Investigation Into the Natural History and Metabolic and Molecular Basis of RASopathies.
Conditions: 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, MAPK1 Gene Mutation
Sponsor: Children's Hospital Medical Center, Cincinnati

 
 
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Investigation into the Natural History and Metabolic and 
Molecular Basis of RASopathies 
 
NCT04395495 
 
 
Principal Investigator: 
K. Nicole Weaver, MD 
Principal Investigator 
Clinical Director, RASopathies Clinic 
Cincinnati Children’s Hospital Medical Center 
 
 
 

 
 
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Title: Investigation into the Natural History and Metabolic and Molecular Basis of 
RASopathies. 
Principal Investigator: 
K. Nicole Weaver, MD 
Principal Investigator 
Clinical Director, RASopathies Clinic 
Cincinnati Children’s Hospital Medical Center 
 
Abstract: 
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. 
 
Purpose of the Research Project: 
Patients who are being evaluated for a RASopathy may have overlapping features, but 
the disorders individually can be exceedingly rare and many are not yet well 
characterized.  Additionally, available clinical testing is not always diagnostic in this 
group of patients. We propose to study disorders across the RAS/MAPK pathway, 
identifying both commonalities and differences, under one unified ongoing research 
protocol.  We propose: 
 
1) To investigate the metabolic and molecular basis of established and suspected 
RASopathies. 
 
2) 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.   
 
3) Non-invasive or minimally invasive procedures to collect tissues for research 
purposes only, such as saliva, skin, or blood samples are also allowed.  The 

 
 
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collection of all samples from minor subjects will be done only if it is safe for the 
participant. Clinical studies will take precedence over research procedures. 
 
4) 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). 
 
5) Provide a facility for long-term storage of bio-specimens and clinical data from 
participants with suspected or diagnosed RASopathies and their unaffected 
relatives.  
 
Overall Study Design Summary: 
Samples will be stored and tracked by the Cincinnati Biobank team. Demographic 
information, test results, and medical records will be stored in a REDCap database and 
maintained by Dr. Weaver’s study team. The study team will also maintain a key to track 
samples and data back to the participant’s identity. However, data and samples from 
the repository will be released in a de-identified state to researchers. Research 
procedures will not be conducted on the samples or the available data unless the 
research question is related to RASopathies, the project is approved by the Repository 
Use Committee, and IRB approval is obtained. Additional detail as below. 
 
Significance of the Study in Relation to Human Health: 
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.  
This pathway is essential in the regulation of the cell cycle and the determination of cell 
fate and differentiation.  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 (Tidyman, 2009; Schubbert 2007; Smpokou 2015; Tidyman, 2016). 
 
Individually, each of these syndromes are rare.  Together, they are one of the most 
common groups of genetic conditions in the world.  Currently, there is no cure or 
treatment for the underlying cause of the disease.  RASopathies are treated by 
addressing the manifestations of disease as they appear while also monitoring for 
progression of symptoms.   
 
We aim to develop a tissue repository and longitudinal database that will aid in the 
development of new diagnostic tools and treatment strategies for patients with 
suspected or diagnosed RASopathies.  Results from this research may also have 
implications for those affected by cancer due to the Ras/MAPK pathway’s role in the 
development of malignancies. 
 
Previous Work Done in this Area: 
Neurobehavioral and Psychometric Assessments 

 
 
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Alfieri et al (2014) used the Child Behavior Checklist (CBCL), Social Communication 
Questionnaire version lifetime (SCQ-L), and Modified Checklist for Autism in Toddlers 
(M-CHAT) to characterize the neurobehavioral features of patients with RASopathies. 
We have experience with evaluation of the PANESS test, abbreviated IQ test, 
CogState, and Parents Questionnaires including BRIEF, CBCL, SRS, Conners-3, and 
the Y-BOCS. They found that mutations in the RAS-MAPK pathway mark an increased 
psychopathological risk and highlight that autistic-like behavior could be 
underdiagnosed in patients with RASopathies (Alfieri, 2014). 
 
Results from a 2016 study “indicate that children with CFC syndrome, another 
RASopathy, are at heightened risk for psychopathology, with attention problems, social 
difficulties, and unusual behaviors (e.g., obsessive thoughts, strange behaviors, 
repetitive acts) found to be especially prevalent. With regard to the impact of child 
neurocognitive and behavioral issues on the caregiving experience, parent self-reported 
stress was significantly higher among parents of children who engaged in more problem 
behaviors, and lower among parents whose children could communicate effectively with 
others. This highlights the need for educational and treatment interventions aimed at 
addressing sensory needs, increasing functional communication, and identifying and 
managing challenging behaviors (Pierpont 2016).” 
 
