RASopathy Biorepository

NCT04395495 | Recruiting

• 1 other identifier: 2016-7017
• Study Type: observational
• Target: 1,000
• Locations: 1 country
• Sites: 1

Brief Summary

The RASopathies are a group of developmental disorders caused by genetic changes in the genes that compose the Ras/mitogen activated protein kinase (MAPK) pathway. New RASopathies are being diagnosed frequently. This pathway is essential in the regulation of the cell cycle and the determination of cell function. Thus, appropriate function of this pathway is critical to normal development. Each syndrome in this group of disorders has unique phenotypic features, but there are many overlapping features including facial features, heart defects, cutaneous abnormalities, cognitive delays, and a predisposition to malignancies. This research study proposes to collect and store human bio-specimens from patients with suspected or diagnosed RASopathies. Once obtained, blood and/or tissue samples will be processed for: metabolic function studies, biomarkers, genetic studies, and/or the establishment of immortalized cell lines. In addition, data from the medical record (including neuropsychological evaluations) and surveys will be stored to create a longitudinal database for research conducted at CCHMC or at other research institutions.

Conditions

MAPK1 Gene Mutation; RAS Mutation; Neurofibromatosis 1; Noonan Syndrome; Noonan Syndrome With Multiple Lentigines; Noonan Neurofibromatosis Syndrome; Cardiofaciocutaneous Syndrome; Costello Syndrome; Legius Syndrome; Smith-Kingsmore Syndrome; MTOR Gene Mutation; GATOR-1 Gene Mutation; SYNGAP1-Related Intellectual Disability; DLG4

Outcome Measures

Primary Outcomes (2)

• Collection of biospecimen

  Collect specimens derived from blood, buccal cells, sputum, urine, bone marrow, tumor tissue and residual specimens, including but not limited to pleural fluid, ascetic fluid, chyle, skin, lung, lymphatic or renal tissue and/or bronchoalveolar lavage fluid, tissue specimens, and/or cells that are left over from clinical procedures from enrolled patients for research purposes only.

  50 years

• Collection of medical history

  Collect demographic information, medical history, and clinical test results to create a longitudinal research database of participants with suspected or diagnosed RASopathies. Participants will also complete surveys to be included in the research database (see "Research Database" section for details).

  50 years

Secondary Outcomes (1)

• Release of Specimens and Clinical Data to Other Investigators for use in RASopathy Research

  50 years

Study Arms (14)

Neurofibromatosis 1 (NF1)

Individuals with a confirmed or suspected diagnosis of Neurofibromatosis Type 1 (NF1). Diagnosis may be made clinically and/or confirmed through genetic testing. Clinical (non-genetic) diagnosis requires that individuals meet the National Institute of Health's (NIH) clinical diagnostic criteria for NF1.

Noonan Syndrome

Individuals with a confirmed or suspected diagnosis of Noonan Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

Noonan Syndrome with Multiple Lentigines

Individuals with a confirmed or suspected diagnosis of Noonan Syndrome with Multiple Lentigines. Diagnosis may be made clinically and/or confirmed through genetic testing.

Noonan Neurofibromatosis Syndrome

Individuals with a confirmed or suspected diagnosis of Noonan Neurofibromatosis Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

Cardiofaciocutaneous Syndrome

Individuals with a confirmed or suspected diagnosis of Cardiofaciocutaneous Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

Costello Syndrome

Individuals with a confirmed or suspected diagnosis of Costello Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

Legius Syndrome

Individuals with a confirmed or suspected diagnosis of Legius Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

Smith-Kingsmore Syndrome

Individuals with a confirmed or suspected diagnosis of Smith-Kingsmore Syndrome. Diagnosis may be made clinically and/or confirmed through genetic testing.

GATOR-1 Mutation

Individuals with a suspected or known mutation of GATOR-1.

SYNGAP1-Related Intellectual Disability

Individuals with a suspected or known mutation of SYNGAP1.

DLG4 Mutation

Individuals with a suspected or known mutation of DLG4.

MAPK1 Gene Mutation

Individuals with a suspected or known mutation of MAPK1.

MTOR Gene Mutation

1. Individuals with a suspected or known mutation of a gene associated with the MTOR cellular pathway. Diagnosis may be made clinically and/or confirmed through genetic testing. 2. Unaffected relatives of individuals with a suspected or known mutation of a gene associated with the MTOR cellular pathway.

RAS Mutation

1. Individuals with a suspected or known mutation of a gene associated with the RAS/MAPK cellular pathway. Diagnosis may be made clinically and/or confirmed through genetic testing. 2. Unaffected relatives of individuals with a suspected or known mutation of a gene associated with the RAS/MAPK cellular pathway.

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The RASopathies are a group of developmental disorders caused by genetic changes in the genes that compose the Ras/mitogen activated protein kinase (MAPK) pathway. New RASopathies are being diagnosed frequently. This pathway is essential in the regulation of the cell cycle and the determination of cell function. Thus, appropriate function of this pathway is critical to normal development. Each syndrome in this group of disorders has unique phenotypic features, but there are many overlapping features including facial features, heart defects, cutaneous abnormalities, cognitive delays, and a predisposition to malignancies.

