Further Evidence that Defects in mMain Thyroid Dysgenesis-Related Genes are an Uncommon Etiology for Primary Congenital Hypothyroidism in Mexican Patients: Report of Rare Variants in FOXE1, NKX2-5 and TSHR

Mexico shows a high birth prevalence of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD). PAX8 defects underlie only 1% of these cases and NKX2-1 does not seem to be involved. Here, we analyzed other TD-related genes in 128 non-related Mexican patients (females 77.3%; 6 months to 16.6 years) with non-syndromic CH-TD diagnosis established by clinical evaluation, thyroid hormone serum profiling, and scintigraphy (74%) or ultrasonography (26%). We performed Sanger sequencing of FOXE1, NKX2-5, and TSHR and evaluated copy number variations (CNVs) in TSHR, FOXE1, PAX8, and NKX2-1 by multiplex ligation-dependent probe amplification. Odds ratios for TD risk were explored for FOXE1 polyalanine stretches [polyAla-rs71369530] in cases and controls (N=116). Five rare missense changes cataloged as benign (NKX2-5:p.(Ala119Ser)-rs137852684), of unknown significance (FOXE1:p.(Ala335Gly)-rs543372757; TSHR:p.(Asp118Asn)-rs1414102266), and likely pathogenic (FOXE1:p.(Gly124Arg)-rs774035532; TSHR:p.(Trp422Arg)-rs746029360) accounted for 1.5% (N=2/128) of clinically relevant genotypes (supported in part by protein modeling) in CH-TD. No CNVs were identified, nor did polyAla &gt;14 alanines in FOXE1 significantly protect against TD. The present and previously published data collectively show that small clinically relevant germline variants in PAX8, FOXE1, and TSHR are found in only a very small proportion (2.5%) of isolated CH-TD Mexican patients.

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Further Evidence That Defects in Main Thyroid Dysgenesis-Related Genes Are an Uncommon Etiology for Primary Congenital Hypothyroidism in Mexican Patients: Report of Rare Variants in FOXE1, NKX2-5 and TSHR

Children ◽

10.3390/children8060457 ◽

2021 ◽

Vol 8 (6) ◽

pp. 457

Author(s):

Miguel Angel Alcántara-Ortigoza ◽

Iraís Sánchez-Verdiguel ◽

Liliana Fernández-Hernández ◽

Sergio Enríquez-Flores ◽

Aidy González-Núñez ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Rare Variants ◽

Copy Number Variations ◽

Published Data ◽

Birth Prevalence ◽

Thyroid Dysgenesis ◽

Serum Profiling ◽

Unknown Significance ◽

Dependent Probe ◽

Mexican Patients

Mexico shows a high birth prevalence of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD). PAX8 defects underlie only 1% of these cases and NKX2-1 does not seem to be involved. Here, we analyzed other TD-related genes in 128 non-related Mexican patients (females 77.3%; 6 months to 16.6 years) with non-syndromic CH-TD diagnosis established by clinical evaluation, thyroid hormone serum profiling, and scintigraphy (74%) or ultrasonography (26%). We performed Sanger sequencing of FOXE1, NKX2-5, and TSHR and evaluated copy number variations (CNVs) in TSHR, FOXE1, PAX8, and NKX2-1 by multiplex ligation-dependent probe amplification. Odds ratios for TD risk were explored for FOXE1 polyalanine stretches [polyAla-rs71369530] in cases and controls (N = 116). Five rare missense changes cataloged as benign (NKX2-5:p.(Ala119Ser)-rs137852684), of unknown significance (FOXE1:p.(Ala335Gly)-rs543372757; TSHR:p.(Asp118Asn)-rs1414102266), and likely pathogenic (FOXE1:p.(Gly124Arg)-rs774035532; TSHR:p.(Trp422Arg)-rs746029360) accounted for 1.5% (N = 2/128) of clinically relevant genotypes (supported in part by protein modeling) in CH-TD. No CNVs were identified, nor did polyAla > 14 alanines in FOXE1 significantly protect against TD. The present and previously published data collectively show that small clinically relevant germline variants in PAX8, FOXE1, and TSHR are found in only a very small proportion (2.5%) of isolated CH-TD Mexican patients.

