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

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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.

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References

  • Aoki Y, Matsubara Y (2013) Ras/MAPK syndromes and childhood hemato-oncological diseases. Int J Hematol 97:30–36. doi:10.1007/s12185-012-1239-y

    Article  PubMed  CAS  Google Scholar 

  • Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y (2005) Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 37:1038–1040. doi:10.1038/ng1641

    Article  PubMed  CAS  Google Scholar 

  • Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, S-i Inoue, Watanabe Y, Ogura T, Matsubara Y (2013) Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK Pathway Syndrome. Am J Hum Genet 93:173–180. doi:10.1016/j.ajhg.2013.05.021

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Berger AH, Imielinski M, Duke F, Wala J, Kaplan N, Shi GX, Andres DA, Meyerson M (2014) Oncogenic RIT1 mutations in lung adenocarcinoma. Oncogene 33:4418–4423. doi:10.1038/onc.2013.581

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bertola DR, Yamamoto GL, Almeida TF, Buscarilli M, Jorge AAL, Malaquias AC, Kim CA, Takahashi VNV, Passos-Bueno MR, Pereira AC (2014) Further evidence of the importance ofRIT1in Noonan syndrome. Am J Med Genet Part A 164:2952–2957. doi:10.1002/ajmg.a.36722

    Article  CAS  Google Scholar 

  • Carta C, Pantaleoni F, Bocchinfuso G, Stella L, Vasta I, Sarkozy A, Digilio C, Palleschi A, Pizzuti A, Grammatico P, Zampino G, Dallapiccola B, Gelb BD, Tartaglia M (2006) Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet 79:129–135. doi:10.1086/504394

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Chen PC, Yin J, Yu HW, Yuan T, Fernandez M, Yung CK, Trinh QM, Peltekova VD, Reid JG, Tworog-Dube E, Morgan MB, Muzny DM, Stein L, McPherson JD, Roberts AE, Gibbs RA, Neel BG, Kucherlapati R (2014) Next-generation sequencing identifies rare variants associated with Noonan syndrome. Proc Natl Acad Sci 111:11473–11478. doi:10.1073/pnas.1324128111

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cirstea IC, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, Roberts AE, Lepri F, Merbitz-Zahradnik T, Konig R, Kratz CP, Pantaleoni F, Dentici ML, Joshi VA, Kucherlapati RS, Mazzanti L, Mundlos S, Patton MA, Silengo MC, Rossi C, Zampino G, Digilio C, Stuppia L, Seemanova E, Pennacchio LA, Gelb BD, Dallapiccola B, Wittinghofer A, Ahmadian MR, Tartaglia M, Zenker M (2010) A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet 42:27–29. doi:10.1038/ng.497

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cordeddu V, Di Schiavi E, Pennacchio LA, Ma’ayan A, Sarkozy A, Fodale V, Cecchetti S, Cardinale A, Martin J, Schackwitz W, Lipzen A, Zampino G, Mazzanti L, Digilio MC, Martinelli S, Flex E, Lepri F, Bartholdi D, Kutsche K, Ferrero GB, Anichini C, Selicorni A, Rossi C, Tenconi R, Zenker M, Merlo D, Dallapiccola B, Iyengar R, Bazzicalupo P, Gelb BD, Tartaglia M (2009) Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet 41:1022–1026. doi:10.1038/ng.425

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Denayer E, Devriendt K, de Ravel T, Van Buggenhout G, Smeets E, Francois I, Sznajer Y, Craen M, Leventopoulos G, Mutesa Lo, Vandecasseye W, Massa G, Kayserili H, Sciot R, Fryns J-P, Legius E (2010) Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations. Genes Chromosomes Cancer 49:242–252. doi:10.1002/gcc.20735

    PubMed  CAS  Google Scholar 

  • Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B (2002) Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 71:389–394. doi:10.1086/341528

