marcdubybroad
commented
2 years ago Hello, Does anyone have the curies for the above phenotypes handy? Just trying to avoid doing extra legwork that someone else might have done. We are looking at doing the following process:
- for each phenotype above, if no GWAS available, find related phenotypes for which a GWAS is available
- we'll need some type of phenotype/phenotype similarity measure (EHR data?)
- find genes that have a genetic association with the phenotype
- of those genes, filter out the ones that are not part of a pathway with ATP1A3
- of the genes and pathways, rank the by pathway association with the phenotype
- find drugs that
treatthose genes
Comments welcome
khanspers
andrewsu
colleenXu
cbizon
karafecho
CaseyTa
amfoksinska
suihuang-ISB
sstemann
Submitting team
Exploring Agent, Service Provider (Andrew Su)
SME
Colleagues at the Rady Children's Institute for Genomic Medicine
Jennifer Friedman, MD Clinical Professor Neurosciences and Pediatrics UCSD/Rady Children's Hospital San Diego Clinical Investigator Rady Children's Institute for Genomic Medicine
Laura Forero, MD Genetics Fellow. UCSD/Rady Children’s Hospital
Charlotte Hobbs, MD Vice President for Research & Clinical Management Rady Children's Institute for Genomic Medicine
Challenge Question
Given a mutation in gene ATP1A3 and a case description of associated phenotypes, can Translator propose new therapies?
Background
For this challenge, Translator team members will consider five real-world use cases, all involving mutations in the gene ATP1A3. (Please note that the case summaries provided below were provided by the clinical SMEs and have not been edited for grammar or style.) Please post progress on this challenge to this GitHub ticket.
Case 1 The focus case is a 13 month female with alternating hemiplegia phenotype. She presented initially shortly after birth with abnormal eye movements/nystagmus. She currently displays global developmental delay, and hypotonia with paroxysmal episodes of dystonia, tremors and/or weakness as well as probable seizures.
Gene: ATP1A3 (NCBIGene:478) Variant: c.2591A>G; p.(Gln864Arg)
HPO/Phenotype Terms:
Case 2 A 17-year-old male presenting at age 16 with progressive ataxia, neuro-behavioral impairment and cerebellar atrophy with regression. There is history of expressive language delay and longstanding mild difficulties with coordination. Current symptoms/examination notable for scanning speech, dysmetria, ataxic gait, hand tremor, dystonia, parkinsonism and dysphagia.
Gene: ATP1A3 Variant: c.985G>A; p.Gly329Ser HPO/Phenotype terms:
Case 3
7-year-old male who presented at five months of age with episodic spells described as head turning and head tremor. He has been diagnosed with alternating hemiplegia of childhood, global developmental delay and myoclonic epilepsy.
Gene: ATP1A3 Variant: c.2440G>A p.Asp814Asn HPO/Phenotype terms:
Case 4 17-year-old female who presented with global developmental delay and spells described by caretakers as leg weakness and inability to move limbs. These episodes vary from side to side. She also has multiple behavioral concerns, including depression and self-aggression. She has as well abnormal muscle biopsy with electron chain abnormalities and an array showing deletion 17p12 involving PMP gene. (EDIT 2022-10-12: The 17p12 deletion likely indicates a second genetic disease, though typically the second disorder does not onset till adulthood so the phenotype in child not likely attributable to the deletion.)
Gene: ATP1A3 Variant: c.2303A>G (p.Try768Cys) HPO/Phenotype terms:
Case 5 A 15-year-old male with global developmental delay and paroxysmal episodes of primarily dystonic posturing associated with possible myoclonus and chorea. Brain MRI within normal limits.
Gene: ATP1A3 Variant: c.2767G>A, p.Asp923Asn HPO/Phenotype terms:
Timeline
October 7, 2022 - First Friday of the Month Standup
Check-in/update from teams on progress
October 14, 2022 - Second Friday of the Month Standup Check-in/update from teams on progress
October 20, 2022 - Third Thursday of the Month Translator QotM mini-hackathon Review answers and refine queries with SME; wrap-up challenge
October 28, 2022 - Fourth Friday of the Month Translator QotM Challenge summary published in Gazette; next month's QotM Challenge announced