Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 26 May 2021 / Approved: 28 May 2021 / Online: 28 May 2021 (11:15:14 CEST)

A peer-reviewed article of this Preprint also exists.

Alcántara-Ortigoza, M.A.; Sánchez-Verdiguel, I.; Fernández-Hernández, L.; Enríquez-Flores, S.; González-Núñez, A.; Hernández-Martínez, N.L.; Sánchez, C.; González-del Angel, A. 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 2021, 8, 457. Alcántara-Ortigoza, M.A.; Sánchez-Verdiguel, I.; Fernández-Hernández, L.; Enríquez-Flores, S.; González-Núñez, A.; Hernández-Martínez, N.L.; Sánchez, C.; González-del Angel, A. 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 2021, 8, 457.

Journal reference: Children 2021, 8, 457
DOI: 10.3390/children8060457

Abstract

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.

Keywords

Congenital hypothyroidism; FOXE1; Mexican population; multiplex ligation-dependent probe amplification (MLPA); NKX2-1; NKX2-5; PAX8; polyalanine tract; protein modeling; thyroid dysgenesis; TSH receptor

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