You may qualify if:

• Patients with a suspected or known diagnosis of any of the group of disorders known as RASopathies (e.g., Neurofibromatosis, Costello Syndrome, Noonan Syndrome). Diagnosis may be made clinically and/or confirmed through genetic testing.
• Unaffected relatives of patients with a suspected or known diagnosis of any of the group of disorders known as RASopathies.

You may not qualify if:

• Individuals who do not have a suspected or definite diagnosis of a RASopathy.
• Individuals who do not have a relative with a suspected or definite diagnosis of a RASopathy.
• Patients who do not have the ability/capacity to undergo the informed consent process OR whose parent/legal guardian is unable to undergo the informed consent process.

Sponsors & Collaborators

• Children's Hospital Medical Center, Cincinnati: lead

Study Sites (1)

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

RECRUITING

Related Publications (22)

• Alfieri P, Piccini G, Caciolo C, Perrino F, Gambardella ML, Mallardi M, Cesarini L, Leoni C, Leone D, Fossati C, Selicorni A, Digilio MC, Tartaglia M, Mercuri E, Zampino G, Vicari S. Behavioral profile in RASopathies. Am J Med Genet A. 2014 Apr;164A(4):934-42. doi: 10.1002/ajmg.a.36374. Epub 2014 Jan 23.

  PMID: 24458522 BACKGROUND

• Aoki Y, Niihori T, Inoue S, Matsubara Y. Recent advances in RASopathies. J Hum Genet. 2016 Jan;61(1):33-9. doi: 10.1038/jhg.2015.114. Epub 2015 Oct 8.

  PMID: 26446362 BACKGROUND

• Baldassarre G, Mussa A, Carli D, Molinatto C, Ferrero GB. Constitutional bone impairment in Noonan syndrome. Am J Med Genet A. 2017 Mar;173(3):692-698. doi: 10.1002/ajmg.a.38086.

  PMID: 28211980 BACKGROUND

• Cizmarova M, Hlinkova K, Bertok S, Kotnik P, Duba HC, Bertalan R, Polockova K, Kostalova L, Pribilincova Z, Hlavata A, Kovacs L, Ilencikova D. New Mutations Associated with Rasopathies in a Central European Population and Genotype-Phenotype Correlations. Ann Hum Genet. 2016 Jan;80(1):50-62. doi: 10.1111/ahg.12140. Epub 2015 Nov 26.

  PMID: 26607044 BACKGROUND

• Conboy E, Dhamija R, Wang M, Xie J, Dyck PJ, Bridges AG, Spinner RJ, Clayton AC, Watson RE, Messiaen L, Babovic-Vuksanovic D. Paraspinal neurofibromas and hypertrophic neuropathy in Noonan syndrome with multiple lentigines. J Med Genet. 2016 Feb;53(2):123-6. doi: 10.1136/jmedgenet-2015-103177. Epub 2015 Sep 2.

  PMID: 26337637 BACKGROUND

• da Silva FM, Jorge AA, Malaquias A, da Costa Pereira A, Yamamoto GL, Kim CA, Bertola D. Nutritional aspects of Noonan syndrome and Noonan-related disorders. Am J Med Genet A. 2016 Jun;170(6):1525-31. doi: 10.1002/ajmg.a.37639. Epub 2016 Apr 1.

  PMID: 27038324 BACKGROUND

• Garg S, Brooks A, Burns A, Burkitt-Wright E, Kerr B, Huson S, Emsley R, Green J. Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway. Dev Med Child Neurol. 2017 May;59(5):544-549. doi: 10.1111/dmcn.13394. Epub 2017 Feb 4.

  PMID: 28160302 BACKGROUND

• Gelb BD, Roberts AE, Tartaglia M. Cardiomyopathies in Noonan syndrome and the other RASopathies. Prog Pediatr Cardiol. 2015 Jul 1;39(1):13-19. doi: 10.1016/j.ppedcard.2015.01.002.

  PMID: 26380542 BACKGROUND

• Groesser L, Peterhof E, Evert M, Landthaler M, Berneburg M, Hafner C. BRAF and RAS Mutations in Sporadic and Secondary Pyogenic Granuloma. J Invest Dermatol. 2016 Feb;136(2):481-6. doi: 10.1038/JID.2015.376.

  PMID: 26802240 BACKGROUND

• Hussain MR, Baig M, Mohamoud HS, Ulhaq Z, Hoessli DC, Khogeer GS, Al-Sayed RR, Al-Aama JY. BRAF gene: From human cancers to developmental syndromes. Saudi J Biol Sci. 2015 Jul;22(4):359-73. doi: 10.1016/j.sjbs.2014.10.002. Epub 2014 Oct 23.

  PMID: 26150740 BACKGROUND

• Jhang WK, Choi JH, Lee BH, Kim GH, Yoo HW. Cardiac Manifestations and Associations with Gene Mutations in Patients Diagnosed with RASopathies. Pediatr Cardiol. 2016 Dec;37(8):1539-1547. doi: 10.1007/s00246-016-1468-6. Epub 2016 Aug 23.

