Next-Generation Sequencing Analysis Reveals Frequent Familial Origin and Oligogenism in Congenital Hypothyroidism With Dyshormonogenesis

Abstract

ContextCongenital hypothyroidism (CH) is related to dyshormonogenesis in 15% to 40% of the world population and associated with homozygous or heterozygous variants in the main genes of the hormone synthesis pathway. Emerging diagnostic tools, such as next-generation sequencing (NGS), have been used to efficiently explore panels of genes and identify complex mechanisms of pathogenesis.ObjectiveWe explored 19 candidate genes known to be causative for permanent or transient CH to evaluate the role of complex gene variations in CH phenotype.Patients, Design and SettingUsing the NGS approach, we studied 65 newborns with thyroid dyshormonogenesis (TDH). New variants were assessed in silico for pathogenicity.ResultsAmong the 65 infants, 56.9% presented a variant in one or more genes of the thyroid hormone synthesis axis. We identified homozygous or compound heterozygous variants in the TG, DUOX2, TPO, or SLC5A5 genes in 10 infants and heterozygous variants in DUOX2, TG, TPO, and TSHR in 19 others. In seven cases, a heterozygous variant in the TG gene was the unique anomaly detected, but related to disturbed hormonal balance. Oligogenic variants were found in eight infants associated with severe CH and goiter in five of them.ConclusionThe systematic exploration of genes involved in thyroid hormone synthesis by NGS in TDH showed high diagnostic relevance. Oligogenic inheritance could be related to phenotypic heterogeneity and a high frequency of goiter.

JAG1 Variants Confer Genetic Susceptibility to Thyroid Dysgenesis and Thyroid Dyshormonogenesis with Different Mechanisms

“…out of 8 cases were severe CH. Pearson chi-square analysis showed that oligogenic inheritance was signi cantly associated with severe CH (P = 0.007), and the nding is supported by previous study [23]. To examine the correlation between variant dosage and severity, we compared the fT4 levers in monogenic and oligogenic groups, the results indicated that oligogenicity may contribute to the disease severity of DH, Takeshi et al had come to the same conclusion [20].…”

Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.

“…p.Pro138Leu, p.Pro142Arg and p.Leu264Cysfs*57 are located in the peroxidase-like domain, whereas p.Gln899Serfs*21, p.Thr920Ile and p.Phe966Serfs*29 are present in the transmembrane domain. Only two variants were described previously associated with congenital hypothyroidism, the p.Pro138Leu [46, 47] and the p.Phe966Serfs*29 variant [6, 11,24,40,41,46,[48][49][50][51]. The frameshift p.Phe966Serfs*29, commonly reported as p.S965fsX994 is one of the most frequent mutations in DUOX2 gene.…”

Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect

“…Genomic DNA was purified from peripheral blood mononuclear cells using the Wizard Genomic DNA Purification Kit (Promega, Madison, WI, USA). Genomic DNA (10 ng/per sample) was used for library preparation, using the DNA prep with an enrichment protocol (Illumina, San Diego, CA, USA) and a custom targeted panel of the 17 congenital hypothyroidism-causative genes TG (NM_003235.4), TPO (NM_000547.5), DUOXA2 (NM_207581.3), DUOX2 (NM_014080.4), SLC5A5 (NM_000453.2), SLC16A2 (NM_006517.4), SLC26A4 (NM_000441.1), TSHR (NM_000369.2), GNAS1 (NM_000516.4), THRB (NM_000461.4), THRA (NM_003250.5), PAX8 (NM_003466.3), NKX2.1 (NM_001079668.2), NKX2.5 (NM_004387.3), FOXE1 (NM_004473.3), IYD (NM_001164694.1), and SECISBP2 (NM_024077.4) [ 41 ]. Next-generation sequencing was performed on the NextSeq 550 platform using the Mid Output kit v2.5 (Illumina).…”