NKX2-5 Variant in Two Siblings with Thyroid Hemiagenesis

Abstract

Thyroid hemiagenesis (THA) is an inborn absence of one thyroid lobe of largely unknown etiopathogenesis. The aim of the study was to reveal genetic factors responsible for thyroid maldevelopment in two siblings with THA. None of the family members presented with congenital heart defect. The samples were subjected to whole-exome sequencing (WES) (Illumina, TruSeq Exome Enrichment Kit, San Diego, CA 92121, USA). An ultra-rare variant c.839C>T (p.Pro280Leu) in NKX2-5 gene (NM_004387.4) was identified in both affected children and an unaffected father. In the mother, the variant was not present. This variant is reported in population databases with 0.0000655 MAF (GnomAD v3, dbSNP rs761596254). The affected amino acid position is moderately conserved (positive scores in PhyloP: 1.364 and phastCons: 0.398). Functional prediction algorithms showed deleterious impact (dbNSFP v4.1, FATHMM, SIFT) or benign (CADD, PolyPhen-2, Mutation Assessor). According to ACMG criteria, variant is classified as having uncertain clinical significance. For the first time, NKX2-5 gene variants were found in two siblings with THA, providing evidence for its potential contribution to the pathogenesis of this type of thyroid dysgenesis. The presence of the variant in an unaffected parent, carrier of p.Pro280Leu variant, suggests potential contribution of yet unidentified additional factors determining the final penetrance and expression.

Keywords: NKX2-5 gene; thyroid dysgenesis; thyroid hemiagenesis; thyroid transcription factor; whole-exome sequencing.

Figure 1

The thyroid scintiscan and ultrasound picture of both siblings with left-sided thyroid hemiagenesis. (A)—thyroid Tc-99m scintiscan of the male proband. The “+” in the image corresponds to the jugular notch of the sternum. (B)—thyroid ultrasound of the male proband. (C)—thyroid Tc-99m scintiscan of the male proband’s sister. The “+” in the image corresponds to the jugular notch of the sternum. (D)—thyroid ultrasound of the male proband’s sister.

Figure 2

Abbreviated pedigree of the family under study. Symbols are presenting phenotypical manifestation (affected individuals are presented using shaded symbols). Below the symbols, sequencing chromatograms presenting genetic status (zygosity), and HGVS description of corresponding genotypes on protein and coding level, were presented.

Figure 3

Evolutionary conservativeness of sequence surrounding variant p.Pro280Leu (A), comparison of sequence surrounding variant p.P280L among entire class of human NKX2 genes (NKX2-1 to NKX2-5) (B) and in silico prediction of conformational change caused by a p.Pro280Leu substitution (C) in two predicted structures for NKX2-5 protein. The normal protein is depicted in gray, while the impact of mutation is shown in color.