Severe Congenital Hypothyroidism Due to a Novel Deep Intronic Mutation in the TSH Receptor Gene Causing Intron Retention

Larrivée-Vanier, Stéphanie; Magne, Fabien; Hamdoun, Elwaseila; Petryk, Anna; Kibar, Zoha; Vliet, Guy Van; Deladoëy, Johnny

doi:10.1210/jendso/bvaa183

Cited by 4 publications

(1 citation statement)

References 5 publications

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“…One study, in a Saudi Arabian cohort, identified causative variants in 44% (11/25) of the cases with TD ( 40 ). However, in that study, when cases with TSHR variants, a gene associated with hypoplasia or apparent athyreosis but neither with ectopy nor with true athyreosis ( 41 , 42 ), were excluded, the discovery rate drops to 16%. Two other studies used targeted NGS to identify variants in CH-related genes in cases with CHTD ( 38 , 43 ).…”

Section: Discussionmentioning

confidence: 94%

Whole-Exome Sequencing in Congenital Hypothyroidism Due to Thyroid Dysgenesis

Larrivée-Vanier

Jean‐Louis

Magne

et al. 2022

Thyroid

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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.

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Section: Discussionmentioning

confidence: 94%

Whole-Exome Sequencing in Congenital Hypothyroidism Due to Thyroid Dysgenesis

Larrivée-Vanier

Jean‐Louis

Magne

et al. 2022

Thyroid

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G protein-coupled receptor (GPCR) gene variants and human genetic disease

Thompson,

Percy,

Cole

et al. 2024

Critical Reviews in Clinical Laboratory Sciences

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Severe Aldosterone Synthase Deficiency in a 9-Day-Old Lebanese Boy: The Importance of Functional Studies to Establish Pathogenicity of Seemingly Benign Variants in <i>CYP11B2</i>

Ghaddhab,

Capper,

Larrivée-Vanier

et al. 2024

Horm Res Paediatr

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Introduction Aldosterone synthase deficiency is a rare autosomal recessive disease characterized by vomiting, dehydration, salt wasting, life-threatening hyperkalemia in infancy, followed by failure to thrive. It results from pathogenic variants in CYP11B2. Case Presentation A boy, born in Montreal to Lebanese parents who are first cousins, was referred at nine days of life for severe dehydration. A diagnosis of primary adrenal insufficiency was made, and treatment was started with fludrocortisone and hydrocortisone. Exome sequencing revealed a homozygous variant p.(Asn201Asp)(N201D). In silico, this variant was considered benign, but in vitro functional expression studies established it caused the severe aldosterone deficiency. It ended the diagnostic odyssey and allowed to safely stop hydrocortisone replacement. Conclusion If a gene variant co-segregates with a phenotype, in vitro functional studies are required even if in silico studies are negative

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Severe Congenital Hypothyroidism Due to a Novel Deep Intronic Mutation in the TSH Receptor Gene Causing Intron Retention

Cited by 4 publications

References 5 publications

Whole-Exome Sequencing in Congenital Hypothyroidism Due to Thyroid Dysgenesis

Whole-Exome Sequencing in Congenital Hypothyroidism Due to Thyroid Dysgenesis

G protein-coupled receptor (GPCR) gene variants and human genetic disease

Severe Aldosterone Synthase Deficiency in a 9-Day-Old Lebanese Boy: The Importance of Functional Studies to Establish Pathogenicity of Seemingly Benign Variants in <i>CYP11B2</i>

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