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CFERV 2019 Simons Searchlight

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Simons Searchlight is an initiative of the Simons Foundation Autism Research Initiative (SFARI) that aims to better understand genetic neurodevelopmental conditions, including those associated with autism spectrum disorder. Over 1,500 individuals with rare disorders and their families are currently
registered in Simons Searchlight, including participants from both the GRIN2A and GRIN2B groups. These numbers are expected to grow significantly in the coming years, and so are the research opportunities for participants as well as investigators studying these conditions.

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CFERV 2019 Simons Searchlight

  1. 1. GRIN2B Family Meeting Jennifer Bain, MD, PhD September 2019 © Jennifer Bain, MD, PhD
  2. 2. What is the goal of Simons Searchlight? Collect detailed medical and behavioral histories along with blood and saliva samples Synthesize the information you provide and share results back to families Freely share data and samples with qualified researchers Connect participants around the world Promote better understanding of these genetic changes © Jennifer Bain, MD, PhD
  3. 3. How has Simons Searchlight changed over time? • The study began in 2011 and focused on families living with one specific genetic change. • The first participants traveled to study centers to provide medical, behavioral and neuropsychiatric data to researchers. • Today, families living with one of more than 100 different genetic changes can provide their data to researchers from home. © Jennifer Bain, MD, PhD
  4. 4. What do you do as a participant? • Provide medical and behavioral histories and samples. • Update us annually. • Samples can be collected locally or at family meetings. • All of the information is used to fuel studies by doctors and scientists across the globe. © Jennifer Bain, MD, PhD
  5. 5. What are the benefits of being involved? • Become part of a large network of scientists, doctors, and families united in their goal to move research forward. • Connect through social media, newsletters, webinars, regular contact with study staff, national and international family meetings, and more. © Jennifer Bain, MD, PhD
  6. 6. Data Collection What information is collected? Whose information is collected? Individuals with the genetic change Parents Siblings Medical records • Clinical Genetic Lab Results X X X Phone Interviews • Medical History Interview • Previous Diagnosis interview • Adaptive functioning interview – Vineland Adaptive Behavior X X X Online surveys • Seizure History • Background History • Child/Adult Behavior Checklist • Social Responsiveness Scale • Social Communication Questionnaire • Other surveys in development X X X X X X X X X X X © Jennifer Bain, MD, PhD
  7. 7. How does the Simons Foundation help further GRIN2B research? Sabo Impact of NR2B/GRIN2B subunit mutations on NMDA receptors and synapse formation • GRIN2B data and samples available at Simons Foundation SFARI Base (base.sfari.org) • Approved researchers can use the data and samples • The Simons Foundation funds research on genes that affect NMDA receptors Fagiolini Probing synaptic receptor composition in mouse models of autism Traynelis Functional role of rare missense glutamate receptor variants in neurological disease © Jennifer Bain, MD, PhD
  8. 8. How to link up with the new Simons Searchlight Receive email “Important changes to Simons VIP - please read for access instructions” If you had an account on the Simons VIP Connect registry – DO THIS ASAP!! Click link in email “By clicking the link, you’re agreeing to the site’s terms and conditions and privacy policy. Click here to get started.” Reset password © Jennifer Bain, MD, PhD
  9. 9. Our Genome 23 from Mom 23 from Dad © Jennifer Bain, MD, PhD
  10. 10. Not all Genetic Conditions Run in Families Some are de novo mutations © Jennifer Bain, MD, PhD