Using the Collaborative Programme for Excellence in Autism criteria, Garg et al (2017) 
found that 12 of 40 (30%) children with Noonan syndrome had autism spectrum 
disorder (ASD), 12 of 40 (30%) had some symptoms of ASD, and the remaining 40% 
had no symptoms of ASD.  In the Noonan syndrome ASD group, there was a 5:1 male 
predominance. Nineteen of 40 (48%) in the Noonan syndrome group and 8 of 9 (88.9%) 
in the CFC group met clinical criteria for ADHD (Garg 2017). 
 
Genetic Research 
Approximately 20-30% of the causative genes behind Noonan syndrome and similar 
disorders are unidentified. Novel gene variants in RIT1, RRAS, RASA2, A2ML1, SOS2, 
and LZTR1 were shown to be associated with RASopathies, malignancies, and 
cardiovascular abnormalities. Additional studies were recommended to characterize the 
associated phenotypes and functional role of these genes (Aoki, 2016).  Cizmarova et al 
(2016) used direct sequencing and next-generation sequencing of all the known 
RASopathy genes for 51 patients with typical features of RASopathy syndromes. They 
found 35 mutations, two of which were novel and potentially pathogenic (one each in 
BRAF and MAP2K1). Mutations were observed in 68.63% of cases (35/51).  
 
Phenotypic Research 
The prenatal and neonatal findings are less widely studied than the postnatal effects of 
this group of disorders. Perinatal findings in Noonan, Costello, and CFC are 
overlapping: polyhydramnios, prematurity, lymphatic dysplasia, macrosomia, relative 
macrocephaly, respiratory distress, hypotonia, and cardiac and renal anomalies. Fetal 
arrhythmia and neonatal hypoglycemia are specific for Costello. When there is a normal 
karyotype and ultrasound findings as above, Noonan, Costello, and CFC should be 

 
 
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considered. Recognition of common perinatal findings of a RASopathy should facilitate 
perinatal and neonatal diagnosis (Myers 2014). 
 
Neurogenic tumors and hypertrophic neuropathy are unusual complications of Noonan 
syndrome with multiple letigines and may be an under-recognized manifestation that 
would warrant surveillance; this observation may have implications for other disorders in 
their pathway (Conboy 2015). 
 
In the first study to characterize body composition in individuals with RASopathies, 
researchers collected growth parameters, body compositions, and nutrition for both 
children and adults with RASopathies. They found that both adipose tissue and muscle 
mass are compromised in individuals with RASopathies. They called for studies using 
dual-energy X-ray absorptiometry or imaging studies to more precisely delineate fat and 
non-fat mass to confirm their findings, which could have an impact on clinical 
management (da Silva 2016). 
 
Tamburrino et al in 2015 studied 88 individuals with a molecularly confirmed 
RASopathy.  Thirty-three showed growth hormone deficiency and were treated with 
growth hormone for an average of 6.8 years. Long-term growth hormone therapy, 
starting in early childhood, resulted in a positive height response compared to untreated 
patients. During growth hormone treatment, no significant change in bone age velocity, 
body proportions, or cardiovascular function was observed (Tamburrino 2015). 
 
Researchers in several studies have hypothesized that there is a role for the RAS 
pathway in regulating bone metabolism due to the short stature and skeletal 
dysmorphisms that are almost constant in patients with Noonan syndrome. Baldassarre 
et al found that phalangeal quantitative ultrasound measurements indicated that bone 
impairment persists in nearly 15% of their cohort with Noonan syndrome, even after 
correcting for growth retardation, delayed bone age, retarded puberty, and reduced 
body mass index.  They concluded that bone impairment in Noonan syndrome is likely 
primary and not secondary to any of the phenotypic traits of the disorder (Baldassarre, 
2016). 
 
Cardiac symptoms are the most common initial presentation for patients with 
RASopathies and patients with congenital heart disease (CHD) are diagnosed much 
younger than patients without CHD (Jhang 2016). Hypertrophic cardiomyopathy (HCM) 
is frequently observed in patients with RASopathies, with varied prevalence by 
diagnosis.  The elucidation of the genetic mutations for Noonan syndrome has made 
clear that the risk for HCM is dependent on genotype. Diagnostic genetic testing can be 
helpful in determining an individual’s risk for HCM. Treatment for cardiomyopathy 
associated with mutations in RAF1 may also be possible.  MEK inhibitors and HMG-
CoA reductase inhibitors are potential avenues for treatment (Gelb 2015). 
 
