title: A Homozygous Nonsense Thyroid Peroxidase Mutation (R540X) Consistently Causes Congenital Hypothyroidism in Two Siblings Born to a Consanguineous Family.
abstract: OBJECTIVE
  Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, and mutations in the thyroid peroxidase (TPO) gene have been reported to cause the disease. Our aim in this study was to determine the genetic basis of CH in two affected children coming from a consanguineous family.
  
  
  METHODS
  First, we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in the linked gene by Sanger sequencing. By using next-generation sequencing, we also checked if any other mutation was present in the remaining 10 causative CH genes.
  
  
  RESULTS
  The family showed potential linkage to the TPO gene, and we detected a homozygous nonsense mutation (R540X) in both cases. The two patients had total iodide organification defect (TIOD). Both the microsatellite marker haplotypes and the mutation segregated with the disease status in the family, i.e. all healthy subjects were either heterozygous carriers or homozygous wild-type, confirming the pathogenic nature of the mutation. Neither was the mutation present in any of the 400 control chromosomes nor were there any other mutations in the remaining causative CH genes.
  
  
  CONCLUSIONS
  This study proves the pathogenicity of R540X mutation and demonstrates the strong genotype/phenotype correlation associated with this mutation. It also highlights the power of working with familial cases in revealing the molecular basis of CH and in establishing accurate genotype/phenotype relationships associated with disease causing mutations.
authors.affiliation: Medipol University International Faculty of Medicine, Department of Medical Genetics, İstanbul, Turkey Phone: +90 216 681 51 00 E-mail: hcangul@medipol.edu.tr.
authors.forename: Hakan
authors.initials: H
authors.lastname: Cangül
authors.forename: Murat
authors.initials: M
authors.lastname: Doğan
authors.forename: Duran
authors.initials: D
authors.lastname: Üstek
mesh_terms: D001324:Autoantigens / Q000235:genetics*; D002648:Child; D018389:Codon, Nonsense; D003409:Congenital Hypothyroidism / Q000235:genetics* / Q000503:physiopathology*; D003241:Consanguinity; D005260:Female; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics*; D033862:Iron-Binding Proteins / Q000235:genetics*; D008297:Male; D010375:Pedigree; D035781:Siblings; D014421:Turkey
chemical_list: D001324:Autoantigens; D018389:Codon, Nonsense; D033862:Iron-Binding Proteins; C056658:TPO protein, human; D007453:Iodide Peroxidase