children’s Medical CenterYokohamaJapan
  18. 18.Division of Medical GeneticsSaitama Children’s Medical CenterSaitamaJapan
  19. 19.National Research Institute for Child Health and DevelopmentTokyoJapan
  20. 20.Department of PediatricsTohoku University School of MedicineSendaiJapan

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