Mutations that cause Noonan syndrome have been associated with delayed puberty. A 
case series of 4 patient with Costello or CFC developed precocious puberty, suggesting 
complex regulation of the hypothalamic–pituitary–gonadal axis and the timing of puberty 

 
 
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by the RAS-MAPK pathway. Additional study of the timing of puberty in this population 
is warranted (van der Kaay 2016). 
 
Tumor and Cancer Research 
Individuals with NF1 have an increased risk for tumor development and therapy with 
MEK inhibitors have shown a reponse in tumor size in pediatric patients with inoperable 
plexiform neurofibromas (Dombi 2016). The BRAF gene encodes a serine/threonine 
protein kinase that participate in the MAPK/ERK signaling pathway and plays a vital role 
in cancers and the RASopathies. BRAF has been shown to be associated with CFC, 
Noonan syndrome, and NSML as well as papillary thyroid tumors, melanomas, 
colorectal tumors, prostate tumors, and lung cancers. One study confirmed the 
occurrence of the BRAF V600E mutation in Langerhans cell histiocytosis (Hussain 
2014; OMIM 164757). BRAF and RAS mutations have been identified in sporadic and 
secondary pyogenic granulomas, a common benign vascular skin lesion (Groesser 
2016). 
 
In a cohort of 735 individuals with germline mutations in the RAS signaling pathway, 
there were 12 cases of cancer compared to an expected 1.12 cases based on German 
population-based incidence rate.  This corresponds to a 10.5-fold increased risk of all 
childhood cancers combined (specifically, juvenile myelomonocytic leukemia, brain 
tumor, acute lymphoblastic leukemia, rhabdomyosarcoma, and neuroblastoma) (Kratz, 
2015). 
 
Somatic mutations in NF1 occur in 5-10% of human sporadic cancers and may 
contribute to resistance to therapy (Ratner 2015). 
 
Research Plan: 
 
Study Population: 
The study is open to all eligible patients regardless of gender or ethnicity. Minors 
as well as adults will be enrolled in this study. The parent(s)/legal guardian(s) will 
provide informed consent for minors.  Informed consent will be obtained in the 
format of the participating institution and in accordance with International 
Conference on Harmonization (ICH) guidance documents. 
 
The total number of participants is not a targeted number, and there will be no 
cap on the number of people who can enroll in this study.  Initial enrollment of 
approximately 50 and subsequent new enrollment of approximately 50 patients 
annually is expected. 
 
Selection and Recruitment of Participants: 
There are different ways by which participants may be recruited: 
1. Participants may be recruited in CCHMC’s primary care or specialty clinics 
(to include, but not limited to Human Genetics, Hematology/Oncology, 
Neurology, Developmental and Behavioral Pediatrics (DDBP) or any other 
clinic or department at CCHMC that cares for individuals with RASopathies).  

 
 
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a.  Clinicians at CCHMC may request that we recruit participants under their 
care after they determine the participant’s eligibility and obtain participant 
permission to forward their contact information to our study team. 
Alternatively, CCHMC clinicians may provide individuals under their care 
with our contact information for the family to contact us directly. 
b. Eligible participants may be approached for participation when they are 
scheduled for a clinical visit. Every attempt will be made to obtain 
specimens at the time of clinically indicated procedures. 
2. Eligible participants may be contacted by telephone, mail, mychart, or email. 
a. We may develop recruitment materials (i.e. flyers, social media posts, 
websites, et cetera) that we will use for the purpose of informing families 
about the opportunity to enroll in this study.  All materials will be 
submitted to the IRB for approval.  We may work with Research 
Marketing to ensure high quality and appropriate CCHMC branding of all 
materials. 
3. Physicians and any collaborators at sites other than CCHMC who learn of 
our research study may request that we recruit participants currently under 
their care. A physician must first determine their participant's eligibility and 
obtain participant permission before forwarding any contact information to 
our research team.  
4. When research staff are able to attend, eligible patients registered for and/or 
in attendance at scientific or patient advocate meetings will be invited to 
participate. Appropriate application and collaboration with the meeting’s 
research staff will occur. Families may be offered the opportunity to enroll 
prior to, during, or following conferences/events that the study team has 
been invited to attend, but immediate enrollment will not be required.     
a.  RASopathiesNet is one organization that holds meetings for scientists 
and patients. Their meetings are held in the United States 
approximately every two years. 
5. The study team may perform an electronic medical record query (i.e. slicer 
dicer) to aide participant recruitment. 
6. A participant may be self-referred if they become aware of our research 
study through our website, any other website, clinicaltrials.gov registration, 
other participants, conferences/events or any promotional materials 
(brochures, newsletters, flyers). A self-referred participant may contact the 
research coordinator or any member of the study team directly to learn more 
about the study and potentially proceed in the enrollment process.  
7. Family members of individuals with a RASopathy will be recruited 
during/after the index participant recruitment. 
8. On rare occasions, medical history and/or specimen from deceased persons 
with a known or suspected RASopathy, not previously enrolled in this 
protocol, may be included if permission is obtained from the deceased 
person’s appointee (i.e., parent/guardian, closest living relative, or person 
with medical power of attorney).  This data may be acquired and studied.  
 