  11. 11. When do de novo mutations occur? • In the egg • In the sperm • At or shortly after conception • No way to know • Recurrence risk of 1% in future pregnancies © Jennifer Bain, MD, PhD
  12. 12. The GRIN2B Registry in Simons Searchlight © Jennifer Bain, MD, PhD
  13. 13. 84 Registered 42 Consented and Labs reviewed 36 pathogenic or likely pathogenic 31* Medical History by 7-1-2019 * 4 Others with different types of variants completed the MHI. Others may have completed it after 8-16-19 Simons Searchlight Individuals with GRIN2B Mutation 12 female, 19 male Ages 2 - 21 years © Jennifer Bain, MD, PhD
  14. 14. Variants in GRIN2B Observed 36 individuals with pathogenic or likely pathogenic variants Likely gene disrupting mutations Glu236* Arg393* Arg847* (2) Arg926* • 6 additional participants with non-conforming variants Missense mutations Gly499Glu Asn694Ser Asn516Ser (2) Arg696His Ser526Pro Cys746Tyr Gly543Arg Ile751Thr (3) Ser555Ile Leu781Val Val558Ile Gly820Ala (3) Gly611Val Gly820Glu Val620Met Val821Phe Tyr646Cys Gly826Glu (2) Pro687Leu Glu839Lys Gly689Ser Thr888Thr Deletions Intragenic deletions (2) In-Frame Deletion/ Insertions (Substitutions) Arg682_Val686delinsSerPheGlyThrLeu © Jennifer Bain, MD, PhD
  15. 15. Developmental Milestones • 52% (12) of children attained first words between age 9 months and 5 years • 11 children (ages 2-14 years) were not reported to have spoken first words • 68% (15) of children attained first steps between age 1 and 7 years • 7 children (ages 2- 14 years) were not reported to have taken first steps First steps in 22 individualsFirst words in 23 individuals * 4 individuals were not included because they were too young * 5 individuals were not included because they were too young or had incomplete data Does not take into account any regressions © Jennifer Bain, MD, PhD
  16. 16. • 25% (4) of children attained bladder control between age 3 and 4 years • 12 children (4-14 years old) were not reported to have gained bladder control • 25% (4) children attained bowel control between age 2 and 4 years • 12 children (4-14 years old) were not reported to have gained bowel control Age at bowel control in 16 individualsAge at bladder control in 16 individuals *11 individuals were not included because they were too young or had incomplete data * 11 individuals were not included because they were too young or had incomplete data Does not take into account any regressions Developmental Milestones © Jennifer Bain, MD, PhD
  17. 17. Simons Searchlight GRIN2B Medical History Data 31 individuals, age 2 years - 21 years * 4 other individuals with different types of variants also completed the MHI © Jennifer Bain, MD, PhD
  18. 18. Common Developmental and Behavioral Diagnoses in 29 GRIN2B participants Condition Percent of children (n) Intellectual disability/ developmental delay* 100% (29) Autism spectrum disorder 28% (8) Attention deficit/hyperactivity disorder 10% (3) Sleep apnea 3% (1) Dystonia 3% (1) * 22 of whom have language impairment, disorder, or delays © Jennifer Bain, MD, PhD
  19. 19. Language Difficulties • Expressive,receptive or pragmatic (conversational)speech • Poor/absent speech =motor speechdisturbance • Apraxia of speech • Motor planning problem between the brain and the output from your mouth. • Techniquesfor intervention: speechtherapy, PROMPTtherapy, Augmentative/Alternative Communication(AAC). © Jennifer Bain, MD, PhD
  20. 20. • Nolonger subcategories: autistic disorder,Aspergerdisorder, Rett disorder, childhood disintegrative disorder, pervasive developmental disorder(PDD-NOS) Corebehaviors Persisting deficits of social communication and interaction Restricted and repetitive behaviors, interests and activities Autism Spectrum Disorder (ASD) © Jennifer Bain, MD, PhD
  21. 21. Condition Percent of children (n) Strabismus (crossed eyes) 55% (17) Nystagmus (repetitive, uncontrolled eye movements) 15% (5) Nearsighted 13% (4) Cortical blindness 10% (3) Farsighted 10% (3) Ptosis (drooping upper eyelid) 3% (1) Depth perception 3% (1) Other (not specified) 3% (1) Eye & Vision Problems © Jennifer Bain, MD, PhD
