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. 2022 Dec 1;79(12):1267-1276.
doi: 10.1001/jamaneurol.2022.3651.

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice

Dianalee McKnight  1 , Ana Morales  1 , Kathryn E Hatchell  1 , Sara L Bristow  1 , Joshua L Bonkowsky  2   3 , Michael Scott Perry  4 , Anne T Berg  5   6 , Felippe Borlot  7   8 , Edward D Esplin  1 , Chad Moretz  1 , Katie Angione  9   10 , Loreto Ríos-Pohl  11 , Robert L Nussbaum  1 , Swaroop Aradhya  1 ; ELEVIATE Consortium; Chad R Haldeman-Englert  12 , Rebecca J Levy  13   14 , Venu G Parachuri  15 , Guillermo Lay-Son  16 , David J Dávila-Ortiz de Montellano  17 , Miguel Angel Ramirez-Garcia  17 , Edmar O Benítez Alonso  17 , Julie Ziobro  18 , Adela Chirita-Emandi  19   20 , Temis M Felix  21 , Dianne Kulasa-Luke  22 , Andre Megarbane  23   24 , Shefali Karkare  25 , Sarah L Chagnon  26 , Jennifer B Humberson  27 , Melissa J Assaf  28 , Sebastian Silva  29 , Katherine Zarroli  30 , Oksana Boyarchuk  31 , Gary R Nelson  2 , Rachel Palmquist  2 , Katherine C Hammond  32 , Sean T Hwang  33 , Susan B Boutlier  34 , Melinda Nolan  35 , Kaitlin Y Batley  36 , Devraj Chavda  37 , Carlos Alberto Reyes-Silva  38 , Oleksandr Miroshnikov  39 , Britton Zuccarelli  40 , Louise Amlie-Wolf  41 , James W Wheless  42   43 , Syndi Seinfeld  44 , Manoj Kanhangad  45 , Jeremy L Freeman  46 , Susana Monroy-Santoyo  47 , Natalia Rodriguez-Vazquez  48 , Monique M Ryan  46   49   50 , Michelle Machie  36 , Patricio Guerra  51 , Muhammad Jawad Hassan  52 , Meghan S Candee  2 , Caleb P Bupp  53 , Kristen L Park  9   10   54 , Eric Muller 2nd  55 , Pamela Lupo  56 , Robert C Pedersen  57 , Amir M Arain  58 , Andrea Murphy  59 , Krista Schatz  60 , Weiyi Mu  60 , Paige M Kalika  61 , Lautaro Plaza  62 , Marissa A Kellogg  63 , Evelyn G Lora  64 , Robert P Carson  65 , Victoria Svystilnyk  66 , Viviana Venegas  67 , Rebecca R Luke  4 , Huiyuan Jiang  68 , Tetiana Stetsenko  69 , Milagros M Dueñas-Roque  70 , Joseph Trasmonte  71 , Rebecca J Burke  72   73 , Anna C E Hurst  74 , Douglas M Smith  75 , Lauren J Massingham  76   77 , Laura Pisani  33   78 , Carrie E Costin  79 , Betsy Ostrander  2 , Francis M Filloux  2 , Amitha L Ananth  32 , Ismail S Mohamed  32 , Alla Nechai  80 , Jasmin M Dao  81   82 , Michael C Fahey  45 , Ermal Aliu  83 , Stephen Falchek  41   84 , Craig A Press  9   10   54 , Lauren Treat  9   10   54 , Krista Eschbach  9   10   54 , Angela Starks  9   10   54 , Ryan Kammeyer  9   10   54 , Joshua J Bear  9   10   54 , Mona Jacobson  9   10   54 , Veronika Chernuha  85 , Bailey Meibos  86 , Kristen Wong  2 , Matthew T Sweney  2 , A Chris Espinoza  2 , Colin B Van Orman  2 , Arie Weinstock  87   88 , Ashutosh Kumar  89 , Claudia Soler-Alfonso  90 , Danielle A Nolan  91 , Muhammad Raza  92 , Miguel David Rojas Carrion  93 , Geetha Chari  37   94 , Eric D Marsh  95   96 , Yael Shiloh-Malawsky  97 , Sumit Parikh  98 , Ernesto Gonzalez-Giraldo  99 , Stephen Fulton  42   43 , Yoshimi Sogawa  100 , Kaitlyn Burns  101 , Myroslava Malets  102 , Johnny David Montiel Blanco  103 , Christa W Habela  60 , Carey A Wilson  2 , Guillermo G Guzmán  104 , Mariia Pavliuk  105
Affiliations

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice

Dianalee McKnight et al. JAMA Neurol. .

Abstract

Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.

Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes.

Design, setting, and participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals.

Exposures: Genetic test results.

Main outcomes and measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms.

Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%).