 

 
 
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Eligible patients who are willing to participate will be invited to submit data to the 
database and/or specimens to the repository.   
 
Unless a participant requests that his/her samples, study records, and medical 
information be removed from the repository, samples and medical information will 
remain in the repository indefinitely. 
 
In addition to conducting research at CCHMC, de-identified samples and/or 
relevant clinical information may also be sent to outside institutions and/or 
researchers or for-profit organizations that are conducting relevant research. The 
outside institution and/or researcher must provide Dr. Weaver and/or her 
designees with a copy of the IRB approval letter for their study.  Clinical 
information sent to outside institutions or for-profit agencies will be identified with 
a unique study ID only. 
 
Inclusion Criteria: 
1) 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. 
2) Unaffected relatives of patients with a suspected or known diagnosis of 
any of the group of disorders known as RASopathies. 
 
Exclusion Criteria: 
1) Individuals who do not have a suspected or definite diagnosis of a 
RASopathy. 
2) Individuals who do not have a relative with a suspected or definite 
diagnosis of a RASopathy. 
3) 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. 
 
Study Procedures and Collection of Samples: 
The patient population that is being studied is heterogeneous. Studying this 
group of disorders necessitates a customized approach to investigation in order 
to address the unique pathology of each clinical presentation. The procedures 
expected to be performed may include: 
• Thorough review of the patient’s medical history including extensive 
description of the phenotype. 
• Genetic studies involving DNA and RNA, such as gene sequencing, 
microarray analysis, and genotyping. 
• The establishment of induced pluripotent cell lines from blood or fibroblast 
cells obtained via skin biopsy to serve as a source of cellular and genetic 
material for study. 
• Storage of cells, tissues, DNA, and/or RNA for potential study. 

 
 
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• Storage of plasma and/or serum for future currently undefined research 
related to RASopathies. 
• Clinical information and outcomes will be collected from patient 
evaluations, surveys/assessments, medical intake form(s), and treatment 
plans. 
• Behavior, learning, IQ assessments (ex: Kauffman Brief Intelligence Test, 
Second Edition KBIT-2; Pediatric Anxiety Rating Scale PARS, DuPaul 
ADHD rating scale)  
• Neurodevelopment surveys (ex: NISONGER, Vineland Adaptive Behavior 
Scales III, and SRS™-2  Social Responsiveness Scale) 
• Collection/use/disclosure of images/video/audio recordings. These records 
may be used for purposes of study, research, and teaching and may be 
published in scientific publications. The patient’s or family’s name may not 
be used. This release is effective until revoked in writing by the 
undersigned. Such revocation shall only be effective to prevent any 
expanded future use of the records. 
• Collection and possible storage of blood, skin fibroblasts, left-over tissue 
from clinically obtained tissue samples.  
• De-Identified samples obtained under this protocol may also be sent to 
institutions outside of CCHMC to investigators or for-profit organizations 
that are conducting relevant research. Information that could identify 
subjects will not be released to non-CCHMC investigators. 
 
Bone Marrow Biopsy Collection 
Bone marrow will only be collected if a participant is already undergoing a 
clinically indicated bone marrow biopsy. 
 
