| [ | |
| { | |
| "id": "AITX-00001", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "DMD", | |
| "transcript": "NM_004006.2", | |
| "variant_hgvs": "c.7544_9286del", | |
| "protein_hgvs": "p.(Thr2516_Ala3096del)", | |
| "zygosity": "hemizygous" | |
| } | |
| ], | |
| "clinical_context": "Progressive muscle weakness" | |
| }, | |
| "question": "To which of the following targeted therapies would this variant be most likely amenable: Golodirsen, Viltolarsen, Eteplirsen, Casimersen, Ataluren, or None?", | |
| "answer": "Eteplirsen", | |
| "answer_type": "multipleChoice", | |
| "category": "Established_Targeted", | |
| "sub_category": "ASO", | |
| "rationale": "Variant results in deletion of exons 52-63, which is listed as amenable to exon 51 skipping" | |
| }, | |
| { | |
| "id": "AITX-00002", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "DMD", | |
| "transcript": "NM_004006.2", | |
| "variant_hgvs": "c.10453_10454delinsTA", | |
| "protein_hgvs": "p.(Leu3485Ter)", | |
| "zygosity": "hemizygous" | |
| } | |
| ], | |
| "clinical_context": "Progressive muscle weakness" | |
| }, | |
| "question": "To which of the following targeted therapies would this variant be most likely amenable: Golodirsen, Viltolarsen, Eteplirsen, Casimersen, Ataluren, or None?", | |
| "answer": "Ataluren", | |
| "answer_type": "multipleChoice", | |
| "category": "Established_Targeted", | |
| "sub_category": "Small Molecule", | |
| "rationale": "Variant results in a nonsense in exon 74, which is amenable to nonsense readthrough" | |
| }, | |
| { | |
| "id": "AITX-00003", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "DMD", | |
| "transcript": "NM_004006.2", | |
| "variant_hgvs": "c.70T>C", | |
| "protein_hgvs": "p.(Trp24Arg)", | |
| "zygosity": "hemizygous" | |
| } | |
| ], | |
| "clinical_context": "Progressive muscle weakness" | |
| }, | |
| "question": "To which of the following targeted therapies would this variant be most likely amenable: Eteplirsen, Golodirsen, Viltolarsen, Casimersen, Ataluren, or None?", | |
| "answer": "None", | |
| "answer_type": "multipleChoice", | |
| "category": "Established_Targeted", | |
| "sub_category": "ASOs", | |
| "rationale": "Results in a missense in exon 2, which is not amenable to nonsense readthrough and is upstream from skippable exons" | |
| }, | |
| { | |
| "id": "AITX-00004", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "AGXT", | |
| "transcript": "NM_000030.3", | |
| "variant_hgvs": "c.508G>A", | |
| "protein_hgvs": "p.(Gly170Arg)", | |
| "zygosity": "homozygous" | |
| } | |
| ], | |
| "clinical_context": "Recurrent nephrocalcinosis and chronic kidney disease" | |
| }, | |
| "question": "What targeted, small molecule therapy is available for this patient? Provide the generic name or None.", | |
| "answer": "Pyridoxine", | |
| "answer_type": "exactMatch", | |
| "category": "Established_Targeted", | |
| "sub_category": "Small Molecule", | |
| "rationale": "Missense variants are amenable to pyridoxine treatment https://www.ncbi.nlm.nih.gov/books/NBK1283/" | |
| }, | |
| { | |
| "id": "AITX-00005", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "AGXT", | |
| "transcript": "NM_000030.3", | |
| "variant_hgvs": "c.33dup", | |
| "protein_hgvs": "p.(Lys12GlnfsTer156)", | |
| "zygosity": "homozygous" | |
| } | |
| ], | |
| "clinical_context": "Recurrent nephrocalcinosis and chronic kidney disease" | |
| }, | |
| "question": "Is this patient predicted to be responsive to pyridoxine? Answer yes or no.", | |
| "answer": "No", | |
| "answer_type": "exactMatch", | |
| "category": "Established_Targeted", | |
| "sub_category": "Small Molecule", | |
| "rationale": "Pyridoxine is not effective for patients with null variants https://www.ncbi.nlm.nih.gov/books/NBK1283/" | |
| }, | |
| { | |
| "id": "AITX-00006", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "AGXT", | |
| "transcript": "NM_000030.3", | |
| "variant_hgvs": "c.33dup", | |
| "protein_hgvs": "p.(Lys12GlnfsTer156)", | |
