Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2016

Open Access 01-12-2016 | Research

Improving diagnosis of inherited peripheral neuropathies through gene panel analysis

Authors: Petra Laššuthová, Dana Šafka Brožková, Marcela Krůtová, Jana Neupauerová, Jana Haberlová, Radim Mazanec, Pavel Dřímal, Pavel Seeman

Published in: Orphanet Journal of Rare Diseases | Issue 1/2016

Login to get access

Abstract

Background

Inherited peripheral neuropathies (IPN) are the most common inherited neurological condition. It represents a highly heterogeneous group, both clinically and genetically.
Targeted disease specific gene panel massively parallel sequencing (MPS) seems to be a useful tool in diagnosis of disorders with high genetic heterogeneity.

Methods

In our study, we have designed, validated and updated our own custom gene panel of all known genes associated with IPN. One hundred and ninety-eight patients have been tested so far. Only patients in whom mutations in more common causes or relevant genes have already been excluded were enrolled. Five consecutive panel designs were prepared according to recent literature search, the last one covering ninety-three genes. Each patient was tested only once. All data were evaluated with at least two different pipelines.

Results

In summary, causative mutation has been found in fifty-one patients (26 %). The results were inconclusive in thirty-one (16 %) patients. No variants of likely significance to IPN were found in one hundred and sixteen (58 %) patients.

