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.