Deciphering the mystery of CHNG3

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Congenital hypothyroidism (CH) is the most common congenital endocrine disorder, often caused by genetic defects in the hypothalamic-pituitary-thyroid axis.
• Previous genetic screening in Japanese CH patients identified mutations in known CH-related genes, but approximately 80% of cases remained genetically unexplained.
• Congenital hypothyroidism, nongoitrous, 3 (CHNG3) represents a form of CH with unknown genetic etiology, with identified pedigrees not explained by standard genetic analyses.

Purpose of the Study:

• To identify the genetic cause of CHNG3 in undiagnosed pedigrees.
• To investigate the prevalence of identified mutations in a larger cohort of Japanese CH patients.
• To explore the role of noncoding genetic variants in the pathogenesis of CH.

Main Methods:

• Whole genome sequencing was performed on 11 undiagnosed CH pedigrees to analyze a 3-Mb linkage region.
• A disease-causing variant in a TTTG microsatellite within a noncoding region on chromosome 15 was identified.
• Genotyping of the TTTG microsatellite was conducted in 989 Japanese CH patients to determine mutation frequency.

Main Results:

• A pathogenic variant in a TTTG microsatellite in a noncoding region on chromosome 15 was identified as the cause of CHNG3.
• Abnormalities involving this TTTG microsatellite were found in 13.9% of 989 Japanese CH patients.
• A significant proportion (41.5%) of familial CH cases carried these TTTG microsatellite mutations.

Conclusions:

• The genetic cause of CHNG3 has been identified as a variant in a TTTG microsatellite in a noncoding region.
• This discovery provides new insights into the pathogenesis of CH and explains previously unexplained cases.
• The findings underscore the importance of investigating noncoding genomic regions for diagnosing Mendelian disorders with unknown genetic causes.