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Gomez-Segui I, Makishima H, Jerez A, Yoshida K, Przychodzen B, Miyano S, Shiraishi Y, Husseinzadeh HD, Guinta K, Clemente M, Hosono N, McDevitt MA, Moliterno AR, Sekeres MA, Ogawa S, Maciejewski JP (2013) Novel recurrent mutations in the RAS-like GTP-binding gene RIT1 in myeloid malignancies. Leukemia 27:1943–1946. doi:10.1038/leu.2013.179

    Article  PubMed  CAS  Google Scholar 

  • Gos M, Fahiminiya S, Poznanski J, Klapecki J, Obersztyn E, Piotrowicz M, Wierzba J, Posmyk R, Bal J, Majewski J (2014) Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: four new cases and further evidence of heterogeneity. Am J Med Genet A 164A:2310–2316. doi:10.1002/ajmg.a.36646

    Article  PubMed  Google Scholar 

  • Jongmans M, Sistermans EA, Rikken A, Nillesen WM, Tamminga R, Patton M, Maier EM, Tartaglia M, Noordam K, van der Burgt I (2005) Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature. Am J Med Genet Part A 134A:165–170. doi:10.1002/ajmg.a.30598

    Article  PubMed  Google Scholar 

  • Ko JM, Kim J-M, Kim G-H, Yoo H-W (2008) PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype–phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet 53:999–1006. doi:10.1007/s10038-008-0343-6

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi T, Aoki Y, Niihori T, Cavé H, Verloes A, Okamoto N, Kawame H, Fujiwara I, Takada F, Ohata T, Sakazume S, Ando T, Nakagawa N, Lapunzina P, Meneses AG, Gillessen-Kaesbach G, Wieczorek D, Kurosawa K, Mizuno S, Ohashi H, David A, Philip N, Guliyeva A, Narumi Y, Kure S, Tsuchiya S, Matsubara Y (2010) Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Hum Mutat 31:284–294. doi:10.1002/humu.21187

    Article  PubMed  CAS  Google Scholar 

  • Koenighofer M, Hung CY, McCauley JL, Dallman J, Back EJ, Mihalek I, Gripp KW, Sol-Church K, Rusconi P, Zhang Z, Shi GX, Andres DA, Bodamer OA (2015) Mutations inRIT1cause Noonan syndrome—additional functional evidence and expanding the clinical phenotype. Clin Genet. doi:10.1111/cge.12608

    PubMed  Google Scholar 

  • Lee CH, Della NG, Chew CE, Zack DJ (1996) Rin, a neuron-specific and calmodulin-binding small G-protein, and Rit define a novel subfamily of ras proteins. J Neurosci 16:6784–6794

    PubMed  CAS  Google Scholar 

  • Lee BH, Kim J-M, Jin HY, Kim G-H, Choi J-H, Yoo H-W (2011) Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. J Pediatr 159:1029–1035. doi:10.1016/j.jpeds.2011.05.024

    Article  PubMed  Google Scholar 

  • Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, Cordeddu V, Williams BJ, Dentici ML, Caputo V, Venanzi S, Bonaguro M, Kavamura I, Faienza MF, Pilotta A, Stanzial F, Faravelli F, Gabrielli O, Marino B, Neri G, Silengo MC, Ferrero GB, Torrrente I, Selicorni A, Mazzanti L, Digilio MC, Zampino G, Dallapiccola B, Gelb BD, Tartaglia M (2011) SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype–phenotype correlations. Hum Mutat 32:760–772. doi:10.1002/humu.21492

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Lo F-S, Lin J-L, Kuo M-T, Chiu P-C, Shu S-G, Chao M-C, Lee Y-J, Lin S-P (2008) Noonan syndrome caused by germline KRAS mutation in Taiwan: report of two patients and a review of the literature. Eur J Pediatr 168:919–923. doi:10.1007/s00431-008-0858-z

    Article  PubMed  Google Scholar 

  • Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F, Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM, Zampino G, van der Burgt I, Ferrero GB, Mazzanti L, Screpanti I, Yntema HG, Nillesen WM, Savarirayan R, Zenker M, Dallapiccola B, Gelb BD, Tartaglia M (2010) Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet 87:250–257. doi:10.1016/j.ajhg.2010.06.015

