title: Detection of Novel Gene Variants Associated with Congenital Hypothyroidism in a Finnish Patient Cohort.
abstract: Congenital hypothyroidism (CH) is defined as the lack of thyroid hormones at birth. Mutations in at least 15 different genes have been associated with this disease. While up to 20% of CH cases are hereditary, the majority of cases are sporadic with unknown etiology. Apart from a monogenic pattern of inheritance, multigenic mechanisms have been suggested to play a role in CH. The genetics of CH has not been studied in Finland so far. Therefore, multigenic sequencing of CH candidate genes was performed in a Finnish patient cohort with both familial and sporadic CH.
  
  
  
  A targeted next-generation sequencing (NGS) panel, covering all exons of the major CH genes, was applied for 15 patients with sporadic and 11 index cases with familial CH.
  
  
  
  Among the familial cases, six pathogenic mutations were found in the TPO, PAX8, and TSHR genes. Furthermore, pathogenic NKX2.1 and TG mutations were identified from sporadic cases, together with likely pathogenic variants in the TG, NKX2.5, SLC26A4, and DUOX2 genes. All identified novel pathogenic mutations were confirmed by Sanger-sequencing and characterized in silico and/or in vitro.
  
  
  
  In summary, the CH panel provides an efficient, cost-effective, and multigenic screening tool for both known and novel CH gene mutations. Hence, it may be a useful method to identify accurately the genetic etiology for dyshormogenic, familial, or syndromic forms of CH.
authors.affiliation: 1 Department of Physiology, Institute of Biomedicine, University of Turku , Turku, Finland .
authors.forename: Christoffer
authors.initials: C
authors.lastname: Löf
authors.affiliation: 1 Department of Physiology, Institute of Biomedicine, University of Turku , Turku, Finland .
authors.forename: Konrad
authors.initials: K
authors.lastname: Patyra
authors.affiliation: 2 Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland , Kuopio, Finland .
authors.forename: Teemu
authors.initials: T
authors.lastname: Kuulasmaa
authors.affiliation: 2 Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland , Kuopio, Finland .
authors.forename: Jagadish
authors.initials: J
authors.lastname: Vangipurapu
authors.affiliation: 1 Department of Physiology, Institute of Biomedicine, University of Turku , Turku, Finland .
authors.forename: Henriette
authors.initials: H
authors.lastname: Undeutsch
authors.affiliation: 1 Department of Physiology, Institute of Biomedicine, University of Turku , Turku, Finland .
authors.forename: Holger
authors.initials: H
authors.lastname: Jaeschke
authors.affiliation: 1 Department of Physiology, Institute of Biomedicine, University of Turku , Turku, Finland .
authors.forename: Tuulia
authors.initials: T
authors.lastname: Pajunen
authors.affiliation: 1 Department of Physiology, Institute of Biomedicine, University of Turku , Turku, Finland .
authors.forename: Andreina
authors.initials: A
authors.lastname: Kero
authors.affiliation: 3 Institute of Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin , Berlin, Germany .
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.affiliation: 3 Institute of Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin , Berlin, Germany .
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.affiliation: 3 Institute of Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin , Berlin, Germany .
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
authors.affiliation: 3 Institute of Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin , Berlin, Germany .
authors.forename: Peter
authors.initials: P
authors.lastname: Kühnen
authors.affiliation: 4 Hospital for Children and Adolescents, Hospital District of Helsinki and Uusimaa , Helsinki, Finland .
authors.forename: Krista
authors.initials: K
authors.lastname: Rantakari
authors.affiliation: 4 Hospital for Children and Adolescents, Hospital District of Helsinki and Uusimaa , Helsinki, Finland .
authors.forename: Päivi
authors.initials: P
authors.lastname: Miettinen
authors.affiliation: 4 Hospital for Children and Adolescents, Hospital District of Helsinki and Uusimaa , Helsinki, Finland .
authors.forename: Turkka
authors.initials: T
authors.lastname: Kirjavainen
authors.affiliation: 5 Turku Clinical Sequencing Laboratory, Institute of Biomedicine, University of Turku , Turku, Finland .
authors.forename: Juha-Pekka
authors.initials: JP
authors.lastname: Pursiheimo
authors.affiliation: 6 Department of Pediatrics, Seinäjoki Central Hospital , Seinäjoki, Finland .
authors.forename: Taina
authors.initials: T
authors.lastname: Mustila
authors.affiliation: 6 Department of Pediatrics, Seinäjoki Central Hospital , Seinäjoki, Finland .
authors.forename: Jarmo
authors.initials: J
authors.lastname: Jääskeläinen
authors.affiliation: 7 Department of Children and Adolescents, Oulu University Hospital , Oulu, Finland .
authors.forename: Marja
authors.initials: M
authors.lastname: Ojaniemi
authors.affiliation: 1 Department of Physiology, Institute of Biomedicine, University of Turku , Turku, Finland .|8 Department of Pediatrics, Turku University Hospital , Turku, Finland .
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: 9 Department of Clinical Genetics, Turku University Hospital , Turku, Finland .
authors.forename: Jaakko
authors.initials: J
authors.lastname: Ignatius
authors.affiliation: 2 Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland , Kuopio, Finland .
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: 1 Department of Physiology, Institute of Biomedicine, University of Turku , Turku, Finland .|8 Department of Pediatrics, Turku University Hospital , Turku, Finland .
authors.forename: Jukka
authors.initials: J
authors.lastname: Kero
mesh_terms: D001324:Autoantigens / Q000235:genetics*; D015331:Cohort Studies; D003409:Congenital Hypothyroidism / Q000235:genetics*; D005260:Female; D005387:Finland; D005820:Genetic Testing; D006801:Humans; D007231:Infant, Newborn; D007453:Iodide Peroxidase / Q000235:genetics*; D033862:Iron-Binding Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D000072636:PAX8 Transcription Factor / Q000235:genetics*; D010375:Pedigree; D011989:Receptors, Thyrotropin / Q000235:genetics*
chemical_list: D001324:Autoantigens; D033862:Iron-Binding Proteins; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D011989:Receptors, Thyrotropin; C056658:TPO protein, human; D007453:Iodide Peroxidase