Skin Tissue Collection 
Skin tissue may be obtained: 
a) When the patient is undergoing a clinically indicated dermatologic 
procedure, 
b) When the patient has consented to a skin biopsy for research purposes.   
1) Punch biopsy, shaving, or excision may be used as clinically 
appropriate, using the appropriate aseptic and anesthetic techniques. 
The specimen collection will not exceed more than one collection per 
year unless the collection is being performed as part of clinical 
management. 
2) Squame adhesive tape disks may be used to collect samples of the 
stratum corneum.  This is a non-invasive collection technique.  There is 
some discomfort when the tape is removed similar to pulling a band-
aid off the skin.  There are no other risks from this procedure.   
 
Blood, Buccal Cell, Sputum, and Urine Collection 
Specimen collection specifically for this biorepository should not exceed more 
than three collections per year; this will be tracked in the REDCap database. 
Additional samples may be included in the biorepository if they are collected for 

 
 
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clinical purposes or as part of another research study in which the patient is 
enrolled.  
 
The collection of blood will be coordinated with clinically indicated procedures 
whenever possible.  No more than 3 ml of blood per kg of body weight will be 
collected during any single blood draw. 
 
Residual Tissue Specimens 
Residual tissue specimens that are normally discarded after a clinically indicated 
procedure (i.e., tumor excision, bronchoalveolar lavage, etc.) may be collected 
and stored after every procedure.  Identifying information will not be transferred 
to the storage container, which will only be marked with a unique sample 
identifier that is not related to any clinical identifiers. 
 
 
1) Blood Draw 
Preferably, patients will be undergoing a clinically indicated blood draw at 
the time of this procedure; however, we will ask that participants consider 
donating blood up to a total of three collections per year. The specimen 
will be processed, frozen, and subsequently stored at CCHMC or 
processed and frozen at an outside institution and sent to CCHMC.  
 
Blood volumes will be based on patient weight and estimated blood 
volume. No more than 5% of the patient’s estimated blood volume will be 
taken for both clinically indicated and research purposes. The first priority 
will be clinically indicated volumes. 
 
2) Skin Biopsy 
The skin biopsy will be processed (including skin fibroblast cultures), 
frozen, and subsequently stored at CCHMC or processed and frozen at 
outside institution and sent to CCHMC. 
 
3) Buccal Cells 
Samples may be collected using a swab, saliva, or oral-rinse and collected 
per institutional standards. Samples may be collected for research 
purposes only or as residual tissue. The cells will be processed, frozen, 
and subsequently stored at CCHMC or processed and frozen at outside 
institution and sent to CCHMC. 
 
4) Sputum 
Sputum samples will be collected per institutional practice. Samples may 
be collected for research purposes only or as residual samples. These 
samples will be processed, frozen, and subsequently stored at CCHMC or 
processed and frozen at outside institution and sent to CCHMC. 
 
5) Urine Collection 

 
 
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Urine samples will be collected per institutional practice. Samples may be 
collected for research purposes only or as residual samples. These 
samples will be processed, frozen, and subsequently stored at CCHMC or 
processed and frozen at outside institution and sent to CCHMC. 
 
6) Tissue Samples 
A sample of any tissue (i.e., malignancy, hamartoma, plexiform 
neurofibroma, or any other clinical specimen) which is removed for clinical 
purposes will be processed fresh or frozen and stored for further research. 
The specimens will be obtained from the diagnostic biopsy, as available, 
or from resected tissue if it is removed for therapeutic reasons. The tissue 
specimen will be processed, frozen, and subsequently stored at CCHMC 
or processed and frozen at outside institution and sent to CCHMC. 
 
7) Bone Marrow Aspiration 
Samples will be collected from participants who are undergoing a clinically 
indicated bone marrow aspirate. A bone marrow aspiration will be 
conducted per standard procedure and no more than 10 mL of additional 
bone marrow for research purposes will be aspirated. The sample will be 
processed, frozen and subsequently stored at CCHMC or processed and 
frozen at outside institution and sent to CCHMC. 
 
Sample Acquisition and Storage 
Samples will be acquired after participants are recruited and consented.  For patients 
undergoing sample collection for clinical purposes, every effort will be made to combine 
the research sample collection with the clinical collection to minimize risk to the 
participants. The method of specimen collection will be recorded by the Clinical Research 
Coordinator (CRC) in the REDCap database. 
Samples will be logged and stored in the Cincinnati Biobank.  
 
Research Database  
A REDCap database will be used to store the collected information, which will be 
labeled with a unique sample identifier that is not related to any clinical identifiers. 
Access to the database will be restricted to the Principal Investigator and his designees, 
where each designated individual will be assigned a unique User ID/password 
combination. Specimen and medical history/information will be entered into the 
database.  
 