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Musante L, Kehl HG, Majewski F, Meinecke P, Schweiger S, Gillessen-Kaesbach G, Wieczorek D, Hinkel GK, Tinschert S, Hoeltzenbein M, Ropers H-H, Kalscheuer VM (2003) 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 11:201–206. doi:10.1038/sj.ejhg.5200935

    Article  PubMed  CAS  Google Scholar 

  • Myers A, Bernstein JA, Brennan ML, Curry C, Esplin ED, Fisher J, Homeyer M, Manning MA, Muller EA, Niemi AK, Seaver LH, Hintz SR, Hudgins L (2014) Perinatal features of the RASopathies: Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome. Am J Med Genet A 164A:2814–2821. doi:10.1002/ajmg.a.36737

    Article  PubMed  Google Scholar 

  • Nava C, Hanna N, Michot C, Pereira S, Pouvreau N, Niihori T, Aoki Y, Matsubara Y, Arveiler B, Lacombe D, Pasmant E, Parfait B, Baumann C, Heron D, Sigaudy S, Toutain A, Rio M, Goldenberg A, Leheup B, Verloes A, Cave H (2007) Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype phenotype relationships and overlap with Costello syndrome. J Med Genet 44:763–771. doi:10.1136/jmg.2007.050450

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Sakamoto KM, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Schneider M, Stary J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML (2010) Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42:794–800. doi:10.1038/ng.641

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Niihori T, Aoki Y, Narumi Y, Neri G, Cave H, Verloes A, Okamoto N, Hennekam RC, Gillessen-Kaesbach G, Wieczorek D, Kavamura MI, Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G, Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, Kure S, Matsubara Y (2006) Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet 38:294–296. doi:10.1038/ng1749

    Article  PubMed  CAS  Google Scholar 

  • Niwa H, Yamamura K, Miyazaki J (1991) Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108:193–199

    Article  PubMed  CAS  Google Scholar 

  • Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, López Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD (2007) Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 39:1007–1012. doi:10.1038/ng2073

    Article  PubMed  CAS  Google Scholar 

  • Perez B, Mechinaud F, Galambrun C, Ben Romdhane N, Isidor B, Philip N, Derain-Court J, Cassinat B, Lachenaud J, Kaltenbach S, Salmon A, Desiree C, Pereira S, Menot ML, Royer N, Fenneteau O, Baruchel A, Chomienne C, Verloes A, Cave H (2010) Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia. J Med Genet 47:686–691. doi:10.1136/jmg.2010.076836

    Article  PubMed  CAS  Google Scholar 

  • Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M, Fujiwara Y, Matsushima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J, Higashinakagawa T, Matsuoka R (2007) Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet 39:1013–1017. doi:10.1038/ng2078

    Article  PubMed  CAS  Google Scholar 

  • Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG, Kucherlapati RS (2006) Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 39:70–74. doi:10.1038/ng1926

    Article  PubMed  Google Scholar 

  • Roberts AE, Allanson JE, Tartaglia M, Gelb BD (2013) Noonan syndrome. The Lancet 381:333–342. doi:10.1016/s0140-6736(12)61023-x

    Article  CAS  Google Scholar 

  • Rodriguez-Viciana P, Rauen KA (2008) Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. Methods Enzymol 438:277–289. doi:10.1016/S0076-6879(07)38019-1

    Article  PubMed  CAS  Google Scholar 

  • Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA (2010) Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 126:746–759. doi:10.1542/peds.2009-3207

    Article  PubMed  Google Scholar 

  • Rusyn EV, Reynolds ER, Shao H, Grana TM, Chan TO, Andres DA, Cox AD (2000) Rit, a non-lipid-modified Ras-related protein, transforms NIH3T3 cells without activating the ERK, JNK, p38 MAPK or PI3 K/Akt pathways. Oncogene 19:4685–4694. doi:10.1038/sj.onc.1203836