| "zygosity": "homozygous" | |
| } | |
| ], | |
| "clinical_context": "7 year old with recurrent nephrocalcinosis and chronic kidney disease" | |
| }, | |
| "question": "What targeted, genetic therapies are approved for this patient in the US? Provide the generic name.", | |
| "answer": "Lumasiran", | |
| "answer_type": "exactMatch", | |
| "category": "Established_Targeted", | |
| "sub_category": "siRNA", | |
| "rationale": "Lumasiran is approved for patients of all ages whereas Nedosiran is only approved for patients age >9. https://www.ncbi.nlm.nih.gov/books/NBK1283/" | |
| }, | |
| { | |
| "id": "AITX-00007", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "DDC", | |
| "transcript": "NM_001082971.2", | |
| "variant_hgvs": "c.286G>A", | |
| "protein_hgvs": "p.(Gly96Arg)", | |
| "zygosity": "homozygous" | |
| } | |
| ], | |
| "clinical_context": "Global developmental delay" | |
| }, | |
| "question": "What is the youngest age for which a gene therapy is approved for this patient's genetic condition in the united kingdom? Answer with the format \"X months\".", | |
| "answer": "18 months", | |
| "answer_type": "exactMatch", | |
| "category": "Established_Targeted", | |
| "sub_category": "Gene Therapy", | |
| "rationale": "https://www.ncbi.nlm.nih.gov/books/NBK595821/" | |
| }, | |
| { | |
| "id": "AITX-00008", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "COL1A1", | |
| "transcript": "NM_000088.4", | |
| "variant_hgvs": "c.1678G>A", | |
| "protein_hgvs": "p.(Gly560Ser)", | |
| "zygosity": "heterozygous" | |
| } | |
| ], | |
| "clinical_context": "joint hypermobility, skin hyperextensibility, and easy bruising" | |
| }, | |
| "question": "What two medications are most established for decreasing bruising? List generic names in alphabetical order", | |
| "answer": "ascorbic acid, desmopressin", | |
| "answer_type": "exactMatch", | |
| "category": "Established_Supportive", | |
| "sub_category": "Treatment_Identification", | |
| "rationale": "https://www.ncbi.nlm.nih.gov/books/NBK1244/#eds.Management" | |
| }, | |
| { | |
| "id": "AITX-00009", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "SLC35A2", | |
| "transcript": "NM_005660.3", | |
| "variant_hgvs": "c.3G>A", | |
| "protein_hgvs": "p.Met1Ile", | |
| "zygosity": "heterozygous" | |
| } | |
| ], | |
| "clinical_context": "Patient with SLC35A2-CDG who is experiencing seizures and global developmental delay" | |
| }, | |
| "question": "What clinical trial developing a new therapeutic for this condition is recruiting or listed as upcoming/not yet recruiting? Return a clinical trials ID", | |
| "answer": "NCT05402384", | |
| "answer_type": "exactMatch", | |
| "category": "Clinical_Trials", | |
| "sub_category": "Trial_Identification", | |
| "rationale": "https://clinicaltrials.gov/study/NCT05402384" | |
| }, | |
| { | |
| "id": "AITX-00010", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "SLC35A2", | |
| "transcript": "NM_005660.3", | |
| "variant_hgvs": "c.3G>A", | |
| "protein_hgvs": "p.Met1Ile", | |
| "zygosity": "heterozygous" | |
| } | |
| ], | |
| "clinical_context": "seizures and global developmental delay. Age 2 months, Hemoglobin 5, Normal liver labs, Not enrolled in other trials" | |
| }, | |
| "question": "Is this patient eligible for clinical trial NCT05402384? Answer yes or no.", | |
| "answer": "No", | |
| "answer_type": "exactMatch", | |
| "category": "Clinical_Trials", | |
| "sub_category": "Eligibility", | |
| "rationale": "Exclusion criteria lists hemoglobin <7 https://clinicaltrials.gov/study/NCT05402384" | |
| }, | |
| { | |
| "id": "AITX-00011", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "KCNT1", | |
| "transcript": "NM_020822.3", | |
| "variant_hgvs": "c.2849G>A", | |
| "protein_hgvs": "p.Arg950Gln", | |
| "zygosity": "heterozygous" | |
| } | |
| ], | |
| "clinical_context": "early-onset seizures and developmental delays" | |
| }, | |
| "question": "For which clinical trials evaluating new therapeutics is this patient eligible? Provide a clinical trial ID or answer None.", | |
