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Published on: August 15, 2019
THRB Gene Mosaicism Confirmed by Next-Generation Sequencing in a Clinically Symptomatic Infant
Jenny Yeuk Ki Cheng1,2, Shreenidhi Ranganatha Subramaniam1,2, Hoi Shan Leung1
1Department of Chemical Pathology, Prince of Wales Hospital, Hong Kong, China.
Insights
This study identifies a de novo mosaic variant in the THRB gene causing resistance to thyroid hormone beta syndrome in a neonate. This genetic finding explains the infant's symptoms and highlights the unique inheritance pattern of mosaic variants.
Area of Science:
- Endocrinology
- Genetics
- Neonatal Medicine
Background:
- Neonatal jaundice can be associated with thyroid dysfunction.
- Resistance to thyroid hormone (RTH) is a rare genetic disorder affecting thyroid hormone action.
Observation:
- A 4-day-old infant presented with neonatal jaundice, tachycardia, and tachypnea.
- Elevated free T4 and a blunted TSH response to TRH stimulation suggested RTH.
- Initial genetic analysis revealed a questionable variant in the THRB gene.
Findings:
- Next-generation sequencing confirmed a de novo mosaic variant (NM_000461.5:c.1352T > C p.(Phe451Ser)) in the THRB gene in the infant.
- This variant was absent in the infant's asymptomatic parents, indicating it occurred de novo.
- The mosaic nature of the variant was confirmed in blood and buccal swab samples.
Implications:
- The identified mosaic THRB variant is likely pathogenic and explains the infant's clinical presentation of resistance to thyroid hormone beta syndrome.
- Mosaic variants present unique diagnostic challenges and have distinct inheritance patterns compared to constitutional variants.
- Understanding the mosaic state is crucial for accurate genetic counseling regarding recurrence risk in future 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.
