Detection of Novel Gene Variants Associated with Congenital Hypothyroidism in a Finnish Patient Cohort

Abstract

Background: Congenital hypothyroidism (CH) is defined as the lack of thyroid hormones at birth. Mutations in at least 15 different genes have been associated with this disease. While up to 20% of CH cases are hereditary, the majority of cases are sporadic with unknown etiology. Apart from a monogenic pattern of inheritance, multigenic mechanisms have been suggested to play a role in CH. The genetics of CH has not been studied in Finland so far. Therefore, multigenic sequencing of CH candidate genes was performed in a Finnish patient cohort with both familial and sporadic CH.Methods: A targeted next-generation sequencing (NGS) panel, covering all exons of the major CH genes, was applied for 15 patients with sporadic and 11 index cases with familial CH.Results: Among the familial cases, six pathogenic mutations were found in the TPO, PAX8, and TSHR genes. Furthermore, pathogenic NKX2.1 and TG mutations were identified from sporadic cases, together with likely pathogenic variants in the TG, NKX2.5, SLC26A4, and DUOX2 genes. All identified novel pathogenic mutations were confirmed by Sanger-sequencing and characterized in silico and/or in vitro.Conclusion: In summary, the CH panel provides an efficient, cost-effective, and multigenic screening tool for both known and novel CH gene mutations. Hence, it may be a useful method to identify accurately the genetic etiology for dyshormogenic, familial, or syndromic forms of CH.

Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy

“…The sequencing panel was designed to include all genes suggested to be associated with non-syndromic cardiomyopathies at the time of the study onset. Sequencing methods applied in this study have been previously reported, 11 and the details are presented in the Supporting Information. All pathogenic (P)/likely pathogenic (LP) variants were confirmed by Sanger sequencing.…”

Resistance to thyrotropin

“…The presence of RTSH-associated PAX8 promoter variants [69–71], the observation of a frameshift mutation with demonstrated protein instability [72], and the autoregulation of PAX8 by binding to its own promoter [73] are also consistent with a haploinsufficiency mechanism. A noteworthy mutational hotspot is the CpG dinucleotide at codon 31, for which frequent mutational events (R31H and R31C) have been reported [61, 65, 67, 74–77]. For some of the reported mutations, the primary defect is the impaired synergism with other thyroid transcription factors (NKX2-1) or insufficient recruitment of coactivators (p300) without altering DNA binding [78–80].…”

“…Thus, there is no clear correlation between the activity of mutant PAX8 proteins in vitro and the severity of RTSH in patients. In addition, incomplete penetrance [83], parental mosaicism [84], and late-onset of RTSH phenotype due to insufficient postnatal thyroid growth [64, 77, 85, 86] have been shown to potentially mask the inherited nature of the condition.…”

“…Thus, kidney organogenesis in Pax8 mutant mice is generally normal [59]. Yet, several human carriers of PAX8 gene mutation were reported to have associated kidney and urogenital abnormalities [28, 77, 85, 88]. It is tempting to speculate that the PAX8 mutations may have contributed to these non-thyroidal developmental defects.…”

“…In contrast, mutations in PAX8 have been repeatedly reported to manifest RTSH that progresses during postnatal growth of the thyroid gland indicating that the defect in growth and/or survival of follicular thyroid cells cannot be permanently compensated [64, 77, 85, 86]. Genetic analysis may therefore provide a diagnostic tool to guide therapy and follow-up of RTSH patients.…”