Conclusion

MPS gene panel enables testing of all known IPN causes at once with high coverage and at an affordable cost making it truly a method of choice also in IPN. Gene panel testing results in several interesting results and findings.
Appendix
Available only for authorised users
Literature
1.
Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth's disease. Clin Genet. 1974;6:98–118.CrossRefPubMed
2.
3.
Murphy SM, Laura M, Reilly MM. DNA testing in hereditary neuropathies. Handb Clin Neurol. 2013;115:213–32.CrossRefPubMed
4.
Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014;133:1–9.CrossRefPubMed
5.
Schabhuttl M, Wieland T, Senderek J, Baets J, Timmerman V, De Jonghe P, Reilly MM, Stieglbauer K, Laich E, Windhager R, et al. Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges. J Neurol. 2014;261:970–82.CrossRefPubMed
6.
Haberlova J, Claeys KG, De Jonghe P, Seeman P. Cranial nerves palsy as an initial feature of an early onset distal hereditary motor neuropathy--a new distal hereditary motor neuropathy phenotype. Neuromuscul Disord. 2009;19:427–8.CrossRefPubMed
7.
8.
9.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.CrossRefPubMedPubMedCentral
10.
11.
Latour P, Thauvin-Robinet C, Baudelet-Mery C, Soichot P, Cusin V, Faivre L, Locatelli MC, Mayencon M, Sarcey A, Broussolle E, et al. A major determinant for binding and aminoacylation of tRNA(Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet. 2010;86:77–82.CrossRefPubMedPubMedCentral
12.
Lassuthova P, Brozkova DS, Krutova M, Neupauerova J, Haberlova J, Mazanec R, Dvorackova N, Goldenberg Z, Seeman P. Mutations in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom. Neurogenetics. 2015;16:43–54.CrossRefPubMed
13.
Brozkova DS, Posadka J, Lassuthova P, Mazanec R, Haberlova J, Siskova D, Sakmaryova I, Neupauerova J, Seeman P. Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients. Mol Med Rep. 2013. doi:10.​3892/​mmr.​2013.​1730.PubMed
14.
Lassuthova P, Mazanec R, Vondracek P, Siskova D, Haberlova J, Sabova J, Seeman P. High frequency of SH3TC2 mutations in Czech HMSN I patients. Clin Genet. 2011;80:334–45.CrossRefPubMed
15.
Irobi J, Van den Bergh P, Merlini L, Verellen C, Van Maldergem L, Dierick I, Verpoorten N, Jordanova A, Windpassinger C, De Vriendt E, et al. The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. Brain. 2004;127:2124–30.CrossRefPubMed
16.
Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Horl G, Malli R, Reed JA, Dierick I, Verpoorten N, et al. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet. 2004;36:271–6.CrossRefPubMed
17.
Punetha J, Monges S, Franchi ME, Hoffman EP, Cirak S, Tesi-Rocha C. Exome Sequencing Identifies DYNC1H1 Variant Associated With Vertebral Abnormality and Spinal Muscular Atrophy With Lower Extremity Predominance. Pediatr Neurol. 2015;52:239–44.CrossRefPubMed
18.
Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, de Jonge R, Blechschmidt K, Angelicheva D, Chandler D, Worsley P, et al. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet. 2000;67:47–58.CrossRefPubMedPubMedCentral
19.
Hewamadduma C, McDermott C, Kirby J, Grierson A, Panayi M, Dalton A, Rajabally Y, Shaw P. New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP). Neurogenetics. 2009;10:105–10.CrossRefPubMed
20.
Hoyer H, Braathen GJ, Busk OL, Holla OL, Svendsen M, Hilmarsen HT, Strand L, Skjelbred CF, Russell MB. Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing. Biomed Res Int. 2014;2014:210401.CrossRefPubMedPubMedCentral
21.
Lupo V, Garcia-Garcia F, Sancho P, Tello C, Garcia-Romero M, Villarreal L, Alberti A, Sivera R, Dopazo J, Pascual-Pascual SI, et al. Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy. J Mol Diagn. 2016;18(2):225–34.
22.
Fridman V, Bundy B, Reilly MM, Pareyson D, Bacon C, Burns J, Day J, Feely S, Finkel RS, Grider T, et al. CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis. J Neurol Neurosurg Psychiatry. 2015;86:873–8.CrossRefPubMed
23.
Gonzaga-Jauregui C, Zhang F, Towne CF, Batish SD, Lupski JR. GJB1/Connexin 32 whole gene deletions in patients with X-linked Charcot-Marie-Tooth disease. Neurogenetics. 2010;11:465–70.CrossRefPubMedPubMedCentral
24.
Rudnik-Schoneborn S, Arning L, Epplen JT, Zerres K. SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy. Neuromuscul Disord. 2012;22:258–62.CrossRefPubMed
25.
26.
DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:491–8.CrossRefPubMedPubMedCentral
27.
28.
29.
Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics. 2011;27:2987–93.CrossRefPubMedPubMedCentral
30.
Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv. 2013;1303:3997.
31.
Garrison E, Marth G. Haplotype-based variant detection from short-read sequencing. axXiv. 2012;1207:3907.
32.
Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, et al. Mutant dynactin in motor neuron disease. Nat Genet. 2003;33:455–6.CrossRefPubMed
33.
Soong BW, Huang YH, Tsai PC, Huang CC, Pan HC, Lu YC, Chien HJ, Liu TT, Chang MH, Lin KP, et al. Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease. Am J Hum Genet. 2013;92:422–30.CrossRefPubMedPubMedCentral
Metadata
Title
Improving diagnosis of inherited peripheral neuropathies through gene panel analysis
Authors
Petra Laššuthová
Dana Šafka Brožková
Marcela Krůtová
Jana Neupauerová
Jana Haberlová
Radim Mazanec
Pavel Dřímal
Pavel Seeman
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2016
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-016-0500-5

Other articles of this Issue 1/2016

Orphanet Journal of Rare Diseases 1/2016 Go to the issue

Research

Health survey of adults with hereditary spastic paraparesis compared to population study controls

Research

Systematic reviews in paediatric multiple sclerosis and Creutzfeldt-Jakob disease exemplify shortcomings in methods used to evaluate therapies in rare conditions

Research

Potential impact of the implementation of multiple-criteria decision analysis (MCDA) on the Polish pricing and reimbursement process of orphan drugs

Research

GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females

Research

Experiences of caregivers of children with inherited metabolic diseases: a qualitative study

Research

The rare and undiagnosed diseases diagnostic service – application of massively parallel sequencing in a state-wide clinical service