Molecular Genetic Epidemiology of Charcot-Marie-Tooth Disease
Prosjekt
- Prosjektnummer
- 2012093
- Ansvarlig person
- Michael Bjørn Russell
- Institusjon
- Sykehuset Telemark HF
- Prosjektkategori
- Doktorgradsstipend
- Helsekategori
- Neurological
- Forskningsaktivitet
- 4. Detection and Diagnosis
Rapporter
1. Biomed Res Int. 2015;2015:960404. doi: 10.1155/2015/960404. Epub 2015 Jan 8.
Copy number variations in a population-based study of charcot-marie-tooth
disease.
Høyer H(1), Braathen GJ(1), Eek AK(2), Nordang GB(2), Skjelbred CF(2), Russell
MB(3).
Author information:
(1)Section of Medical Genetics, Department of Laboratory Medicine, Telemark
Hospital, 3710 Skien, Norway ; Head and Neck Research Group, Research Centre,
Akershus University Hospital, 1478 Lørenskog, Norway ; Campus Akershus University
Hospital, University of Oslo, 1474 Nordbyhagen, Norway. (2)Section of Medical
Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien,
Norway. (3)Head and Neck Research Group, Research Centre, Akershus University
Hospital, 1478 Lørenskog, Norway ; Campus Akershus University Hospital,
University of Oslo, 1474 Nordbyhagen, Norway.
Copy number variations (CNVs) are important in relation to diversity and
evolution but can sometimes cause disease. The most common genetic cause of the
inherited peripheral neuropathy Charcot-Marie-Tooth disease is the PMP22
duplication; otherwise, CNVs have been considered rare. We investigated CNVs in a
population-based sample of Charcot-Marie-Tooth (CMT) families. The 81 CMT
families had previously been screened for the PMP22 duplication and point
mutations in 51 peripheral neuropathy genes, and a genetic cause was identified
in 37 CMT families (46%). Index patients from the 44 CMT families with an unknown
genetic diagnosis were analysed by whole-genome array comparative genomic
hybridization to investigate the entire genome for larger CNVs and multiplex
ligation-dependent probe amplification to detect smaller intragenomic CNVs in
MFN2 and MPZ. One patient had the pathogenic PMP22 duplication not detected by
previous methods. Three patients had potentially pathogenic CNVs in the CNTNAP2,
LAMA2, or SEMA5A, that is, genes related to neuromuscular or neurodevelopmental
disease. Genotype and phenotype correlation indicated likely pathogenicity for
the LAMA2 CNV, whereas the CNTNAP2 and SEMA5A CNVs remained potentially
pathogenic. Except the PMP22 duplication, disease causing CNVs are rare but may
cause CMT in about 1% (95% CI 0-7%) of the Norwegian CMT families.
PMCID: PMC4306395
PMID: 25648254 [PubMed - in process]
2. Biomed Res Int. 2014;2014:210401. doi: 10.1155/2014/210401. Epub 2014 Jun 16.
Genetic diagnosis of Charcot-Marie-Tooth disease in a population by
next-generation sequencing.
Høyer H(1), Braathen GJ(1), Busk ØL(2), Holla ØL(2), Svendsen M(2), Hilmarsen
HT(2), Strand L(2), Skjelbred CF(2), Russell MB(3).
Author information:
(1)Section of Medical Genetics, Department of Laboratory Medicine, Telemark
Hospital, 3710 Skien, Norway ; Head and Neck Research Group, Research Centre,
Akershus University Hospital, Lørenskog, Norway ; Campus Akershus University
Hospital, University of Oslo, Nordbyhagen, Norway. (2)Section of Medical
Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien,
Norway. (3)Head and Neck Research Group, Research Centre, Akershus University
Hospital, Lørenskog, Norway ; Campus Akershus University Hospital, University of
Oslo, Nordbyhagen, Norway.
Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy.
Today more than 40 CMT genes have been identified. Diagnosing heterogeneous
diseases by conventional Sanger sequencing is time consuming and expensive. Thus,
more efficient and less costly methods are needed in clinical diagnostics. We
included a population based sample of 81?CMT families. Gene mutations had
previously been identified in 22 families; the remaining 59 families were
analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing
other inherited neuropathies were included in a custom panel. Variants were
classified into five pathogenicity classes by genotype-phenotype correlations and
bioinformatics tools. Gene mutations, classified certainly or likely pathogenic,
were identified in 37 (46%) of the 81 families. Point mutations in known CMT
genes were identified in 21 families (26%), whereas four families (5%) had point
mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven
families (14%) carried the PMP22 duplication and one family carried a MPZ
duplication (1%). Most mutations were identified not only in known CMT genes but
also in other neuropathy genes, emphasising that genetic analysis should not be
restricted to CMT genes only. Next-generation sequencing is a cost-effective tool
in diagnosis of CMT improving diagnostic precision and time efficiency.
