title: Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges.
abstract: Inherited peripheral neuropathies (IPN) are one of the most frequent inherited causes of neurological disability characterized by considerable phenotypic and genetic heterogeneity. Based on clinical and electrophysiological properties, they can be subdivided into three main groups: HMSN, dHMN, and HSN. At present, more than 50 IPN genes have been identified. Still, many patients and families with IPN have not yet received a molecular genetic diagnosis because clinical genetic testing usually only covers a subset of IPN genes. Moreover, a considerable proportion of IPN genes has to be identified. Here we present results of WES in 27 IPN patients excluded for mutations in many known IPN genes. Eight of the patients received a definite diagnosis. While six of these patients carried bona fide pathogenic mutations in known IPN genes, two patients had mutations in genes known to be involved in other types of neuromuscular disorders. A further group of eight patients carried sequence variations in IPN genes that could not unequivocally be classified as pathogenic. In addition, combining data of WES and linkage analysis identified SH3BP4, ITPR3, and KLHL13 as novel IPN candidate genes. Moreover, there was evidence that particular mutations in PEX12, a gene known to cause Zellweger syndrome, could also lead to an IPN phenotype. We show that WES is a useful tool for diagnosing IPN and we suggest an expanded phenotypic spectrum of some genes involved in other neuromuscular and neurodegenerative disorders. Nevertheless, interpretation of variants in known and potential novel disease genes has remained challenging.
authors.affiliation: Department of Orthopaedics, Medical University Vienna, Währingergürtel 18-20, 1090, Vienna, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Schabhüttl
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.forename: Karl
authors.initials: K
authors.lastname: Stieglbauer
authors.forename: Eva
authors.initials: E
authors.lastname: Laich
authors.forename: Reinhard
authors.initials: R
authors.lastname: Windhager
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Erwa
authors.forename: Slave
authors.initials: S
authors.lastname: Trajanoski
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases / Q000175:diagnosis* / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D016896:Treatment Outcome; D055815:Young Adult