Rubinstein-Taybi Syndrome

Simons Searchlight has expanded over the last several years to include additional gene changes and participation through remote formats, either online or by phone. This allows English and Spanish-speaking families from across the world to participate at times that are convenient to their schedule. Participants can donate blood, saliva, or both. These samples are then linked to medical, behavioral, learning, and developmental data in order to understand the effects of specific gene changes. Information provided by participants will be stripped of any personal identifying information and made available to qualified scientists around the world. The Simons Foundation, a New York-based private foundation, is committed to finding science-based solutions and working towards the development of targeted treatments to improve the lives of people who have genetic and developmental differences.

Each potential adult with ID or family who contacts the research team will be called and screened for eligibility in the study. To determine eligibility, screening questions will include asking if the adult participant has a formal diagnosis of ID; report of intellectual ability level will be confirmed with direct cognitive testing during the screening assessment visit using scales completed by the participant and caregiver. Also at the screening visit, caregivers will complete the dementia screener for the participants, and participants will be provided with an Actigraph GT9X Link device so they can complete a weeklong physical activity baseline measure. At the second study visit, participants and caregivers will complete the pre-assessments (described below and attached), and participants will have their body composition measured. Questions to all scorable assessments will be required to prevent missing data. Select demographic information will have an additional "prefer not to answer" choice. Participants will complete demographic measures, primary and secondary outcome measures, and feasibility and acceptability measures across the first two study visits. Those who qualify will be randomly assigned to one of two conditions: (1) initial intervention or (2) waitlist control. Individuals assigned to the waitlist control group will begin the intervention after the initial group completes post-assessments. The 16-week intervention includes: (1) a weekly group fitness class for adults with ID, (2) web based training and resources for coaches and exercise professionals; (3) weekly coaching meetings for coaches and adults with ID, and (4) daily/weekly interactions with the PACE interactive web based dashboard for adults with ID. A post-assessment visit will be conducted to repeat the pre-assessment measures, and a subset of participants and coaches will also complete an interview to answer open-ended questions about their program experiences. A 12-month follow-up visit will also be scheduled to measure body composition again. Brief description of measures to be completed by Caregivers as follows: Vineland Adaptive Behavior Scales-3: (VABS) (Vineland-3) is a standardized assessment tool that utilizes semi-structured interview to measure adaptive behavior and support the diagnosis of intellectual and developmental disabilities, autism, and developmental delays. Interviews are expected to take 1-2 hours and will take place during the screening visit. National Task Group-Early Detection Screen for Dementia: (NTG-EDSD) This measure was adapted from the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID) and can be used for the early detection screening of those adults with an intellectual disability who are suspected of or may be showing early signs of mild cognitive impairment or dementia. The NTG-EDSD is not an assessment or diagnostic instrument, but an administrative screen that can be used by staff and family caregivers to note functional decline and health problems and record information useful for further assessment. This assessment will take place during the screening visit. Add Health Wave 5 Questionnaire: Questions will be used from the Wave 5 Survey including questions on background (biological sex, gender, race/ethnicity), health and health care (co-occurring conditions and medical treatments, illness and physical limitations, and fitness tracking (experiences using fitness tracking devices, current exercise habits). This measure will take place during the pre and post study visits. Waisman Activities of Daily Living (W-ADL): The W-ADL is a caregiver-report that measures activities of daily living and assesses functioning. It has demonstrated high internal consistency (Cronbach alphas= .88-.94) and reliability over time (Kappas= .92-.93) in adults with ID. This measure will take place during the pre and post study visits. Brief description of adult with ID measures as follows: The Leiter-3: is a widely used nonverbal measure of intelligence and cognitive abilities that is suitable to use for individuals with cognitive delays, speech or hearing problems, Attention Deficit Hyperactivity Disorder (ADHD), or traumatic brain injury. The battery subtest scores are converted to a scaled score and the sum of the scaled scores yields a nonverbal intelligence quotient (IQ)/composite score. This assessment will take place during the screening visit. World Health Organization Quality of Life Brief Version Assessment (WHOQoL-BREF and WHO Disabilities Module): The WHOQoL-BREF and WHO Disabilities module is an abbreviated 39-item version of the original WHOQOL tool that has been used in adults with ID. The domain scores will be used to measure the general quality of life (Overall, Health, Physical, Psychological, Social, Environment, and Disabilities Module). This measure will take place during the pre and post study visits. NIH-Toolbox Cognitive Battery (NIHTB-CB): The NIHTB-CB will measure mental and cognitive functioning. It has been validated in individuals with ID and adults across the spectrum of Alzheimer's disease and age-related cognitive decline. It is an iPad-based assessment of memory, executive function, and crystallized intelligence. This measure will take place during the pre and post study visits. NIH-Toolbox Emotional Battery: The NIHTB-EB will measure emotional health across several domains: Psychological Well-Being, Social Relationships, Stress and Self-Efficacy, and Negative Affect. This is an iPad-based assessment that will take place during the pre and post study visits. Physical Activity Measures: These measures will take place during the pre and post study visits. Grip strength (NIH Toolbox): This test consists of squeezing the hand dynamometer for a 1-rep max strength assessment. The 4-Stage Balance Test: This test consists of four standing positions that are progressively harder to maintain. 30-Second Chair Stand: This test consists of participants getting up from a chair without using their arms. They get up and sit down repeatedly for 30 seconds. Their score is the number of times they can get up from the chair Timed Up \& Go (TUG): This test consists of participants getting up from a chair, walking 10 feet across the room around a cone, and sitting back down. 2-Minute Walk Endurance: This test consists of participants walking as fast as they can for two-minutes up and down the hallway of the assessment spaces. Bod Pod: This scan will measure body composition using Air Displacement Plethysmograph (ADP). Participants at the University of North Carolina site will be briefed on the Bod Pod and sit inside for up to 5 minutes. This measure will take place during the pre- and post-study visits, as well as the one-year follow-up visit. DXA Scan: This scan will measure body composition using dual energy X-ray absorptiometry. Participants at the University of Arkansas site will be briefed and lay on the DXA scan table for around 15 minutes. This measure will take place during the pre- and post-study visits, as well as the one-year follow-up visit. Participants who are pregnant, think they may be pregnant, or have had unprotected sex in the last 30 days will not receive a DXA scan.