| "answer": "None", | |
| "answer_type": "exactMatch", | |
| "category": "Clinical_Trials", | |
| "sub_category": "Trial_Identification", | |
| "rationale": "Only a natural history study is listed. Source: https://clinicaltrials.gov/search?cond=KCNT1" | |
| }, | |
| { | |
| "id": "AITX-00012", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "GRIN2B", | |
| "transcript": "NM_000834.5", | |
| "variant_hgvs": "c.2755C>T", | |
| "protein_hgvs": "p.Gln919Ter", | |
| "zygosity": "heterozygous" | |
| } | |
| ], | |
| "clinical_context": "intellectual disability, seizures, and developmental delays" | |
| }, | |
| "question": "Is it more likely amenable to treatment with Memantine, L-serine, or Radiprodil", | |
| "answer": "L-Serine", | |
| "answer_type": "exactMatch", | |
| "category": "Drug_Development_and_Repurposing", | |
| "sub_category": "Mechanism_Of_Action", | |
| "rationale": "Variant is a LOF variant. L-serine is being used for LOF variants whereas the others are being used for GOF variants https://academic.oup.com/brain/article/147/5/1653/7611854?login=false" | |
| }, | |
| { | |
| "id": "AITX-00013", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "ANO10", | |
| "transcript": "NM_018075.5", | |
| "variant_hgvs": "c.289del", | |
| "protein_hgvs": "p.(Met97Ter)", | |
| "zygosity": "homozygous" | |
| } | |
| ], | |
| "clinical_context": "progressive cerebellar ataxia and peripheral neuropathy" | |
| }, | |
| "question": "How many amino acids are coded for by the exon in which this variant occurs? Answer with a number", | |
| "answer": "66", | |
| "answer_type": "exactMatch", | |
| "category": "Variant_Assessment", | |
| "sub_category": "Exon_Evaluation", | |
| "rationale": "Source: Ensembl" | |
| }, | |
| { | |
| "id": "AITX-00014", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "ANO10", | |
| "transcript": "NM_018075.5", | |
| "variant_hgvs": "c.289del", | |
| "protein_hgvs": "p.(Met97Ter)", | |
| "zygosity": "homozygous" | |
| } | |
| ], | |
| "clinical_context": "progressive cerebellar ataxia and peripheral neuropathy" | |
| }, | |
| "question": "What percentage of the total coding transcript for this gene are encoded by the exon in which this variant occurs? Answer with a decimal to nearest tenth.", | |
| "answer": "0.1", | |
| "answer_type": "exactMatch", | |
| "category": "Variant_Assessment", | |
| "sub_category": "Exon_Evaluation", | |
| "rationale": "66/660 = 0.1 Source: Ensembl" | |
| }, | |
| { | |
| "id": "AITX-00015", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "KMT2B", | |
| "transcript": "NM_014727.3", | |
| "variant_hgvs": "c.8079delC", | |
| "protein_hgvs": "p.(Ile2694SerfsTer44)", | |
| "zygosity": "heterozygous" | |
| } | |
| ], | |
| "clinical_context": "childhood-onset generalized dystonia" | |
| }, | |
| "question": "Based on typical prediction rules, is this variant likely to result in nonsense mediated decay? Answer yes or no.", | |
| "answer": "No", | |
| "answer_type": "exactMatch", | |
| "category": "Variant_Assessment", | |
| "sub_category": "Nonsense_Mediated_Decay", | |
| "rationale": "At the end of the last exon, after the main domain" | |
| }, | |
| { | |
| "id": "AITX-00016", | |
| "patient": { | |
| "genotype": [ | |
| { | |
| "gene": "NF1", | |
| "transcript": "NM_001042492.3", | |
| "variant_hgvs": "c.3728T>C", | |
| "protein_hgvs": "p.(Leu1243Pro)", | |
| "zygosity": "heterozygous" | |
| } | |
| ], | |
| "clinical_context": "Malignant Peripheral Nerve Sheath Tumor and Pheochromocytoma" | |
| }, | |
| "question": "In which functional domain does this variant occur? Answer choices: CSRD, TBD, GRD, Sec14-PH, HLR, NLS, SBR.", | |
| "answer": "GRD", | |
| "answer_type": "exactMatch", | |
| "category": "Variant_Assessment", | |
| "sub_category": "Exon_Skipping", | |
| "rationale": "GRD, GAP related domain (1198–1549 residues) https://www.mdpi.com/2073-4425/13/7/1130#" | |
| } | |
| ] |