  22. 22. Condition Percent of children (n) Low muscle tone 94% (29) Clumsy 39% (12) High muscle tone 23% (7) Large head size 10% (3) Small head size 10% (3) Movement disorder 10% (3) Cerebral palsy 6% (2) Tics 3% (1) Neurological Issues © Jennifer Bain, MD, PhD
  23. 23. Condition Percent of children (n) Seizures 19% (6) Grand mal 3% (1) Infantile spasms 3% (1) Petit mal 3% (1) Complex partial 3% (1) Simple partial 3% (1) Febrile seizures 3% (1) Seizure History Age of onset: 1-3 years old Effective medications endorsed by 2 families: • Keppra • Phenobarbital 50% (3) of children have had their seizures resolve © Jennifer Bain, MD, PhD
  24. 24. Condition Percent of children (n) Gastric reflux (heartburn) 55% (17) Constipation 39% (12) Diarrhea 10% (3) Other (not specified) 6% (2) Gastrointestinal Issues © Jennifer Bain, MD, PhD
  25. 25. Condition Percent of children (n) Otitis media (middle ear infections) 52% (16) Requiring ear tubes 10% (3) Pneumonia 13% (4) Recurrent pneumonia 6% (2) Urinary tract infection 3% (1) Infections © Jennifer Bain, MD, PhD
  26. 26. Condition Percent of children (n) Chronic pneumonia 6% (2) Recurrent chest infection 3% (1) Lung Issues © Jennifer Bain, MD, PhD
  27. 27. Condition Percent of children (n) Kidney stones 3% (1) Undescended testicles 3% (1) Kidney, Urinary and Genital Issues © Jennifer Bain, MD, PhD
  28. 28. Condition Percent of children (n) Failure to thrive (difficulty growing/gaining weight) 35% (11) Short stature 6% (2) Hypothyroidism (underactive thyroid) 6% (2) Hyperthyroidism (overactive thyroid) 3% (1) Diabetes 3% (1) Growth and Hormone Issues © Jennifer Bain, MD, PhD
  29. 29. Condition Percent of children (n) Scoliosis (curvature of spine) 10% (3) Pectus excavatum (caved in chest) 10% (3) Hip dysplasia (partially or fully dislocated hip joint) 6% (2) Pectus carinatum (“pigeon chest”) 3% (1) Bone Abnormalities © Jennifer Bain, MD, PhD
  30. 30. Condition High pain tolerance Dental issues Vascular problems Sleep issues Autonomic signs New medical history questions implemented this year Percentages & numbers of children in the GRIN2B population with these conditions will be reported at the next meeting © Jennifer Bain, MD, PhD
  31. 31. Condition Percent of children (n) Feeding tube 19% (6) ENT (i.e., ear tubes, adenoidectomy, and/or tonsillectomy) 16% (5) Broken bone 13% (4) Eye 6% (2) Surgeries © Jennifer Bain, MD, PhD
  32. 32. Condition Percent of children (n) Gastrointestinal 31% (8) Allergies/asthma 23% (6) Sleep 15% (4) Mood & behavior† 15% (4) Seizures 8% (2) Diabetes 4% (1) Baclofen for dyskinesia 4% (1) Current Medication Use 26 Individuals † includes cannabidiol © Jennifer Bain, MD, PhD
  33. 33. • 73% of kids are taking at least 1 prescribed medication • Of those taking more than 1 prescribed medication, most are related to gastrointestinal problems • Additionally, 50% of participants are taking at least 1 vitamin or supplement (not represented in the graph) • 31% are taking 2 or more supplements Current Medication Use 26 Individuals © Jennifer Bain, MD, PhD
  34. 34. Summary of GRIN2B Common issues Less common or less serious issues• Vision/eye problems • Seizures • Growth - failure to thrive • Neurological – clumsy, low tone • Developmental delay • Autism spectrum disorders • Low muscle tone • GI issues • Ear and other infections • Attention deficit/hyperactivity disorder © Jennifer Bain, MD, PhD
  35. 35. For researchers: how to access SFARI Base https://base.sfari.org • Create a SFARI Base Account • Create a Project with your IRB Approval and register your institution • Sign a Researcher Distribution Agreement and joinder • Create a request for data or biospecimens • Request will be reviewed by the SFARI science team, and if approved, access to data is granted © Jennifer Bain, MD, PhD
  36. 36. Thank you P A G E 3 7 © Jennifer Bain, MD, PhD

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