Genetic test utilization and diagnostic yield in adult patients with neurological disorders
To determine the diagnostic yield of different genetic test modalities in adult patients with neurological disorders, we evaluated all adult patients seen for genetic diagnostic evaluation in the outpatient neurology practice at the University of Pennsylvania between January 2016 and April 2017 as part of the newly created Penn Neurogenetics Program. Subjects were identified through our electronic medical system as those evaluated by the Program’s single clinical genetic counselor in that period. A total of 377 patients were evaluated by the Penn Neurogenetics Program in different settings and genetic testing recommended. Of those, 182 (48%) were seen in subspecialty clinic setting and 195 (52%) in a General Neurogenetics Clinic. Genetic testing was completed in over 80% of patients in whom it was recommended. The diagnostic yield was 32% across disease groups. Stratified by testing modality, the yield was highest with directed testing (50%) and array comparative genomic hybridization (45%), followed by gene panels and exome testing (25% each). In conclusion, genetic testing can be successfully requested in clinic in a large majority of adult patients. Age is not a limiting factor for a genetic diagnostic evaluation and the yield of clinical testing across phenotypes (almost 30%) is consistent with previous phenotype-focused or research-based studies. These results should inform the development of specific guidelines for clinical testing and serve as evidence to improve reimbursement by insurance payers.
KeywordsDiagnostic yield Next-generation sequencing Whole exome sequencing Neurology
Compliance with ethical standards
This study was approved by the Institutional Review Committee at the University of Pennsylvania. As an IRB-approved retrospective analysis, approval to conduct this study by an ethical standards committee was received.
- 2.Kutscher EJ, Joshi SM, Patel AD, Hafeez B, Grinspan ZM (2017) Barriers to genetic testing for pediatric Medicaid beneficiaries with epilepsy. Pediatr Neurol 73:28–35. https://doi.org/10.1016/j.pediatrneurol.2017.04.014 CrossRefPubMedGoogle Scholar
- 3.Dixon-Salazar TJ, Silhavy JL, Udpa N, Schroth J, Bielas S, Schaffer AE, Olvera J, Bafna V, Zaki MS, Abdel-Salam GH, Mansour LA, Selim L, Abdel-Hadi S, Marzouki N, Ben-Omran T, Al-Saana NA, Sonmez FM, Celep F, Azam M, Hill KJ, Collazo A, Fenstermaker AG, Novarino G, Akizu N, Garimella KV, Sougnez C, Russ C, Gabriel SB, Gleeson JG (2012) Exome sequencing can improve diagnosis and alter patient management. Sci Transl Med 4(138):138ra178. https://doi.org/10.1126/scitranslmed.3003544 CrossRefGoogle Scholar
- 4.Fogel BL, Lee H, Deignan JL, Strom SP, Kantarci S, Wang X, Quintero-Rivera F, Vilain E, Grody WW, Perlman S, Geschwind DH, Nelson SF (2014) Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol 71(10):1237–1246. https://doi.org/10.1001/jamaneurol.2014.1944 CrossRefPubMedPubMedCentralGoogle Scholar
- 5.van Egmond ME, Lugtenberg CHA, Brouwer OF, Contarino MF, Fung VSC, Heiner-Fokkema MR, van Hilten JJ, van der Hout AH, Peall KJ, Sinke RJ, Roze E, Verschuuren-Bemelmans CC, Willemsen MA, Wolf NI, Tijssen MA, de Koning TJ (2017) A post hoc study on gene panel analysis for the diagnosis of dystonia. Mov Disord 32(4):569–575. https://doi.org/10.1002/mds.26937 CrossRefPubMedGoogle Scholar
- 6.Lazaridis KN, Schahl KA, Cousin MA, Babovic-Vuksanovic D, Riegert-Johnson DL, Gavrilova RH, McAllister TM, Lindor NM, Abraham RS, Ackerman MJ, Pichurin PN, Deyle DR, Gavrilov DK, Hand JL, Klee EW, Stephens MC, Wick MJ, Atkinson EJ, Linden DR, Ferber MJ, Wieben ED, Farrugia G, Individualized Medicine Clinic M (2016) Outcome of whole exome sequencing for diagnostic odyssey cases of an individualized medicine clinic: the Mayo Clinic experience. Mayo Clin Proc 91(3):297–307. https://doi.org/10.1016/j.mayocp.2015.12.018 CrossRefPubMedGoogle Scholar
- 7.Moller RS, Larsen LH, Johannesen KM, Talvik I, Talvik T, Vaher U, Miranda MJ, Farooq M, Nielsen JE, Svendsen LL, Kjelgaard DB, Linnet KM, Hao Q, Uldall P, Frangu M, Tommerup N, Baig SM, Abdullah U, Born AP, Gellert P, Nikanorova M, Olofsson K, Jepsen B, Marjanovic D, Al-Zehhawi LI, Penalva SJ, Krag-Olsen B, Brusgaard K, Hjalgrim H, Rubboli G, Pal DK, Dahl HA (2016) Gene panel testing in epileptic encephalopathies and familial epilepsies. Mol Syndromol 7(4):210–219. https://doi.org/10.1159/000448369 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Rudnik-Schoneborn S, Tolle D, Senderek J, Eggermann K, Elbracht M, Kornak U, von der Hagen M, Kirschner J, Leube B, Muller-Felber W, Schara U, von Au K, Wieczorek D, Bussmann C, Zerres K (2016) Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients. Clin Genet 89(1):34–43. https://doi.org/10.1111/cge.12594 CrossRefPubMedGoogle Scholar
- 9.Zech M, Boesch S, Jochim A, Weber S, Meindl T, Schormair B, Wieland T, Lunetta C, Sansone V, Messner M, Mueller J, Ceballos-Baumann A, Strom TM, Colombo R, Poewe W, Haslinger B, Winkelmann J (2017) Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up. Mov Disord 32(4):549–559. https://doi.org/10.1002/mds.26808 CrossRefPubMedGoogle Scholar
- 10.Wang W, Wang C, Dawson DB, Thorland EC, Lundquist PA, Eckloff BW, Wu Y, Baheti S, Evans JM, Scherer SS, Dyck PJ, Klein CJ (2016) Target-enrichment sequencing and copy number evaluation in inherited polyneuropathy. Neurology 86(19):1762–1771. https://doi.org/10.1212/WNL.0000000000002659 CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Valencia CA, Husami A, Holle J, Johnson JA, Qian Y, Mathur A, Wei C, Indugula SR, Zou F, Meng H, Wang L, Li X, Fisher R, Tan T, Hogart Begtrup A, Collins K, Wusik KA, Neilson D, Burrow T, Schorry E, Hopkin R, Keddache M, Harley JB, Kaufman KM, Zhang K (2015) Clinical impact and cost-effectiveness of whole exome sequencing as a diagnostic tool: a pediatric center’s experience. Front Pediatr 3:67. https://doi.org/10.3389/fped.2015.00067 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Fridman V, Bundy B, Reilly MM, Pareyson D, Bacon C, Burns J, Day J, Feely S, Finkel RS, Grider T, Kirk CA, Herrmann DN, Laura M, Li J, Lloyd T, Sumner CJ, Muntoni F, Piscosquito G, Ramchandren S, Shy R, Siskind CE, Yum SW, Moroni I, Pagliano E, Zuchner S, Scherer SS, Shy ME, Inherited Neuropathies C (2015) CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis. J Neurol Neurosurg Psychiatry 86(8):873–878. https://doi.org/10.1136/jnnp-2014-308826 CrossRefPubMedGoogle Scholar