PMID- 35272499
OWN - NLM
STAT- MEDLINE
DCOM- 20220520
LR  - 20221207
IS  - 1557-9077 (Electronic)
IS  - 1050-7256 (Print)
IS  - 1050-7256 (Linking)
VI  - 32
IP  - 5
DP  - 2022 May
TI  - Whole-Exome Sequencing in Congenital Hypothyroidism Due to Thyroid Dysgenesis.
PG  - 486-495
LID - 10.1089/thy.2021.0597 [doi]
AB  - Context: Congenital hypothyroidism due to thyroid dysgenesis (CHTD) is a 
      predominantly sporadic and nonsyndromic (NS) condition of unknown etiology. 
      NS-CHTD shows a 40-fold increase in relative risk among first-degree relatives (1 
      in 100 compared with a birth prevalence of 1 in 4000 in the general population), 
      but a discordance rate between monozygotic (MZ) twins of 92%. This suggests a 
      two-hit mechanism, combining a genetic predisposition (incomplete penetrance of 
      inherited variants) with postzygotic events (accounting for MZ twin discordance). 
      Objective: To evaluate whether whole-exome sequencing (WES) allows to identify 
      new predisposing genes in NS-CHTD. Methods: We performed a case-control study by 
      comparing the whole exome of 36 nonconsanguineous cases of NS-CHTD (33 with 
      lingual thyroid ectopy and 3 with athyreosis, based on technetium pertechnetate 
      scintigraphy at diagnosis) with that of 301 unaffected controls to assess for 
      enrichment in rare protein-altering variants. We performed an unbiased approach 
      using a gene-based burden with a false discovery rate correction. Moreover, we 
      identified all rare pathogenic and likely pathogenic variants, based on in silico 
      prediction tools, in 27 genes previously associated with congenital 
      hypothyroidism (CH) (thyroid dysgenesis [TD] and dyshormonogenesis). Results: 
      After correction for multiple testing, no enrichment in rare protein-altering 
      variants was observed in NS-CHTD. Pathogenic or likely pathogenic variants (21 
      variants in 12 CH genes) were identified in 42% of cases. Eight percent of cases 
      had variants in more than one gene (oligogenic group); these were not more 
      severely affected than monogenic cases. Moreover, cases with protein-altering 
      variants in dyshormonogenesis-related genes were not more severely affected than 
      those without. Conclusions: No new predisposing genes were identified following 
      an unbiased analysis of WES data in a well-characterized NS-CHTD cohort. 
      Nonetheless, the discovery rate of rare pathogenic or likely pathogenic variants 
      was 42%. Eight percent of the cases harbored multiple variants in genes 
      associated with TD or dyshormonogenesis, but these variants did not explain the 
      variability of hypothyroidism observed in dysgenesis. WES did not identify a 
      genetic cause in NS-CHTD cases, confirming the complex etiology of this disease. 
      Additional studies in larger cohorts and/or novel discovery approaches are 
      required.
FAU - Larrivee-Vanier, Stephanie
AU  - Larrivee-Vanier S
AD  - Research Center of Centre Hospitalier Universitaire Sainte-Justine, Universite de 
      Montreal, Montreal, Canada.
AD  - Department of Biochemistry, Universite de Montreal, Montreal, Canada.
FAU - Jean-Louis, Martineau
AU  - Jean-Louis M
AD  - Research Center of Centre Hospitalier Universitaire Sainte-Justine, Universite de 
      Montreal, Montreal, Canada.
FAU - Magne, Fabien
AU  - Magne F
AD  - Research Center of Centre Hospitalier Universitaire Sainte-Justine, Universite de 
      Montreal, Montreal, Canada.
FAU - Bui, Helen
AU  - Bui H
AD  - Department of Endocrinology, McGill University Health Center, Montreal, Canada.
FAU - Rouleau, Guy A
AU  - Rouleau GA
AD  - Montreal Neurological Institute, McGill University, Montreal, Canada.
FAU - Spiegelman, Dan
AU  - Spiegelman D
AD  - Montreal Neurological Institute, McGill University, Montreal, Canada.
FAU - Samuels, Mark E
AU  - Samuels ME
AD  - Research Center of Centre Hospitalier Universitaire Sainte-Justine, Universite de 
      Montreal, Montreal, Canada.
AD  - Department of Medicine, Universite de Montreal, Montreal, Canada.
FAU - Kibar, Zoha
AU  - Kibar Z
AD  - Research Center of Centre Hospitalier Universitaire Sainte-Justine, Universite de 
      Montreal, Montreal, Canada.
AD  - Department of Neurosciences, Universite de Montreal, Montreal, Canada.
FAU - Van Vliet, Guy
AU  - Van Vliet G
AD  - Research Center of Centre Hospitalier Universitaire Sainte-Justine, Universite de 
      Montreal, Montreal, Canada.
AD  - Department of Pediatrics, Universite de Montreal, Montreal, Canada.
FAU - Deladoey, Johnny
AU  - Deladoey J
AUID- ORCID: 0000-0002-2060-1730
AD  - Research Center of Centre Hospitalier Universitaire Sainte-Justine, Universite de 
      Montreal, Montreal, Canada.
AD  - Department of Pediatrics, Universite de Montreal, Montreal, Canada.
AD  - Pediatric Institute of Southern Switzerland, Bellinzona, Switzerland.
AD  - Faculty of Biomedical Sciences, University of Southern Switzerland, Lugano, 
      Switzerland.
LA  - eng
GR  - CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220425
PL  - United States
TA  - Thyroid
JT  - Thyroid : official journal of the American Thyroid Association
JID - 9104317
SB  - IM
MH  - Case-Control Studies
MH  - *Congenital Hypothyroidism/genetics/pathology
MH  - Exome
MH  - Humans
MH  - Mutation
MH  - *Thyroid Dysgenesis/complications/genetics
MH  - Exome Sequencing
PMC - PMC9145262
OTO - NOTNLM
OT  - athyreosis
OT  - birth defects
OT  - nonsyndromic congenital hypothyroidism
OT  - thyroid dysgenesis
OT  - thyroid ectopy
COIS- No competing financial interests exist.
EDAT- 2022/03/12 06:00
MHDA- 2022/05/21 06:00
PMCR- 2022/05/17
CRDT- 2022/03/11 05:31
PHST- 2022/03/12 06:00 [pubmed]
PHST- 2022/05/21 06:00 [medline]
PHST- 2022/03/11 05:31 [entrez]
PHST- 2022/05/17 00:00 [pmc-release]
AID - 10.1089/thy.2021.0597 [pii]
AID - 10.1089/thy.2021.0597 [doi]
PST - ppublish
SO  - Thyroid. 2022 May;32(5):486-495. doi: 10.1089/thy.2021.0597. Epub 2022 Apr 25.