Participants may be contacted by phone, mail, e-mail, or in person by a study 
investigator, coordinator, or designee to request participation in 
questionnaires/surveys/assessments.  Interested study participants may receive 
surveys/assessments via a printout or electronically (e.g. pdf or REDCap survey link). 
Completion of electronic questionnaires may take place during study visits using 
CCHMC resources (tablet, computer, signature pad) currently available to the study 
team. Alternatively, surveys can be sent to the participants via mail, text, or email or 
administered over the phone by a member of the study team.  

 
 
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As described earlier, this study is customized by disorder, phenotype, and/or individual 
participant. For example, the study team may want to compare participants with a 
particular genetic mutation and/or phenotype. The study team will assess which 
surveys/biospecimen/assessments are appropriate for each participant. Preferences of 
each participant, outlined in the consent form, will direct these decisions. 
 
Examples of Database Records: 
• Demographic information 
• Medical records 
• KBIT-2 (Kaufman Brief Intelligence Test, Second Edition) 
• Surveys (to be assigned by study PI or designee) 
 Condition/disorder/diagnosis specific medical history questionnaires  
• medical intake form used in a specialty clinic for patients with a confirmed 
or suspected diagnosis 
• i.e. Smith Kingsmore Medical History 
 i.e. Costello Clinical QuestionnaireChild Behavior Checklist (CBCL) 
 Physical and Neurological Examination of Subtle Signs (PANESS) 
 Social Communication Questionnaire version Lifetime (SCQ-L) 
 Modified Checklist for Autism in toddlers (M-CHAT) 
 Child Health Questionnaire Parent Form (CHQ-PF50) 
 SF-36 Health Survey 
 PedsQL (child self-report and/or parent proxy report) 
 Functional communication classification system (FCCS) 
 Pediatric Inventory for Parents (PIP) 
 Other questionnaires: BRIEF, SRS, Conners-3, Y-BOCS 
 
Release of Specimens and Clinical Data to Other Investigators 
Release of fresh or frozen specimens and clinical data to both CCHMC and External 
investigators must be approved by the Repository Use Committee through the 
completion of a specimen request form. Among other data, the specimen request form 
will require information concerning: Principal Investigator, funding sources, a research 
synopsis, IRB approval of the research project, and details about the required samples. 
At the time a de-identified sample is requested, the requesting investigator may also 
request de-identified clinical data if needed. 
 
Completion of the specimen request form and approval by the Repository Use 
Committee is required before samples will be distributed. The request form specifies 
that the investigator must not try to re-identify the subjects from whom the samples are 
derived. Under no circumstance may an investigator provide these samples for use to 
additional investigators unless specified otherwise in an approved sample request. 
 
The Repository Use Committee is comprised of at least 1 Co-Investigator and/or the 
Principal Investigator as well as another member of the study team (e.g., CRC) to 
scientifically evaluate applications and ensure proper distribution of the samples. Other 
eligible members of the Repository Use Committee include members of the RASopathy 

 
 
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Program Clinical Team. Members of this team meet regularly to review current clinical 
and research RASopathy topics. 
  
This committee will meet as needed to review sample requests. Projects may also be 
approved via email. Members will excuse themselves during discussions in the case 
that they have requested samples. The chair of the committee, with agreement from at 
least one other member of the committee, will have the authority to approve minor 
changes to requests (i.e. addition of a small number of samples to an already approved 
study).  
 
Once the Repository Use Committee approves the scientific/technical merit of a 
specimen request, the samples will be released to the requesting investigator. 
 
Facilities Utilized in the Study  
The specimens will be collected and processed using the facilities of several divisions 
within Cincinnati Children’s Hospital Medical Center, including the Division of Human 
Genetics and Clinical and Translational Research Center (CTRC). Repository samples 
with unique identifiers will be processed and securely stored in the Cincinnati Biobank.  
 
POTENTIAL BENEFITS  
Participation in this study will benefit science through advancement of knowledge in the 
diagnosis and treatment of patients with RASopathies. There will be no anticipated 
direct benefit to the patient. 
 
