Targeted Gene Panel Use in 2249 Neuromuscular Patients: the Australasian Referral Center Experience

Overview

Journal Ann Clin Transl Neurol

Specialty Neurology

Date 2020 Mar 11

PMID 32153140

Citations 18

Authors

Sarah J Beecroft

Kyle S Yau

Richard J N Allcock

Kym Mina

Rebecca Gooding

Fathimath Faiz

Vanessa J Atkinson

Cheryl Wise

Padma Sivadorai

Daniel Trajanoski

Nina Kresoje

Royston Ong

Rachael M Duff

Macarena Cabrera-Serrano

Kristen J Nowak

Nicholas Pachter

Gianina Ravenscroft

Phillipa J Lamont

Mark R Davis

Nigel G Laing

Affiliations

Soon will be listed here.

Abstract

Objective: To develop, test, and iterate a comprehensive neuromuscular targeted gene panel in a national referral center.

Methods: We designed two iterations of a comprehensive targeted gene panel for neuromuscular disorders. Version 1 included 336 genes, which was increased to 464 genes in Version 2. Both panels used TargetSeq probe-based hybridization for target enrichment followed by Ion Torrent sequencing. Targeted high-coverage sequencing and analysis was performed on 2249 neurology patients from Australia and New Zealand (1054 Version 1, 1195 Version 2) from 2012 to 2015. No selection criteria were used other than referral from a suitable medical specialist (e.g., neurologist or clinical geneticist). Patients were classified into 15 clinical categories based on the clinical diagnosis from the referring clinician.

Results: Six hundred and sixty-five patients received a genetic diagnosis (30%). Diagnosed patients were significantly younger that undiagnosed patients (26.4 and 32.5 years, respectively; P = 4.6326E-9). The diagnostic success varied markedly between disease categories. Pathogenic variants in 10 genes explained 38% of the disease burden. Unexpected phenotypic expansions were discovered in multiple cases. Triage of unsolved cases for research exome testing led to the discovery of six new disease genes.

Interpretation: A comprehensive targeted diagnostic panel was an effective method for neuromuscular disease diagnosis within the context of an Australasian referral center. Use of smaller disease-specific panels would have precluded diagnosis in many patients and increased cost. Analysis through a centralized laboratory facilitated detection of recurrent, but under-recognized pathogenic variants.

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References

Sagath L, Lehtokari V, Valipakka S, Udd B, Wallgren-Pettersson C, Pelin K . An Extended Targeted Copy Number Variation Detection Array Including 187 Genes for the Diagnostics of Neuromuscular Disorders. J Neuromuscul Dis. 2018; 5(3):307-314. PMC: 6087456. DOI: 10.3233/JND-170298. View

Ravenscroft G, Nolent F, Rajagopalan S, Meireles A, Paavola K, Gaillard D . Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita. Am J Hum Genet. 2015; 96(6):955-61. PMC: 4457946. DOI: 10.1016/j.ajhg.2015.04.014. View

Guimier A, Gordon C, Godard F, Ravenscroft G, Oufadem M, Vasnier C . Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy. Am J Hum Genet. 2016; 99(3):666-673. PMC: 5010643. DOI: 10.1016/j.ajhg.2016.06.021. View

van Gassen K, van der Heijden C, de Bot S, den Dunnen W, van den Berg L, Verschuuren-Bemelmans C . Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort. Brain. 2012; 135(Pt 10):2994-3004. DOI: 10.1093/brain/aws224. View

Beecroft S, McLean C, Delatycki M, Koshy K, Yiu E, Haliloglu G . Expanding the phenotypic spectrum associated with mutations of DYNC1H1. Neuromuscul Disord. 2017; 27(7):607-615. DOI: 10.1016/j.nmd.2017.04.011. View

Taroni F, VERDERIO E, Dworzak F, Willems P, Cavadini P, DiDonato S . Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. Nat Genet. 1993; 4(3):314-20. DOI: 10.1038/ng0793-314. View

Witting N, Duno M, Petri H, Krag T, Bundgaard H, Kober L . Anoctamin 5 muscular dystrophy in Denmark: prevalence, genotypes, phenotypes, cardiac findings, and muscle protein expression. J Neurol. 2013; 260(8):2084-93. DOI: 10.1007/s00415-013-6934-y. View

Oates E, Jones K, Donkervoort S, Charlton A, Brammah S, Smith 3rd J . Congenital Titinopathy: Comprehensive characterization and pathogenic insights. Ann Neurol. 2018; 83(6):1105-1124. PMC: 6105519. DOI: 10.1002/ana.25241. View

Hicks D, Sarkozy A, Muelas N, Koehler K, Huebner A, Hudson G . A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy. Brain. 2010; 134(Pt 1):171-182. PMC: 4038512. DOI: 10.1093/brain/awq294. View

10.

Alkan C, Coe B, Eichler E . Genome structural variation discovery and genotyping. Nat Rev Genet. 2011; 12(5):363-76. PMC: 4108431. DOI: 10.1038/nrg2958. View

11.

Lassuthova P, Rebelo A, Ravenscroft G, Lamont P, Davis M, Manganelli F . Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. Am J Hum Genet. 2018; 102(3):505-514. PMC: 5985288. DOI: 10.1016/j.ajhg.2018.01.023. View

12.

Pajusalu S, Kahre T, Roomere H, Murumets U, Roht L, Simenson K . Large gene panel sequencing in clinical diagnostics-results from 501 consecutive cases. Clin Genet. 2017; 93(1):78-83. DOI: 10.1111/cge.13031. View

13.

. Comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseases. Genome Biol. 2015; 16:134. PMC: 4499193. DOI: 10.1186/s13059-015-0693-2. View

14.

Hu X, Li N, Xu Y, Li G, Yu T, Yao R . Proband-only medical exome sequencing as a cost-effective first-tier genetic diagnostic test for patients without prior molecular tests and clinical diagnosis in a developing country: the China experience. Genet Med. 2017; 20(9):1045-1053. DOI: 10.1038/gim.2017.195. View

15.

McKernan K, Peckham H, Costa G, McLaughlin S, Fu Y, Tsung E . Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding. Genome Res. 2009; 19(9):1527-41. PMC: 2752135. DOI: 10.1101/gr.091868.109. View

16.

Roxburgh R, Marquis-Nicholson R, Ashton F, George A, Lea R, Eccles D . The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry. J Neurol. 2012; 260(5):1286-94. DOI: 10.1007/s00415-012-6792-z. View

17.

DiVincenzo C, Elzinga C, Medeiros A, Karbassi I, Jones J, Evans M . The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2015; 2(6):522-9. PMC: 4303222. DOI: 10.1002/mgg3.106. View

18.

Scalco R, Gardiner A, Pitceathly R, Hilton-Jones D, Schapira A, Turner C . CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: Expanding the phenotypic spectrum of caveolinopathies. Neuromuscul Disord. 2016; 26(8):504-10. DOI: 10.1016/j.nmd.2016.05.006. View

19.

Kaplan J . The 2012 version of the gene table of monogenic neuromuscular disorders. Neuromuscul Disord. 2012; 21(12):833-61. DOI: 10.1016/j.nmd.2011.10.008. View

20.

Haskell G, Adams M, Fan Z, Amin K, Guzman Badillo R, Zhou L . Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders. Neurol Genet. 2018; 4(1):e212. PMC: 5798313. DOI: 10.1212/NXG.0000000000000212. View