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Identification of deletions in children with congenital hypothyroidism and thyroid dysgenesis with the use of multiplex ligation-dependent probe amplification

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2014-0040 ◽

2015 ◽

Vol 28 (1-2) ◽

Cited By ~ 1

Author(s):

Malgorzata Kumorowicz-Czoch ◽

Anna Madetko-Talowska ◽

Dorota Tylek-Lemanska ◽

Jacek J. Pietrzyk ◽

Jerzy Starzyk

Keyword(s):

Congenital Hypothyroidism ◽

Copy Number ◽

Genetic Factors ◽

Heterozygous Deletion ◽

Thyroid Dysgenesis ◽

Changes Detection ◽

Probe Hybridization ◽

Copy Number Changes ◽

Encoding Genes ◽

Dependent Probe

AbstractThyroid dysgenesis (TD) is the most common cause of congenital hypothyroidism (CH). Important genetic factors possibly contributing to TD etiologies include mutations of thyroid transcription factors and TSHR-encoding genes.Our objective was to determine multiplex ligation-dependent probe amplification (MLPA) utility in detecting the copy number changes in patients with CH and TD.: The study included 45 children from southeastern Poland selected via already established neonatal screening for CH. Genomic DNA was extracted from peripheral blood samples and used in MLPA analysis. Genetic variations were analyzed within selected fragments of theThree heterozygous deletion types in probe hybridization regions were identified for the following genes:MLPA is a useful tool for copy number changes detection and might both improve and expand genetic analysis for CH and TD.

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Faculty Opinions recommendation of Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.724098926.793503202 ◽

2015 ◽

Author(s):

Guy Van Vliet

Keyword(s):

Congenital Hypothyroidism ◽

Genetic Factors ◽

Thyroid Dysgenesis ◽

Familial Cases

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The mutation screening in candidate genes related to thyroid dysgenesis by targeted next‐generation sequencing panel in the Chinese congenital hypothyroidism

Clinical Endocrinology ◽

10.1111/cen.14577 ◽

2021 ◽

Author(s):

Rui‐Jia Zhang ◽

Guang‐lin Yang ◽

Feng Cheng ◽

Feng Sun ◽

Ya Fang ◽

...

Keyword(s):

Next Generation Sequencing ◽

Candidate Genes ◽

Congenital Hypothyroidism ◽

Mutation Screening ◽

Next Generation ◽

Thyroid Dysgenesis ◽

Targeted Next Generation Sequencing ◽

Generation Sequencing

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Two novel mutations in Gli-similar 3 in patients with congenital hypothyroidism and thyroid dysgenesis

10.21203/rs.3.rs-425460/v1 ◽

2021 ◽

Author(s):

Jie Lan ◽

Chunhui Sun ◽

Xinping Liang ◽

Ruixin Ma ◽

Yuhua Ji ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Transcriptional Activation ◽

Luciferase Assay ◽

Expression Vectors ◽

Luciferase Reporter ◽

Dominant Negative Effect ◽

Wild Type ◽

Thyroid Dysgenesis ◽

Type Protein ◽

Wild Type Protein

Abstract Background: Thyroid dysgenesis (TD) is the main cause of congenital hypothyroidism (CH). As variants of the transcription factor Gli-similar 3 (GLIS3) have been associated with CH and GLIS3 is one of candidate genes of TD, we screened and characterized GLIS3 mutations in Chinese patients with CH and TD.Methods: To detect mutations, we sequenced all GLIS3 exons in the peripheral blood genomic DNA isolated from 50 patients with TD and 100 healthy individuals. Wild-type and mutant expression vectors of Glis3 were constructed. Quantitative real-time PCR, western blotting, and double luciferase assay were performed to investigation the effect of the mutations on GLIS3 protein function and transcriptional activation.Results: Two novel heterozygous missense mutations, c.2710G>A (p.G904R) and c.2507C>A (p.P836Q), were detected in two unrelated patients. Functional studies revealed that p.G904R expression was 59.95% lower and p.P836Q was 31.23% lower than wild-type GLIS3 mRNA expression. The p.G904R mutation also resulted in lower GLIS3 protein expression compared with that encoded by wild-type GLIS3. Additionally, the luciferase reporter assay revealed that p.G904R mediated impaired transcriptional activation compared with the wild-type protein (p < 0.05) but did not have a dominant-negative effect on the wild-type protein.Conclusions: We for the first time screened and characterized the function of GLIS3 mutations in Chinese individuals with CH and TD. Our study not only broadens the GLIS3 mutation spectrum, but also provides further evidence that GLIS3 defects cause TD.

