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 , and .

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