  PMID: 27554254 BACKGROUND

• Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010 Apr;1802(4):396-405. doi: 10.1016/j.bbadis.2009.12.009. Epub 2010 Jan 14.

  PMID: 20079433 BACKGROUND

• Kratz CP, Franke L, Peters H, Kohlschmidt N, Kazmierczak B, Finckh U, Bier A, Eichhorn B, Blank C, Kraus C, Kohlhase J, Pauli S, Wildhardt G, Kutsche K, Auber B, Christmann A, Bachmann N, Mitter D, Cremer FW, Mayer K, Daumer-Haas C, Nevinny-Stickel-Hinzpeter C, Oeffner F, Schluter G, Gencik M, Uberlacker B, Lissewski C, Schanze I, Greene MH, Spix C, Zenker M. Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes. Br J Cancer. 2015 Apr 14;112(8):1392-7. doi: 10.1038/bjc.2015.75. Epub 2015 Mar 5.

  PMID: 25742478 BACKGROUND

• 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. Perinatal features of the RASopathies: Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome. Am J Med Genet A. 2014 Nov;164A(11):2814-21. doi: 10.1002/ajmg.a.36737. Epub 2014 Sep 22.

  PMID: 25250515 BACKGROUND

• Pierpont EI, Wolford M. Behavioral functioning in cardiofaciocutaneous syndrome: Risk factors and impact on parenting experience. Am J Med Genet A. 2016 Aug;170(8):1974-88. doi: 10.1002/ajmg.a.37725. Epub 2016 May 5.

  PMID: 27149079 BACKGROUND

• Ratner N, Miller SJ. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer. 2015 May;15(5):290-301. doi: 10.1038/nrc3911. Epub 2015 Apr 16.

  PMID: 25877329 BACKGROUND

• Schubbert S, Bollag G, Shannon K. Deregulated Ras signaling in developmental disorders: new tricks for an old dog. Curr Opin Genet Dev. 2007 Feb;17(1):15-22. doi: 10.1016/j.gde.2006.12.004.

  PMID: 17208427 BACKGROUND

• Smpokou P, Zand DJ, Rosenbaum KN, Summar ML. Malignancy in Noonan syndrome and related disorders. Clin Genet. 2015 Dec;88(6):516-22. doi: 10.1111/cge.12568. Epub 2015 Mar 4.

  PMID: 25683281 BACKGROUND

• Tamburrino F, Gibertoni D, Rossi C, Scarano E, Perri A, Montanari F, Fantini MP, Pession A, Tartaglia M, Mazzanti L. Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: Patterns of growth, puberty and final height data. Am J Med Genet A. 2015 Nov;167A(11):2786-94. doi: 10.1002/ajmg.a.37260. Epub 2015 Jul 31.

  PMID: 26227443 BACKGROUND

• Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009 Jun;19(3):230-6. doi: 10.1016/j.gde.2009.04.001. Epub 2009 May 19.

  PMID: 19467855 BACKGROUND

• Tidyman WE, Rauen KA. Pathogenetics of the RASopathies. Hum Mol Genet. 2016 Oct 1;25(R2):R123-R132. doi: 10.1093/hmg/ddw191. Epub 2016 Jul 12.

  PMID: 27412009 BACKGROUND

• van der Kaay DC, Levine BS, Doyle D, Mendoza-Londono R, Palmert MR. RASopathies Are Associated With Delayed Puberty; Are They Associated With Precocious Puberty Too? Pediatrics. 2016 Dec;138(6):e20160182. doi: 10.1542/peds.2016-0182.

  PMID: 27940666 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Specimens derived from blood, buccal cells, sputum, urine, bone marrow, tumor tissue and residual specimens, including but not limited to pleural fluid, ascetic fluid, chyle, skin, lung, lymphatic or renal tissue and/or bronchoalveolar lavage fluid, tissue specimens, and/or cells that are left over from clinical procedures from enrolled patients for research purposes only.

MeSH Terms

Conditions

Neurofibromatosis 1; Noonan Syndrome; LEOPARD Syndrome; Neurofibromatosis-Noonan syndrome; Cardiofaciocutaneous syndrome; Costello Syndrome; Legius syndrome

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Pulmonary Valve Stenosis; Heart Valve Diseases; Abnormalities, Multiple; Lentigo; Melanosis; Hyperpigmentation; Pigmentation Disorders; Skin Diseases

Study Officials

• Kathryn N Weaver, MD

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lindsey Aschbacher-Smith, MS

CONTACT

513-803-0077; Lindsey.Aschbacher-Smith@cchmc.org

Laurie Bailey, MS

CONTACT

513-636-4507; Laurie.Bailey@cchmc.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 50 Years
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2020
• First Posted: May 20, 2020
• Study Start: June 27, 2017
• Primary Completion (Estimated): December 1, 2065
• Study Completion (Estimated): December 1, 2065
• Last Updated: December 18, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)