Clinical impact of rapid CSF genotyping. (A) This shows the method of securing final diagnoses among 33 patients diagnosed with a neoplasm in the rapid genotyping cohort. Each illustrated person represents 1 patient; the color of the head represents whether a variant was detected in CSF by rapid genotyping, and the color of the body represents the final diagnosis reached. (B) Among 14 patients in the rapid genotyping cohort with a variant detected in CSF by TetRS, the variant detected is displayed below the final diagnosis established in each case. (C) Plots show the number and percentages of patients with clinical effects of positive variant detection by TetRS. (D) The clinical course of a representative patient with a new CNS neoplasm diagnosed by rapid CSF genotyping without neurosurgical biopsy is shown. A 69-year-old woman (patient RG003) presented with deep periventricular-enhancing lesions concerning for CNS lymphoma, glioma, or metastasis. TetRS detected the MYD88 L265P variant and was negative for TERT promoter variants. Positron-emission tomography computed tomography scan, magnetic resonance imaging of the spine, and ophthalmologic examination were negative for other sites of disease. Primary CNS lymphoma was diagnosed on the basis of TetRS variant detection, enabling methotrexate and rituximab initiation within 4 days. After completion of induction chemotherapy and during consolidation, lumbar punctures were negative for MYD88 L265P, correlating with radiographic response to treatment. MYD88 L265P was again detected in CSF at the time of recurrence; retreatment with radiation and ibrutinib was initiated, with ongoing response 1 month later. Additional TetRS and orthogonal sequencing results are displayed in the supplemental Data. IgH, immunoglobulin heavy chain rearrangement; TERT denotes the TERT C228T and C250T variants.