Somatic Mutations Are Not Observed by Exome Sequencing of Lymphocyte DNA from Monozygotic Twins Discordant for Congenital Hypothyroidism due to Thyroid Dysgenesis

Abstract

Background/Aims: Congenital primary hypothyroidism (CH) is a rare pediatric disorder estimated to occur in about 1:2,500 live births. Approximately half of these cases entail ectopic thyroid tissue, which is believed to result from a migration defect during embryogenesis. Approximately 3% of CH cases are explained by mutation(s) in known genes, most of which are transcription factors implicated in the embryology of the thyroid gland. Surprisingly, monozygotic (MZ) twins are usually discordant for CH due to thyroid dysgenesis, suggesting that most cases are not caused by transmitted genetic variation. One possible explanation is somatic mutation in genes involved in thyroid migration occurring after zygotic twinning. Such mutations should be observed only in the affected twin. Methods: To test the hypothesis of somatic mutation, we performed whole exome sequencing of DNA from three pairs of MZ twins discordant for CH with ectopic glands. Results: We found no somatic mutations exclusive to any of the three affected twins or in any of the unaffected twins. Conclusion: Either somatic mutations are not significant for the etiology of CH or else such mutations lie outside regions of the genome accessible by exome sequencing technology.

Exomic and Epigenomic Analyses in a Pair of Monozygotic Twins Discordant for Cryptorchidism

“…In the present study, no genetic differences were detected in MZ twins discordant for cryptorchidism. The results coincided with the findings of earlier similar studies, in which no genetic discordances were found in MZ twins discordant for several disorders, including renal agenesis (Jin et al, 2014), cataract (Wei et al, 2015), VACTERL association (Solomon et al, 2013), hypothyroidism (Magne et al, 2015), heart defects, and diaphragmatic hernia (Zhang et al, 2016). Our findings provide additional evidence that genetic mutations are not a common cause for phenotypic discordance among MZ twins.…”

Molecular defects in thyroid dysgenesis

“…Furthermore, a recent study showed no peculiar thyroid ectopy‐specific methylation signature after performing a genome‐wide DNA methylation analysis . In addition, somatic mutations were not detected in TD‐discordant monozygotic twins by exome sequencing …”

“…77 In addition, somatic mutations were not detected in TD-discordant monozygotic twins by exome sequencing. 78 Autosomal monoallelic expression (AME) defines unusual autosomal genes with random choice between the maternal and paternal expressed allele. 79 AME can be classified into two groups: (a) fixed, in which the allele-specific expression of a precursor cell is conserved in descendant cells; and (b) dynamic, which is not transmitted along mitosis and, therefore, can be investigated only at the single cell level.…”

DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

“…However, in the only study to investigate this, the gene expression pattern was different in ectopic thyroid, but this was not attributable to significant somatic methylation gene expression profile differences (85). Additionally, frequent somatic mutations were not identified in lymphocyte DNA from monozygotic twins discordant for TD (86) although somatic mosaicism for a PAX8 mutation has been reported (87). Autosomal monoallelic expression has been reported for some genes in both ectopic and eutopic thyroid (88); however, monoallelic expression of a mutant allele has only been reported for TPO in association with dyshormonogeneic CH (89).…”