    Article  PubMed  CAS  Google Scholar 

  • Sakabe K, Teramoto H, Zohar M, Behbahani B, Miyazaki H, Chikumi H, Gutkind JS (2002) Potent transforming activity of the small GTP-binding protein Rit in NIH 3T3 cells: evidence for a role of a p38gamma-dependent signaling pathway. FEBS Lett 511:15–20. doi:10.1016/S0014-5793(01)03264-1

    Article  PubMed  CAS  Google Scholar 

  • Schubbert S, Zenker M, Rowe SL, Böll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner L-E, Nguyen H, West B, Zhang KYJ, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP (2006) Germline KRAS mutations cause Noonan syndrome. Nat Genet 38:331–336. doi:10.1038/ng1748

    Article  PubMed  CAS  Google Scholar 

  • Sznajer Y, Keren B, Baumann C, Pereira S, Alberti C, Elion J, Cave H, Verloes A (2007) The spectrum of cardiac anomalies in Noonan syndrome as a result of mutations in the PTPN11 gene. Pediatrics 119:e1325–e1331. doi:10.1542/peds.2006-0211

    Article  PubMed  Google Scholar 

  • Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD (2002) PTPN11 mutations in Noonan Syndrome: molecular spectrum, genotype–phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 70:1555–1563. doi:10.1086/340847

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, Pandit B, Oishi K, Martinelli S, Schackwitz W, Ustaszewska A, Martin J, Bristow J, Carta C, Lepri F, Neri C, Vasta I, Gibson K, Curry CJ, Siguero JP, Digilio MC, Zampino G, Dallapiccola B, Bar-Sagi D, Gelb BD (2007) Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet 39:75–79. doi:10.1038/ng1939

    Article  PubMed  CAS  Google Scholar 

  • Tidyman WE, Rauen KA (2009) The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 19:230–236. doi:10.1016/j.gde.2009.04.001

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Wes PD, Yu M, Montell C (1996) RIC, a calmodulin-binding Ras-like GTPase. EMBO J 15:5839–5848

    PubMed  CAS  PubMed Central  Google Scholar 

  • Yoshida R, Hasegawa T, Hasegawa Y, Nagai T, Kinoshita E, Tanaka Y, Kanegane H, Ohyama K, Onishi T, Hanew K, Okuyama T, Horikawa R, Tanaka T, Ogata T (2004) Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome. J Clin Endocrinol Metab 89:3359–3364. doi:10.1210/jc.2003-032091

    Article  PubMed  CAS  Google Scholar 

  • Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze H-U, Doerr H-G, Hofbeck M, Singer H, Reis A, Rauch A (2004) Genotype-phenotype correlations in Noonan syndrome. J Pediatr 144:368–374. doi:10.1016/j.jpeds.2003.11.032

    Article  PubMed  CAS  Google Scholar 

  • Zenker M, Lehmann K, Schulz AL, Barth H, Hansmann D, Koenig R, Korinthenberg R, Kreiss-Nachtsheim M, Meinecke P, Morlot S, Mundlos S, Quante AS, Raskin S, Schnabel D, Wehner LE, Kratz CP, Horn D, Kutsche K (2006) Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet 44:131–135. doi:10.1136/jmg.2006.046300

    Article  PubMed  Google Scholar 

  • Zenker M, Horn D, Wieczorek D, Allanson J, Pauli S, van der Burgt I, Doerr HG, Gaspar H, Hofbeck M, Gillessen-Kaesbach G, Koch A, Meinecke P, Mundlos S, Nowka A, Rauch A, Reif S, von Schnakenburg C, Seidel H, Wehner LE, Zweier C, Bauhuber S, Matejas V, Kratz CP, Thomas C, Kutsche K (2007) SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet 44:651–656. doi:10.1136/jmg.2007.051276

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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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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Correspondence to Yoko Aoki.

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Yaoita, M., Niihori, T., Mizuno, S. et al. Spectrum of mutations and genotype–phenotype analysis in Noonan syndrome patients with RIT1 mutations. Hum Genet 135, 209–222 (2016). https://doi.org/10.1007/s00439-015-1627-5

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