Disease-causing variants in genes encoding subunits of the N-methyl-D-aspartate receptor (NMDAR) are an important contributor to neurodevelopmental disorders. While individually rare, GRIN-related disorders due to disease-causing variants in GRIN1, GRIN2A, GRIN2B or GRIN2D collectively represent 5% of all individuals with a positive genetic diagnosis in our ongoing natural history of genetic epilepsies and neurodevelopmental disorders at the Children’s Hospital of Philadelphia. By systematically assessing the disease course of individuals with GRIN-related disorders in this cohort, we delineated shared and distinct phenotypic features in this disease group in comparison to other genetic epilepsies and neurodevelopmental disorders using large-scale electronic medical record data. In our overall cohort of 800 individuals with more than 100 distinct genetic etiologies in 250 individuals, the 12 individuals with GRIN-related disorders showed 32 specific gene-phenotype associations that stood out from the remainder of the cohort. These included associations of GRIN2A and dyslexia (p=0.005), GRIN1 with absent speech (p= 0.008) and GRIN1 with generalized hypotonia (p=0.009) as the three most significant findings. Both GRIN2A and GRIN2B displayed an association with focal impaired awareness seizures (p=0.03), while GRIN2B was associated with epileptic encephalopathy (p=0.02) but no specific seizure types. We did not find an association between GRIN-related disorders and the use of specific anti-seizure medications. Our data provide a general overview how GRIN associated disorders relate to the wider range of genetic epilepsies and neurodevelopmental disorders, which is an important prerequisite for understanding the specificity of phenotypic features and outcome measures for precision medicine trials.

1. Understanding the Clinical Presentation of GRIN-
Related Disorders
Ingo Helbig, MD
Division of Neurology
Department of Biomedical and Health Informatics
Children’s Hospital of Philadelphia
© Ingo Helbig, MD

2. Understanding the Clinical Presentation of GRIN-
Related Disorders
Ingo Helbig, MD
Division of Neurology
Department of Biomedical and Health Informatics
Children’s Hospital of Philadelphia
© Ingo Helbig, MD

3. The Where, When and What
of the GRIN landscape
Ingo Helbig, MD
Division of Neurology
Department of Biomedical and Health Informatics
Children’s Hospital of Philadelphia
© Ingo Helbig, MD

4. About myself…
• Child Neurologist
– University of Kiel, Germany (until 2014)
– Children’s Hospital of Philadelphia
• Clinical role
– Clinical Co-Director, Epilepsy Genetics Program (ENGIN)
– Focus on children with genetic epilepsies
– >20 patients with GRIN-related disorders
• Research
– Gene discovery in epilepsies
– Analysis of “big data”, machine learning
© Ingo Helbig, MD

5. Take home messages
• How GRIN disorders are discovered
–The bias towards genes and variants, not disease presentations
• Building a landscape of the GRIN genes
– Understanding what sets the GRIN genes apart
– If we want to treat GRIN-related disorders, we have to understand them first
© Ingo Helbig, MD

6. Take home messages
• How GRIN disorders are discovered
–The bias towards genes and variants, not disease presentations
• Building a landscape of the GRIN genes
– Understanding what sets the GRIN genes apart
– If we want to treat GRIN-related disorders, we have to understand them first
© Ingo Helbig, MD

7. © Ingo Helbig, MD

8. Reutlinger, Helbig, et al., 2010
The almost NOT discovery of GRIN2A
© Ingo Helbig, MD

9. Reutlinger, Helbig, et al., 2010
“This patient
has ESES”
“Many other
patients have
abnormal EEGs,
too”
“This is a very
unusual clinical
presentation”
“Let’s focus on
the gene, the
clinical findings
are non-specific”
© Ingo Helbig, MD

10. The road we’re travelling
© Ingo Helbig, MD

11. © Ingo Helbig, MD

12. The phenotypic bottleneck
Genetic findings Clinical findings
• Can be generated at scale
• Standardized annotation
• (Mostly) 1-2 dimensional
• Computable
• Requires overview by hand
• Not standardized
• Highly complex
• Non-computable
© Ingo Helbig, MD

13. What do we know about the GRIN disorders?
• GRIN2A
– “Epilepsy and speech”
– Epilepsy-aphasia spectrum, speech apraxia
• GRIN1
– ”Early developmental issues”
– Early epileptic encephalopathy, spasticity, non-verbal
• GRIN2B
– “Unusual features”
– Uncommon features, unexpectedly mild phenotypes
© Ingo Helbig, MD

14. Age
Single visit
© Ingo Helbig, MD

15. Age
All prior information
Single visit
© Ingo Helbig, MD

16. Age
All information on all patients
© Ingo Helbig, MD

17. Age
All information on all patients, sorted
© Ingo Helbig, MD

18. © Ingo Helbig, MD

19. © Ingo Helbig, MD

20. © Ingo Helbig, MD

21. All information on all patients,
on as many patients
as possible
© Ingo Helbig, MD

22. © Ingo Helbig, MD

23. 1,121,690
neurology notes
103,145
individuals
123,144
patient years
© Ingo Helbig, MD

24. 1,121,690
neurology notes
103,145
individuals
123,144
patient years
© Ingo Helbig, MD

25. Individuals with genetic epilepsies (662 patients)
© Ingo Helbig, MD

26. What do patients actually have?
© Ingo Helbig, MD

27. Age
© Ingo Helbig, MD

28. Age
© Ingo Helbig, MD

29. Age
Hypotonia
© Ingo Helbig, MD

30. Age
Hypotonia
© Ingo Helbig, MD

31. ”The Cube”
• Data tool to process patient data with rare epilepsies
–Electronic medical records
• Data input
–Information on >650 patients with genetic epilepsies
–60,000 “dots”, total of >3,200 patient years
–12 GRIN patients followed at CHOP
• Question
–How do GRIN-related disorders stand out from all other patients?
© Ingo Helbig, MD

32. © Ingo Helbig, MD

33. Age
Significance of
clinical features
© Ingo Helbig, MD

34. © Ingo Helbig, MD

35. © Ingo Helbig, MD

36. GRIN1
GRIN2B
GRIN2A
© Ingo Helbig, MD

37. The Where, When and What of GRIN-related disorders
• Comparison of the GRINs to other disorders
–Important for understanding how GRINs stand out
–First step for GRIN-related outcome measures
• GRIN1
–Hypotonia, delay in the first year of life (1-2 years)
• GRIN2B
–Epilepsy, sleep concerns at 3-5 years, more information needed
• GRIN2A
–Speech issues, dyspraxia, behavior at 7-10 years
© Ingo Helbig, MD

38. Take home messages
• How GRIN diseases are discovered
–The bias towards genes and variants, not disease presentations
• Building a landscape of the GRIN genes
– Understanding what sets the GRIN genes apart
– If we want to treat GRIN-related disorders, we have to understand them
© Ingo Helbig, MD