THRB Gene Mosaicism Confirmed by Next-Generation Sequencing in a Clinically Symptomatic Infant

TL;DR

A 4-day-old infant with thyroid hormone resistance had a rare THRB gene variant confirmed by next-generation sequencing, which was not inherited from his parents.

Contribution

This study confirms a de novo mosaic THRB gene variant in an infant using next-generation sequencing, highlighting its non-inherited nature.

Findings

Next-generation sequencing confirmed a de novo mosaic THRB variant in the infant.

The variant was not present in the asymptomatic parents.

The mosaic variant poses inheritance risk only to the patient's offspring.

Abstract

A 4-day-old infant was admitted for neonatal jaundice. He had persistent tachycardia and tachypnea. Initial workup showed a serum free T4 of 75.6 pmol/L (5.87 ng/dL) (reference range: 11.5-28.3 pmol/L; 0.89-2.20 ng/dL) and a nonsuppressed TSH 3.76 mIU/L (reference range: 0.72-11.0 mIU/L). A TRH stimulation test showed an exaggerated TSH response with a peak of 92.1 mIU/L at 30 minutes after TRH injection, which suggested the diagnosis of resistance to thyroid hormone β syndrome. Sanger sequencing showed a questionable pathogenic variant in the THRB gene with low signal amplitude. Restriction fragment length polymorphism was consistent with its presence. The variant was originally reported as heterozygous. Next-generation sequencing was performed on blood and buccal swab samples of the patient and his parents, which confirmed this de novo mosaic variant NM_000461.5:c.1352T > C p.(Phe451Ser) in the patient but not in his asymptomatic parents. As it was in a mosaic state, only the offspring, but not other first-degree relatives, of the patient would have the risk of inheriting that variant.

Figures