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

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