| Summary: | Mexico shows a high birth prevalence of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD). <i>PAX8</i> defects underlie only 1% of these cases and <i>NKX2-1</i> 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 <i>FOXE1</i>, <i>NKX2-5</i>, and <i>TSHR</i> and evaluated copy number variations (CNVs) in <i>TSHR</i>, <i>FOXE1</i>, <i>PAX8</i>, and <i>NKX2-1</i> by multiplex ligation-dependent probe amplification. Odds ratios for TD risk were explored for <i>FOXE1</i> polyalanine stretches [polyAla-rs71369530] in cases and controls (N = 116). Five rare missense changes cataloged as benign (<i>NKX2-5</i>:p.(Ala119Ser)-rs137852684), of unknown significance (<i>FOXE1</i>:p.(Ala335Gly)-rs543372757; <i>TSHR</i>:p.(Asp118Asn)-rs1414102266), and likely pathogenic (<i>FOXE1</i>:p.(Gly124Arg)-rs774035532; <i>TSHR</i>: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 <i>FOXE1</i> significantly protect against TD. The present and previously published data collectively show that small clinically relevant germline variants in <i>PAX8</i>, <i>FOXE1,</i> and <i>TSHR</i> are found in only a very small proportion (2.5%) of isolated CH-TD Mexican patients.
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