Variation spectra in mild isolated hyperthyrotropinemia: pilot cohort and systematic review

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Lowered thyrotropin (TSH) cutoffs increase detection of Mild Isolated Hyperthyrotropinemia (MIH) or Subclinical Hypothyroidism.
• Genetic testing for MIH remains limited, necessitating further investigation into its genetic underpinnings.
• Understanding the genetic basis of MIH is crucial for accurate diagnosis and management of Congenital Hypothyroidism (CH).

Purpose of the Study:

• To evaluate the contribution of genetic variants in MIH.
• To determine the molecular spectrum of genetic variants associated with MIH.
• To expand the understanding of genes and variants implicated in MIH.

Main Methods:

• Targeted Next-Generation Sequencing (NGS) was performed on ten patients with MIH.
• Analysis included Single Nucleotide Variants (SNVs), insertions/deletions, noncanonical splice site (NCSS) variants, and Copy Number Variants (CNVs) in 13 candidate genes.
• A Systematic Review (SR) and variant reclassification were conducted to broaden the scope of identified genes and variants.

Main Results:

• Eight monoallelic SNVs in four genes were found in five subjects.
• Potential digenic or pseudo-digenic inheritance patterns were observed in three infants.
• A novel variant in the thyroglobulin (TG) gene was identified, and a database of 122 unique reclassified SNVs from 173 patients was created via SR.

Conclusions:

• The study provides evidence supporting the genetic etiology of MIH and broadens the phenotypic and variant spectrum of CH.
• Genetic diagnosis was strongly suggested in four patients based on variant analysis and genotype-phenotype correlation.
• Further prospective studies are recommended to explore the role of NGS in guiding MIH treatment and prognosis.