title: Iodotyrosine deiodinase defect identified via genome-wide approach.
abstract: BACKGROUND
  Diagnosis of congenital hypothyroidism is hampered by the heterogeneity of inborn errors of thyroid metabolism and the possible delay in hypothyroidism development leading to missed cases by neonatal screen.
  
  
  OBJECTIVE
  In the current study, we used a whole-genome approach to identify the mutation responsible for severe hypothyroidism and a huge goiter in the eldest child born to healthy first cousins.
  
  
  RESULTS
  We identified a homozygous mutation of the iodotyrosine deiodinase gene (IYD). We delineated the phenotype of this defect in detail, including urinary monoiodotyrosine (MIT) and diiodotyrosine (DIT) excretion. Moreover, a 4.5-yr-old sister was found homozygous for the mutation. Her clinical and biological data were normal, except for elevated MIT and DIT excretion. The urinary loss of MIT and DIT iodine observed in most affected individuals was quite limited compared to the total iodine loss, except for the hypothyroid homozygote. Hypothyroidism could therefore be partially induced by a relative iodine deficiency caused by urinary iodine loss through MIT and DIT excretion, even in cases of normal iodine intake. The wide inter- and intrafamilial variability of the disease severity remains unclear.
  
  
  CONCLUSIONS
  Besides refining the phenotype of the IYD defect, our observation shows that a global, genome-wide approach to the heterogeneous inborn thyroid defects was efficient in rapidly identifying the mutation in the proband and the disease recurrence in the still euthyroid sister. Although facilitated by consanguinity in this family, novel sequencing techniques will soon make whole-genome approaches readily amenable to more common cases.
authors.affiliation: Department of Endocrinology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium. aburniat@ulb.ac.be
authors.forename: Agnès
authors.initials: A
authors.lastname: Burniat
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pirson
authors.forename: Catheline
authors.initials: C
authors.lastname: Vilain
authors.forename: Willem
authors.initials: W
authors.lastname: Kulik
authors.forename: Gijs
authors.initials: G
authors.lastname: Afink
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Moreno-Reyes
authors.forename: Bernard
authors.initials: B
authors.lastname: Corvilain
authors.forename: Marc
authors.initials: M
authors.lastname: Abramowicz
mesh_terms: D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D015894:Genome, Human; D006042:Goiter / Q000175:diagnosis / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007037:Hypothyroidism / Q000175:diagnosis / Q000235:genetics; D007453:Iodide Peroxidase / Q000032:analysis / Q000235:genetics*; D008297:Male; D010375:Pedigree; D017354:Point Mutation / Q000502:physiology; D035781:Siblings; D055815:Young Adult
chemical_list: D007453:Iodide Peroxidase