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Abstract #1004316: Thyroid Dysgenesis and Congenital Hypothyroidism: A Case Study and Literature Review

Endocrine Practice ◽

10.1016/j.eprac.2021.04.852 ◽

2021 ◽

Vol 27 (6) ◽

pp. S181

Author(s):

Zara Z. Alvi ◽

Hassan Mehmood ◽

Farhad Hasan

Keyword(s):

Literature Review ◽

Congenital Hypothyroidism ◽

Thyroid Dysgenesis

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Incidence of congenital hypothyroidism in the city of Uberaba/Minas Gerais and etiological evaluation of the affected subjects

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302012000500005 ◽

2012 ◽

Vol 56 (5) ◽

pp. 305-312 ◽

Cited By ~ 3

Author(s):

Heloísa Marcelina da Cunha Palhares ◽

Lilian Carla Silva ◽

Luciene Mayumi Sato ◽

Beatriz Hallal Jorge Lara ◽

Sybele de Souza Castro Miranzi ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Screening Program ◽

Minas Gerais ◽

The State ◽

Thyroid Dysgenesis ◽

Outpatient Unit ◽

Transient Hypothyroidism ◽

Molecular Studies ◽

Definition Of ◽

The City

OBJECTIVE: The objective of this study was to determine the incidence and etiology of congenital hypothyroidism (CH) in Uberaba, MG. SUBJECTS AND METHODS: From 2001 to 2010, by reviewing patient files from a public reference outpatient unit. The screening program covered 88% of live-born children. RESULTS: CH was diagnosed in 16 children, representing an incidence of 1:2,017 live-born children screened. The etiological evaluation was done in 15 children and revealed seven cases of thyroid dysgenesis, seven of dyshormonogenesis, and one case of transient hypothyroidism. One child moved away from the state before etiological investigation was carried out. CONCLUSION: We concluded that both the incidence of CH and of dyshormonogenesis as the main causes of CH were increased in the investigated region, but molecular studies are necessary for a better definition of etiology.

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Multiplex ligation-dependent probe amplification – a short overview

Revista Romana de Medicina de Laborator ◽

10.2478/rrlm-2020-0016 ◽

2020 ◽

Vol 28 (2) ◽

pp. 123-131

Author(s):

Valeriu Moldovan ◽

Elena Moldovan

Keyword(s):

Copy Number ◽

Genetic Disorders ◽

Cost Effective ◽

Copy Number Variations ◽

Comparative Genomic ◽

Gene Deletions ◽

Conventional Cytogenetic Analysis ◽

Main Technique ◽

Cost Effective Technique ◽

Dependent Probe

AbstractMultiplex Ligation-dependent Probe Amplification is a technique proposed for the detection of deletions or duplications that may lead to copy number variations in genomic DNA, mainly due to its higher resolution, and shorter overall diagnosis time, when compared with techniques traditionally used, namely karyotyping, fluorescence in situ hybridization, and array comparative genomic hybridization. Multiplex Ligation-dependent Probe Amplification is a fast (about 2 days), useful and cost-effective technique, being suitable for the diagnosis of hereditary conditions caused by complete or partial gene deletions or duplications, as these conditions are either more difficult or impossible to be diagnosed by other techniques, such as PCR, Real-Time PCR, or sequencing (Sanger or Next Generation). Due to its numerous advantages over conventional cytogenetic analysis techniques, Multiplex Ligation-dependent Probe Amplification could be used in the near future as the main technique for the molecular investigation of genetic conditions caused by copy number variations, in both rare and complex genetic disorders.

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Clinical Impact of Rare Variants Associated with Inherited Channelopathies: A Five-Year Update

10.21203/rs.3.rs-369063/v1 ◽

2021 ◽

Author(s):

georgia sarquella ◽

Anna Fernandez ◽

sergi cesar ◽

elena arbelo ◽

monica coll ◽

...

Keyword(s):

Rare Variants ◽

Genetic Data ◽

Clinical Impact ◽

Clinical Translation ◽

Clinical Implications ◽

Frequency Data ◽

Unknown Significance ◽

Common Group ◽

Genetics And Genomics ◽

Proper Interpretation

Abstract A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified five years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics’ recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included fourty-nine cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After five years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than five years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified.

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