Conclusions and relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr McKnight, Ms Morales, and Drs Hatchell, Bristow, Esplin, Moretz, Nussbaum, and Aradhya reported being employees and shareholders of Invitae. Dr Bonkowsky reported receiving consultant fees from Autobahn, Bluebird Bio, Calico, Denali Therapeutics, Enzyvant, Neurogene, Passage Bio, and Takeda; research funding from the National Institutes of Health (Clinical and Translational Science Awards Program and National Institute of Neurological Disorders and Stroke); being on the Board of Directors for wFluidx; being a shareholder in Orchard Therapeutics; and receiving royalties from Manson Publishing and BioFire (spouse). Dr Perry reported receiving safety monitoring committee fees from Stoke Therapeutics; consulting fees from BioMarin, Encoded Therapeutics, Greenwich Biosciences, Neurelis, Stoke Therapeutics, Taysha, and Zogenix; speakers’ bureau fees/advisory board fees from Zogenix and Bright Minds; research funds paid to Cook Children’s from Encoded Therapeutics, Greenwich Biosciences, Marinus, Ovid, Stoke Therapeutics, and Zogenix; speakers fees from nobelPharma; and advisory board fees from Eisai outside the submitted work. Dr Berg reported receiving speakers’ fees from Biomarin and advisory panel fees from Neurocrin and Zogenix outside the submitted work. Dr Esplin reported being on the scientific advisory board of Taproot Health. Dr Nussbaum reported being a paid consultant for Pfizer Pharmaceuticals; a paid consultant and stockholder in Genome Medical and Maze Therapeutics; and advisor/consultant fees from Pfizer Pharmaceuticals during the conduct of the study. Dr Monroy-Santoyo reported receiving personal fees from Alnylam Pharmaceuticals, Ultragenyx Pharmaceutical, and Recordati Rare Diseases outside the submitted work. Dr Carson reported receiving grants from Angelman Syndrome Foundation outside the submitted work. Dr Smith reported receiving personal fees from UCB outside the submitted work. Dr Mohamed reported receiving grants from Marinus Pharmaceuticals outside the submitted work. Dr Press reported receiving personal fees from Marinus Pharmaceuticals outside the submitted work. Dr Eschbach reported being a site principal investigator for a clinical trial for UCB pharmaceuticals and Neurocrine Biosciences outside the submitted work; and being a NORSE Institute Medical Science advisory board member. Dr Kammeyer reported receiving personal fees from Genentech and Sanofi outside the submitted work. Dr Bear reported receiving consultant fees from Biomarin outside the submitted work. Dr Kumar reported receiving advisory board/speakers’ bureau fees from PTC Therapeutics outside the submitted work. Dr Marsh reported being a site principal investigator from Stoke Therapeutics, Acadia Pharmaceuticals, Zogenix Pharmaceuticals, and Marinus Pharmaceuticals and personal fees from Medscape for recording an educational video outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Age When Seizures Began, at Clinical Diagnosis, and at Time of Genetic Testing
A, Age at seizure initiation and age of clinical diagnosis were available if respondents indicated that the reason for testing was a clinical presentation of epilepsy. Age was unknown or not applicable for seizure onset (n = 40) and clinical diagnosis (n = 42). B, Violin plots reporting the difference between age at clinical diagnosis and age at time of genetic testing.
Figure 2.
Figure 2.. Reported Clinical Actions After a Definitive Genetic Diagnosis
A, Respondents reported whether the genetic finding influenced a change in clinical management of the patient. B, Those who indicated “yes” selected all of the changes that were implemented or recommended (a patient could have >1 recommendation reported and is counted in each recommendation category). C, Those who indicated “no” reported the reason best describing why no changes were made.
Figure 3.
Figure 3.. Patient Outcomes
A, Overall patient outcomes after treatment changes were reported in question 13 of the case report form (eMethods in the Supplement). B, Patient outcomes after treatment changes were grouped according to positive outcomes, no change in outcomes, or negative outcomes and analyzed by the gene with diagnostic findings. Outcomes associated with the 11 genes with the highest frequency of diagnostic findings with reported follow-up after treatment changes are shown here. Outcomes for all genes with diagnostic findings that had clinical management changes reported and outcomes available are summarized in eTable 3 in the Supplement.
Figure 4.
Figure 4.. Changes in Seizure Frequency After Changes in Clinical Management
Individuals were grouped by their initial reported seizure frequency (daily, weekly, monthly, annually, or no seizures) before genetic testing and treatment changes on the y-axis, based on health care professional–reported responses to question 9 from the case report form (CRF). The reported seizure frequencies after treatment changes are represented on the x-axis, based on health care professional–reported responses to question 20 from the CRF. Only individuals who had a response provided for both pretreatment and posttreatment were included in this analysis.
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Comment in

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