Genetic analyses in a cohort of Portuguese pediatric patients with congenital hypothyroidism

Abstract

Background Permanent primary congenital hypothyroidism (CH) can be caused by thyroid dysgenesis or dyshormonogenesis. A molecular genetic study is recommended in dyshormonogenesis, in syndromic hypothyroidism and when there is a family history of CH. The aim of this study was to identify a monogenic etiology for CH in selected individuals from a cohort of primary permanent CH. Methods From an initial cohort of 79 patients with permanent CH (3–19 years), 11 patients were selected for molecular analyses. Nine patients with dyshormonogenesis (normal in-situ gland or goiter) were screened for causative variants, by next-generation sequencing (NGS), in 28 genes known to be responsible for CH. One patient with a family history of CH was screened for the paired-box gene 8 (PAX8) gene and another patient with a syndromic CH was screened for the NKX2-1 gene. Results We found a monogenic basis of disease in eight patients, involving the thyroid peroxidase (TPO) gene (four patients), the thyroglobulin (TG) gene (two patients), and the PAX8 and NKX2-1 genes (one patient each). Two patients were heterozygotes, one harboring a variant in the TG gene and the other in the SLC5A5 gene. In one patient, we found no potential causative variants in any of the 28 genes screened. We described five novel variants: three in the TG gene, one in the NKX2-1 and one in the SLC5A5 gene, all of them classified as pathogenic. Conclusions In eight of the 11 screened patients, a monogenic disease was found. These results highlight the advantage of using an NGS panel and provide further data regarding the molecular basis of CH.

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

“…This contrasted with a TD risk of OR 3.02 for the 14/16 genotype observed in Sicilian primary permanent CH patients [53]. Despite these contradictory data, which suggest that the polyAla FOXE1 tract should be studied in other populations, recent NGS-based studies in Chinese [6,13] and European [7,34] CH cohorts not explored the association of polyAla FOXE1 alleles and/or genotypes with the risk of TD. This may reflect: the inherent difficulties of using NGS bioinformatics approaches to achieve accurate variant annotation in repetitive sequences, such as polyAla stretches; the high GC content of the FOXE1 gene (~73%), which could lead a low sequencing depth and coverage (i.e., 51.7%) [13]; and/or the inclusion of CH patients regardless of their thyroid phenotype [6,7,13].…”

“…The inclusion of such cases may have biased the accurate estimation of mutational spectrum underlying the most common isolated TD forms in both Caucasian [4,5] and Mexican [17] CH cases. Such a bias could be exemplified by the recurrent identification of brain-lung-thyroid syndrome (MIM#610978) in other studies [34,35].…”

“…However, it still remains to be determined if these and other documented monoallelic NKX2-5 VUSs in CH patients, i.e. p.(Ser139Asn) [6], p.(Arg143Gln) [35], p.(Pro211Leu) [34], and p.(Asp226Asn) [7], could play roles as genetic susceptibility factors, even in a digenic or polygenic model [3,42].…”

A novel mutation in intron 11 donor splice site, responsible of a rare genotype in thyroglobulin gene by altering the pre-mRNA splincing process. Cell expression and bioinformatic analysis

“…We have studied an Argentinean patient that had clinical and biochemical criteria suggestive of CH associated with TG gene deficiency: lower serum TG and high levels of serum TSH with simultaneous low levels of circulating thyroid hormones [Targovnik et al, 2010a[Targovnik et al, , 2011 -Hassan et al, 2013;Brust et al, 2011;Caputo et al, 2007aCaputo et al, , 2007bCitterio et al, 2011Citterio et al, , 2013aGutnisky et al, 2004;Machiavelli et al, 2010;Nicholas et al, 2016;Pardo et al, 2009;Peteiro-Gonzalez et al, 2010;Rivolta et al, 2005;Siffo et al, 2018;Santos-Silva et al, 2019;van de Graaf et al, 1999;Zou et al, 2018]. This mutation was available in heterozygous state from gnomAD database in Ashkenazi Jewish, Latino, Europeans (non Finnish), European (Finnish), African and South Asian populations with an estimated total Minor Allele Frequency (MAF) of 0.0003535 % (100/282,884) for the allele thymine 886 .…”

Prevalence of Pathogenic Germline DICER1 Variants in Young Individuals Thyroidectomised Due to Goitre – A National Danish Cohort

“…Familial clustering of goitre is not uncommon in areas known to be without iodine deficiency, predominately showing an autosomal dominant inheritance pattern. Variations in the genes TG, TPO, NIS, PDS, PAX8, NKX2-1, NKX2-5, IYD, FOXE1, JAG1, DOUX2, DOUXA2 and TSH-R are associated with congenital hypothyroidism and/or nodular goitre ( 14 , 24 , 25 ). Pathogenic variants of the genes RGS12, GRPEL1, CLIC6 and WFS1 are suggested to be associated with an increased risk of nodular goitre, typically developing during the first decade of life – no other manifestations have been associated with the genes expect WFS1 (Wolfram syndrome), though the literature is very sparse ( 26 , 27 ).…”