Commentary on "Deciphering the mystery of CHNG3"
Article information
Congenital hypothyroidism (CH) develops from a developmental or functional defect of the thyroid gland; hypothalamic-pituitary axis malformations; or altered action, transport, or metabolism of thyroid hormones [1]. In the majority of cases (65%), primary CH is due to a developmental defect of the thyroid gland or thyroid dysgenesis. When the thyroid gland is normal sized or hyperplasic (goiter), hypothyroidism occurs due to a defect in thyroid hormone synthesis or dyshormonogenesis [2]. New genetic approaches such as high-throughput sequencing (next-generation sequencing) and the detailed phenotypic description of patients and/or families affected by CH have provided new genetic avenues for CH research. Furthermore, they have made it possible to extend the thyroid phenotype associated with certain mutated genes [1].
Recently, Narumi [3] revealed distinct mutation patterns in the CHNG3 gene affecting a TTTG microsatellite in a noncoding region from the undiagnosed CH pedigree through whole genome sequencing (WGS). They also reported that CHNG3 accounted for 13.9% (95% confidence interval, 11.9–16.1) of the Japanese CH cohort and is one of the leading genetic causes of CH in Japan [4]. A microsatellite is defined as a tract of a repetitive DNA motif composed of short repeating units of 1–6 nucleotides [5]. Microsatellites are observed in almost all known eukaryotic and prokaryotic genomes and are present in both coding and noncoding regions [6]. This makes microsatellites powerful genetic markers for a variety of applications, such as genetic linkage mapping, population genetics, quantitative trait loci-based selection breeding, and evolutionary studies [7]. The mutation rate of microsatellites is higher than that of other genomic regions owing to DNA polymerase slippage during DNA replication and repair [5].
In this study. a novel CH caused by a noncoding region variant in the CHNG3 gene was discovered by combined linkage analysis and WGS. Large-scale WGS has several advantages over whole exome sequencing for discovering noncoding or regulatory regions, copy number variations, repeat expansions, and DNA methylation. WGS is becoming the preferred method for molecular genetic diagnosis of rare and unknown diseases. It can also aid in uncovering potential genetic causes and guide treatment.
The CHNG3 gene plays a crucial role in the regulation of thyroid hormone metabolism, influencing various physiological processes. Recent studies have highlighted its importance in thyroid function and the broader implications for metabolic health [4]. Dysregulation of CHNG3 has been linked to thyroid disorders, which can lead to significant systemic effects including alterations in energy expenditure and growth. However, many questions remain about how specific mutations influence disease susceptibility and phenotype variations, particularly in diverse populations. Understanding the mechanisms behind the interaction of CHNG3 with thyroid hormones may be vital for developing targeted therapies for thyroid-related conditions.
The findings underscore the need for further research to elucidate the mechanisms by which CHNG3 mutations affect thyroid health in the Asian demographic, a vital study area.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported