title: Whole exome sequencing in congenital pain insensitivity identifies a novel causative intronic NTRK1-mutation due to uniparental disomy.
abstract: Congenital insensitivity to pain and anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by recurrent episodes of unexplained high fever, loss of pain perception and temperature sensation, absent sweating, repeated traumatic and thermal injuries, and mild mental retardation. After exclusion of obviously pathogenic mutations in NTRK1, the most common cause of CIPA, whole exome sequencing (WES) was carried out in a CIPA patient with unrelated parents. No mutations in known HSAN genes were identified. However, filtering for genes carrying two rare sequence variations detected 13 homozygous single nucleotide variants (SNV), all being located on chromosome 1. Further analysis strongly suggested that this finding might be best explained by uniparental disomy of chromosome 1. Because NTRK1 is also located on chromosome 1, we re-evaluated WES data and detected a novel intronic sequence variation at position c.2188-12 C>A, homozygously because of uniparental disomy. Subsequent analysis of NTRK1 transcripts in peripheral blood cells of the patient revealed an influence of the variant on mRNA splicing. The C>A transversion generated a novel splice-site, which led to the incorporation of 10 intronic bases into the NTRK1 mRNA and consequently to a non-functional gene product. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Jena, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
authors.affiliation: Department of Neuropaediatrics, Hospital Barmherzige Schwestern Linz, Linz, Austria.
authors.forename: Manuela
authors.initials: M
authors.lastname: Baumgartner
authors.affiliation: Department of Orthopaedics, Medical University Vienna, Vienna, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Schabhüttl
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Jena, Germany.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Tomni
authors.affiliation: Department of Orthopaedics, Medical University Vienna, Vienna, Austria.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Windhager
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Institute for Human Genetics, Technical University Munich, Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Department of Paediatric Orthopedics, Orthopaedical Hospital Speising, Vienna, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Gremel
authors.affiliation: Department of Orthopaedics, Medical University Vienna, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
mesh_terms: D002648:Child; D059472:Exome / Q000235:genetics; D005260:Female; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007438:Introns / Q000235:genetics; D010146:Pain / Q000235:genetics; D000699:Pain Insensitivity, Congenital / Q000235:genetics*; D010375:Pedigree; D020917:Receptor, trkA / Q000235:genetics* / Q000378:metabolism; D024182:Uniparental Disomy / Q000235:genetics / Q000473:pathology
chemical_list: D020917:Receptor, trkA
keywords: CIPA; HSAN IV; NTRK1; uniparental disomy; whole exome sequencing