POTENTIAL RISKS, DISCOMFORTS, INCONVENIENCES AND PRECAUTIONS  
Special Considerations  
Psychiatric Indication: 
Physical and/or emotional stress can occur in this patient population (e.g. related to 
symptom(s) of the disorder). If a participant discloses any suicide ideation or reveals 
compulsions to harm him/herself or others, the study staff will contact the participant’s 
mental health provider or PCP and/or Psychiatric Intake Response Center (PIRC) at 
Cincinnati Children’s Hospital for further assessment and guidance. The Pediatric Intake 
Response Center (PIRC) manages psychiatric patient consultation and intake for 
Cincinnati Children’s Hospital Medical Center. Staff members are available 24 hours a 
day, seven days a week at 513-636-4124 or psychiatryresponse@cchmc.org . 
 
Radiation Safety: Not applicable  
Investigational Drugs and Devices: Not applicable  
CCHMC Pharmacy: Not applicable  
DSMB: Not applicable  
Discarded tissues: De-identified discarded tissues may be used in this study to 
establish reference ranges or normative comparisons for particular assays or 
assessments used in this study. 
Cell Storage: Blood, marrow, skin tissue and/or residual specimens obtained through 
this research protocol will be prepared, frozen, and subsequently stored at CCHMC or 
processed and frozen at outside institutions and sent to CCHMC.  

 
 
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Genetic Studies: The proposed protocol includes genetic studies. These include, but 
are not limited to, molecular, cytogenetic, and epigenetic analyses. Results of genetic 
studies will not be returned to participants. 
 
Standard of care will be followed for all procedures performed to decrease the risk of 
infection, pain, bleeding, and bruising.  
 
There is a small risk that protected health information may be released to an 
unauthorized individual. Collected data will be stored in a secure database maintained 
by Cincinnati Children’s Hospital Medical Center. Only the Principal Investigator and 
designees will have access to the secured database. A unique patient number will be 
assigned to each study subject and corresponding samples. No identifying names will 
be affixed to the specimens in storage. The identifying key will be securely stored and 
accessed only by the study team. 
 
We do not anticipate adverse medical events directly associated with this protocol.  
Adverse events will be monitored by the Principal Investigator and research personnel 
involved in the conduct of the study and reported according to CCHMC IRB guidelines.  
 
Risk evaluation: Minimal risk but without direct benefit to the participants. 
 
DSMB: This is a minimal risk study and does not require a DSMB. The data generated 
during this trial will be monitored by the PI for safety and compliance with protocol-
specified requirements. 
 
CONFIDENTIALITY  
The research study staff will be collecting information from the participant’s medical 
record.  This information will be collected by research study staff, and will only be 
accessible to research study staff of this study, and, when applicable, to research study 
staff of associated future use research studies.  The electronic research data will be 
password-protected and maintained on CCHMC computers.  All non-electronic study 
data will be maintained by the research study staff in the offices of the Division of 
Human Genetics.  Specimens collected for this research study will be stored with the 
Cincinnati Biobank.  Lab staff in the Cincinnati Biobank may access patient identifiers in 
tracking specimens. The Cincinnati Biobank will maintain study data in their sample 
tracking software with restricted permissions to Cincinnati Biobank staff. 
 
A unique study number will be assigned to each study subject and corresponding 
specimen.  The identifying names will be linked through an identifying code to the 
subject number. Only the PI and designees will have access to the key.  
 
Only the database coordinator will be able to link the identity of the patient to the unique 
identifier from the specimens. The database coordinator will only release information to 
the Investigator(s) that is de-identified. 
 

 
 
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Manuscripts or presentations resulting from this protocol will only identify participants by 
an arbitrary subject ID number. 
 
PERIOD OF TIME ESTIMATED TO COMPLETE PROJECT AS DESCRIBED 
The study will continue indefinitely with no specific end date. 
 
FUNDING  
This research study is funded by the Divisions of Human Genetics and Experimental 
Hematology & Cancer Biology at CCHMC.  
 
PAYMENT FOR STUDIES  
There will be no financial compensation for participation in the study. 
 
RESEARCH PROTOCOL, CONSENT FORM, AND CORRESPONDENCE  
A current copy of the approved research protocol, consent form, and all correspondence 
will be maintained by the office of Dr. K. Nicole Weaver (CCHMC).   
 
For outside institutions, the protocol and the informed consent (as applicable) must be 
reviewed and approved by each institution’s IRB before study may be initiated.  Written 
informed consent will be obtained in the format of the participating institution, and in 
accordance with International Conference on Harmonization (ICH) Guidelines.  
 
A verbal discussion will take place with the participant and/or the participant’s 
parent(s)/legal guardian(s) in person or by telephone that will include an opportunity to 
ask any questions. 
 
