Gene Variants in NKX2-1 Do Not Represent a Major Etiological Factor of Primary Congenital Hypothyroidism in Mexican Population

Abstract

Congenital hypothyroidism (CH), attributable to thyroid dysgenesis (TD), has an unusually high prevalence in Mexican population but the causes are unknown. NKX2-1, as a candidate gene, was subjected to automated Sanger sequencing in 122 unrelated Mexican patients with CH/TD. Although this study includes the largest number of TD-related CH patients in whom NKX2-1 has been analyzed, no pathogenic variants were detected; only three benign polymorphic changes were identified. These results suggest that NKX2-1 is not a major contributor to the etiology of CH or its high prevalence in Mexicans. Our work identifies misannotations of NKX2-1 variants in three previous published reports.

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

“…We failed to identify any CNV-type change. Our results add to previous findings that 1% of CH-TD Mexican patients could be attributed to PAX8 missense defects [18], and there was no discernible participation of small-nucleotide NKX2-1 pathogenic changes [19]. Collectively, these data obtained in ≥100 Mexican patients suggest that germline small-nucleotide defects in the main TD-related genes, PAX8 [18], NKX2-1 [19], FOXE1, NKX2-5, and TSHR (this work), could explain ~ 2.5% of isolated CH-TD cases in Mexico, without any identified etiologic role for CNVs in PAX8, NKX2-1, FOXE1, or TSHR (NKX2-5 was not included in the employed MLPA kit).…”

“…Our results add to previous findings that 1% of CH-TD Mexican patients could be attributed to PAX8 missense defects [18], and there was no discernible participation of small-nucleotide NKX2-1 pathogenic changes [19]. Collectively, these data obtained in ≥100 Mexican patients suggest that germline small-nucleotide defects in the main TD-related genes, PAX8 [18], NKX2-1 [19], FOXE1, NKX2-5, and TSHR (this work), could explain ~ 2.5% of isolated CH-TD cases in Mexico, without any identified etiologic role for CNVs in PAX8, NKX2-1, FOXE1, or TSHR (NKX2-5 was not included in the employed MLPA kit). Although this explains only a small proportion of cases, it is higher than that documented in 90 Brazilian CH-TD patients, where PAX8, NKX2-5, TSHR, and HES1 (MIM*139605) did not reveal any pathogenic or VUS change [31,32], and seems quite similar to the rate obtained in Japanese CH patients (2.0%, N=2/102), at least 50% of whom carried a confirmed TD phenotype [16].…”

“…One familial case of neurofibromatosis type 1 (MIM#162200) was identified in a patient (HC-222) and her mother. A normal Sanger sequencing result for the NKX2-1 gene was previously reported for 122 of the 128 patients included herein [19].…”

“…In contrast to the information available in the literature for Caucasian and Asian CH patients [3,6,7,13,16], relatively little is known about the participation of genetic factors in the etiology of CH-TD in Latin-American populations. To date, limited publications are available for Brazilian [31,32] and Mexican [18,19] populations. Given the predominance of TD (~93%) in the etiology of primary permanent CH in Mexicans [17], the aim of this work was to examine whether germline small-nucleotide (NKX2-5, FOXE1, and TSHR) and CNV-type (FOXE1, PAX8, NKX2-1, PAX8, and TSHR) changes in TD-related genes play an etiological role in some Mexican CH patients lacking clinical suspicion of a syndromic form and with a confirmed TD imaging-based diagnosis.…”

“…CNV-type changes in TD-related genes have not been explored in Latin American CH populations [18,19,31,32]. In a small sample of Polish CH-TD patients directly subjected to MLPA, whole-exon heterozygous deletions in PAX8, TSHR, and FOXE1 genes surprisingly comprised 11% (N=5/45) of the underlying TD pathogenic genotypes [15].…”