NKX2-5 Variant in Two Siblings with Thyroid Hemiagenesis

Area of Science:

• Genetics
• Endocrinology
• Developmental Biology

Background:

• Thyroid hemiagenesis (THA) is a congenital condition characterized by the absence of one thyroid lobe.
• The precise genetic causes and etiopathogenesis of THA remain largely unknown.
• Understanding genetic factors is crucial for diagnosing and managing thyroid developmental abnormalities.

Purpose of the Study:

• To investigate the genetic underpinnings of thyroid maldevelopment in two siblings diagnosed with THA.
• To identify potential genetic variants contributing to the pathogenesis of thyroid hemiagenesis.

Main Methods:

• Whole-exome sequencing (WES) was performed on DNA samples from affected siblings and their parents.
• Genetic variants were analyzed using population databases (GnomAD v3, dbSNP) and functional prediction tools.
• Variant pathogenicity was assessed using ACMG criteria and conservation scores (PhyloP, phastCons).

Main Results:

• An ultra-rare variant, c.839C>T (p.Pro280Leu), in the NKX2-5 gene was identified in both affected siblings and their unaffected father.
• The identified NKX2-5 variant (rs761596254) has a low minor allele frequency (MAF) of 0.0000655.
• Functional predictions indicated a potentially deleterious impact, though the variant's clinical significance was classified as uncertain.

Conclusions:

• This study provides the first evidence linking NKX2-5 gene variants to thyroid hemiagenesis in siblings.
• The presence of the variant in an unaffected parent suggests incomplete penetrance and the involvement of additional genetic or environmental factors.
• Further research is needed to elucidate the role of NKX2-5 and other factors in THA pathogenesis.