For minor subjects who are brought to CCHMC by a person other than the parent or 
Legally Authorized Representative (LAR), the consent form may be sent to the parent 
for review. The consent process will take place over the phone. If the parent or LAR 
agrees to allow the participant to take part in the study, a copy of the signed consent will 
be returned and reviewed by a study coordinator before any research procedures occur. 
The consent form can be returned to CCHMC by fax, e-mail, or regular mail.  
 
For participants who do not speak English, we will utilize the short form consent 
process. A translator or qualified bilingual staff member will be present for the consent 
process. The participant will sign both a short form and the full consent document. 
 
A separate consent form will be signed by each participant. Subjects 11 years and older 
will provide documented assent via a signature on the consent form.  
 
When a subject turns 18, they will be asked to re-consent to their specimens remaining 
in the repository. If unable to obtain re-consent from a subject within a year after the 
investigator makes a diligent effort to contact the subject reaching the age of 18, the 
investigator may retain the data as is in the repository. The only exception is if the 
subject contacted the team and asked to have samples removed from the repository, 
then this request would be honored. 

 
 
Protocol v9.0    30JUN2023 
 
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No samples or data will be collected and no research will be performed on the 
specimens until full written consent is obtained from the patient or his/her legally 
authorized representative. 
 
If a participant should choose to withdraw their consent, any collected samples and/or 
data that has already been published or analyzed will remain in the database in a de-
identified state.  No further analysis of the samples for research purposes will be 
conducted and the samples will be discarded.  No additional clinical data will be 
collected and entered into the database, however already existing clinical information 
and/or surveys will remain in the database in a de-identified state. 
eConsent: 
Electronic informed consent will be developed and implemented using REDCap.  
REDCap is a secure web application for building and managing online surveys and 
databases.  While REDCap can be used to collect virtually any type of data (including 
21 CFR Part 22, FISMA, and HIPAA-compliant environments), it is specifically geared to 
support online or offline data capture for research studies and operations. 
 
The IRB approved consent document will be uploaded into the database instrument.  
The IRB approved consent will be modified to an electronic format that includes all the 
same elements found on the paper document. The elements of the consent requiring a 
signature has been added as a generate field. The instrument includes fields to capture 
full name, signature, and date and time of the signature for the consenter. When 
completed REDCap will generate a footer that contains the long date and time the 
document was submitted and “Confidential” listed in the header as an added precaution 
to preserve the research participants confidentiality .  REDCap's 'Auto-Archiver + 
eConsent Framework' will be used.  The 'Auto-Archiver + e-Consent Framework' survey 
option adds two things to the typical survey-taking process.  1) Before a participant 
completes the survey, an extra certification page is added to end of the survey that 
displays an in-line PDF copy of their survey responses in which they will be asked to 
confirm that all information in the document is correct. Once they confirm all is correct, 
the survey will then be marked as complete. The survey will not be considered complete 
until they fulfill the certification step. 2) Upon completion of the survey, a static copy of 
their responses in the form of a consent-specific PDF will be stored in the project's File 
Repository. The consent-specific PDF may have the values of the e-Consent 
Framework Options inserted at the bottom of each page in the PDF. These values (i.e., 
name, date of birth, etc.) are added to the PDF as extra documentation of the identity of 
the person who is consenting. 
 
The HIPAA Consent is queued to automatically open once the consent has been signed 
and all logic is satisfied. 
 
For the HIPAA and Notice of Privacy Practices the IRB approved consent document will 
be uploaded into the database instrument.  The instrument includes fields to capture full 
name, signature, and date and time of the signature for the consenter, and witness and 

 
 
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conditional text that states that all signatures are associated with the Subject ID# 
registered in the database. 
 
Signed and submitted documents will be available as a PDF in REDCap's File 
Repository.  A PDF of the eConsent document will be sent to CCHMC HIM per 
requirements and long-term storage will be at the CCHMC approved vendor, 
LabArchives, which is 21CFRPart11 compliant. 
 
 
MANAGEMENT OF UNANTICIPATED FINDINGS 
We will not return unanticipated research findings to participants or their family 
members. Research results that may be of clinical importance to the participant (based 
on the assessment of Dr. Weaver or designee) may be returned. If results are to be 
returned the study team will inform the IRB to set up an appropriate plan. 
 
PROTOCOL RECORDS  
All study documents will be kept secure. Access to files will be limited to the Principal 
Investigator and designees only. Study records will be maintained in the secure 
database that has restricted access to only the Principal Investigator and designees. 
 
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