Frequent genes in rare diseases: panel‐based next generation sequencing to disclose causal mutations in hereditary neuropathies

Medientyp: E-Artikel
Titel: Frequent genes in rare diseases: panel‐based next generation sequencing to disclose causal mutations in hereditary neuropathies
Beteiligte: Dohrn, Maike F.; Glöckle, Nicola; Mulahasanovic, Lejla; Heller, Corina; Mohr, Julia; Bauer, Christine; Riesch, Erik; Becker, Andrea; Battke, Florian; Hörtnagel, Konstanze; Hornemann, Thorsten; Suriyanarayanan, Saranya; Blankenburg, Markus; Schulz, Jörg B.; Claeys, Kristl G.; Gess, Burkhard; Katona, Istvan; Ferbert, Andreas; Vittore, Debora; Grimm, Alexander; Wolking, Stefan; Schöls, Ludger; Lerche, Holger; Korenke, G. Christoph; [...]
Erschienen: Wiley, 2017
Erschienen in: Journal of Neurochemistry
Sprache: Englisch
DOI: 10.1111/jnc.14217
ISSN: 0022-3042; 1471-4159
Schlagwörter: Cellular and Molecular Neuroscience ; Biochemistry
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Beschreibung: <jats:title>Abstract</jats:title><jats:sec><jats:label /><jats:p>Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot‐Marie‐Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X‐linked inheritance. The most frequently affected genes were <jats:italic><jats:styled-content style="fixed-case">PMP</jats:styled-content>22</jats:italic> (16.4%), <jats:italic><jats:styled-content style="fixed-case">GJB</jats:styled-content>1</jats:italic> (10.7%), <jats:italic><jats:styled-content style="fixed-case">MPZ</jats:styled-content>,</jats:italic> and <jats:italic><jats:styled-content style="fixed-case">SH</jats:styled-content>3<jats:styled-content style="fixed-case">TC</jats:styled-content>2</jats:italic> (both 9.9%), and <jats:italic><jats:styled-content style="fixed-case">MFN</jats:styled-content>2</jats:italic> (8.3%). We further detected likely or known pathogenic variants in <jats:italic><jats:styled-content style="fixed-case">HINT</jats:styled-content>1, <jats:styled-content style="fixed-case">HSPB</jats:styled-content>1, <jats:styled-content style="fixed-case">NEFL</jats:styled-content>,<jats:styled-content style="fixed-case"> PRX</jats:styled-content>,<jats:styled-content style="fixed-case"> IGHMBP</jats:styled-content>2, <jats:styled-content style="fixed-case">NDRG</jats:styled-content>1, <jats:styled-content style="fixed-case">TTR</jats:styled-content></jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">EGR</jats:styled-content>2, <jats:styled-content style="fixed-case">FIG</jats:styled-content>4, <jats:styled-content style="fixed-case">GDAP</jats:styled-content>1, <jats:styled-content style="fixed-case">LMNA</jats:styled-content>,<jats:styled-content style="fixed-case"> LRSAM</jats:styled-content>1, <jats:styled-content style="fixed-case">POLG</jats:styled-content>,<jats:styled-content style="fixed-case"> TRPV</jats:styled-content>4, <jats:styled-content style="fixed-case">AARS</jats:styled-content>,<jats:styled-content style="fixed-case"> BIC</jats:styled-content>2, <jats:styled-content style="fixed-case">DHTKD</jats:styled-content>1, <jats:styled-content style="fixed-case">FGD</jats:styled-content>4, <jats:styled-content style="fixed-case">HK</jats:styled-content>1, <jats:styled-content style="fixed-case">INF</jats:styled-content>2, <jats:styled-content style="fixed-case">KIF</jats:styled-content>5A, <jats:styled-content style="fixed-case">PDK</jats:styled-content>3, <jats:styled-content style="fixed-case">REEP</jats:styled-content>1, <jats:styled-content style="fixed-case">SBF</jats:styled-content>1, <jats:styled-content style="fixed-case">SBF</jats:styled-content>2, <jats:styled-content style="fixed-case">SCN</jats:styled-content>9A,</jats:italic> and <jats:italic><jats:styled-content style="fixed-case">SPTLC</jats:styled-content>2</jats:italic> with a declining frequency. Thirty‐four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in <jats:italic><jats:styled-content style="fixed-case">HK</jats:styled-content>1</jats:italic> were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in <jats:italic><jats:styled-content style="fixed-case">KIF</jats:styled-content>5A</jats:italic> was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in <jats:italic><jats:styled-content style="fixed-case">SPTLC</jats:styled-content>2</jats:italic>. One pathogenic mutation in <jats:italic><jats:styled-content style="fixed-case">MPZ</jats:styled-content></jats:italic> was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time‐ and cost‐effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations.</jats:p></jats:sec><jats:sec><jats:label /><jats:p> <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/jnc14217-fig-0005-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text> </jats:p></jats:sec>
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