PMCID: PMC4082881
PMID: 25025039 [PubMed - in process]
Improved Diagnostics of Charcot-Marie-Tooths Disease by improved screening tecknology
Studiematerialet er analysert for CMT gener. To papers er skrevet og submitted. Ytterligere et paper er under utarbejdelse. PhD avhandling nås innenfor den stipulerte ramme. Prosjektet er tidsmessigt forskudd fordi doktorgradssstipendiaten har hatt barselspermissjon i forbindelse med prosjektet.Charcot-Marie-Tooth disease is the most prevalent inherited neuropathy caused by mutations in >30 different genes. Diagnosing heterogeneous diseases is time consuming and expensive, thus more efficient and less costly methods are in demand.
We included a population based sample of 81 Charcot-Marie-Tooth families. Gene mutations had previously been identified in 22 families, and the remaining 59 families were analysed by next-generation sequencing. Thirty-two Charcot-Maire-Tooth genes and 20 genes causing other inherited neuropathies were included in a custom panel. The pathogenicity of the identified variants was classified into five classes by employing bioinformatic tools.
Gene mutations, classified as certainly or likely pathogenic, were identified in 48% of the families sorted by 11 Charcot-Maire-Tooth genes including a new Charcot-Marie-Tooth gene, and five other inherited neuropathy genes. The most common single gene mutation was the PMP22 duplication (14%), followed by point mutations in GJB1 (7%), MFN2 (5%), SH3TC2 (5%), LMNA (2%), SETX (2%), ARHGEF10 (1%), DNM2 (1%), DYNC1H1 (1%), HSPB1 (1%), KIF1B (1%), MPZ (1%), POLG (1%), REEP1 (1%), SOD1 (1%), new Charcot-Marie-Tooth gene (1%), and a MPZ duplication (1%).
The known Charcot-Marie-Tooth genes account for most of those affected, whereas five other neuropathy genes were important. Several new genes are to be identified in future to cause Charcot-Marie-Tooth. Due to phenotypic and genotypic heterogeneity of Charcot-Marie-Tooth genetic analyses should not be restricted to Charcot-Marie-Tooth genes only. Next-generation sequencing is a cost-effective tool in diagnosis of Charcot-Marie-Tooth improving diagnostic precision and specific management.
Ytterligere 2 papers er i preparation.
Vi har analysert DNA fra et population baseret material av CMT pasienter med next generation sequcing (NGS).Vi har analysert DNA fra et population baseret material av CMT pasienter med next generation sequcing (NGS). Dette er en relativ ny metode både Internationalt og i Norge. På trods av den nye teknologi er det lykkes at få etablert denne metode på Skien sykehus, Telemark HF. Det var noen måneder med utfordringer for at få det nye apparatur og teknikk til at lykkes. Heretter lykkes analyserne i CMT studiet veldig bra. Funnene ble kontrolert med konventionel Sanger seqvensering. Det vesentligste funn er at vi nå hurtigt kan analysere alle kjennte gener for CMT på en hurtig og effektiv måde. Foreløpig kjennes ca. 45 CMT gener og en del familier har gener som ennå ikke er identifisert.
I forbindelse med analyse af vårt materiale identifiserte vi mutasjonen i ca. halvparten av CMT familierne. Derudover fandt vi et IKKE tidlere identifisert CMT gen. Aktuelt jobber vi med sammenskrivning av to mye vesentlige artikler innenfor feltet CMT, som har implikasjoner i diagnosticering samt udvidelse av spektrum for CMT.
Hvorfor er dette viktig? Det er det fordi den patofysiologisk mekanisme er forskjellig ved forskellige gen mutasjoner. Siden der etterhånden er ved at udvikles behandling av CMT, vil behandlingsstrategien være forskellig for de forskellige gen mutasjoner, hvilket i hovedtrekkk handler om der er tale om skade på myelinet i nervefibrene (populært sagt isoleringen af nervefiberen) eller om der påvirkningen av axonet og transporten i dette.
***********************
Vitenskapelige artikler
Høyer Helle, Braathen Geir J, Busk Øyvind L, Holla Øystein L, Svendsen Marit, Hilmarsen Hilde T, Strand Linda, Skjelbred Camilla F, Russell Michael B
Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing.
Biomed Res Int 2014;2014():210401. Epub 2014 jun 16
PMID: 25025039 - Inngår i doktorgradsavhandlingen
Deltagere
- Michael Bjørn Russell Hovedveileder
- Geir Julius Braathen Biveileder
- Camilla Furu Skjelbred Biveileder
- Helle Høyer Doktorgradsstipendiat
eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT
Alle henvendelser rettes til eRapport