CoRDS collects contact, sociodemographic and health information about participants. This information is entered into CoRDS and linked to a unique coded identifier. Below are some examples of information requested on the Questionnaire that will be entered into CoRDS: * Contact information: Name, Mailing Address, Phone Number, Email Address * Sociodemographic information: Date of Birth, Place of Birth, Sex, Gender, Ethnicity * Health information: Family History, Information related to Diagnosis De-identified information in CoRDS will be made available to researchers, if they have obtained approval for their research project from (1) the Institutional Review Board (IRB) at the researcher's institution and (2) a panel of experts. A subset of de-identified information collected from each profile may be shared with certain other databases. This is done in order to help improve understanding of rare diseases, to avoid the duplication of efforts and to collaborate with existing research efforts with organizations dedicated to rare diseases. Participants may elect to have their information shared with patient advocacy groups (PAGs) representing individuals with rare or uncommon diseases who have partnered with CoRDS. The PAG will sign an agreement stating that they will not use the information for Research purposes. CoRDS personnel will not be held responsible for the use of information by the PAG. The CoRDS Registry will not be paid by Researchers, Other Patient Registries or Patient Advocacy Groups (PAGs) for access to information in CoRDS. If a parent/LAR consents on behalf of a minor, CoRDS will contact the participant when he or she reaches the age of 18 in order to obtain consent. If this consent is not obtained in a timely manner, the participant will be withdrawn from CoRDS. CoRDS contacts participants annually to confirm continued interest in participation in CoRDS, and to request that participants update the information they have provided.

In the human genome, about 750 genes contain one intron excised by the minor spliceosome. These genes are named U12 genes, and these introns, minor or U12 introns. The minor spliceosome comprises its own set of snRNAs, among which U4atac. Its non-coding gene, RNU4ATAC, has been found mutated in Taybi-Linder (TALS), Roifman (RFMN) and Lowry-Wood syndromes (LWS). These rare developmental disorders associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy and immunodeficiency. Their physiopathological mechanisms remain unsolved: the number of U12 genes involved, their identity and function, or the cellular mechanisms impacted by the splicing defect, are still unknown. The hypothesis of the study is that U12 genes coding for primary cilia components are particularly sensitive to minor splicing defects caused by RNU4ATAC mutations. Indeed, a child showing signs of TALS but negative for RNU4ATAC was found to carry a homozygous variant in the RTTN gene, coding for the rotatin protein located at the centrosome and the base of the primary cilia and playing a role in maintaining these structures. In addition, bi-allelic RNU4ATAC mutations were identified in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS. To better understand the causes of these pathologies, a cohort of patients with syndromes associated with bi-allele mutations of the RNU4ATAC or RTTN gene will be gathered, in order to conduct studies on the cells of these patients. Blood samples will be taken, as well as skin biopsies, if possible. These samples will be used to create induced pluripotent stem cell lines. Blood samples will also be collected from the parents of RNU4ATAC patients, to eliminate in transcriptomic analyses expression variations due to differences in genetic background. Biopsies of skin, muscle and brain tissue will be collected on foetuses carrying two-allele RNU4ATAC or RTTN mutations whose parents have had a miscarriage or have chosen to have a medical abortion. The biological samples collected will be used to study the transcription level of U12 genes, the splicing of their pre-messenger RNA, their main cellular functions, and the structural characteristics of tissues and cells.