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. 2021 Feb;71(2):514-519.
doi: 10.1007/s12020-020-02422-1. Epub 2020 Jul 21.

Compound heterozygous GLI3 variants in siblings with thyroid hemiagenesis

Ewelina Szczepanek-Parulska  1 , Bartłomiej Budny  2 , Martyna Borowczyk  2 , Katarzyna Zawadzka  3 , Paweł Sztromwasser  3   4 , Marek Ruchała  2
Affiliations

Compound heterozygous GLI3 variants in siblings with thyroid hemiagenesis

Ewelina Szczepanek-Parulska et al. Endocrine. 2021 Feb.

Abstract

Purpose: Thyroid hemiagenesis (THA) is an inborn absence of one thyroid lobe of largely unknown etiopathogenesis, affecting 0.05-0.5% population. The aim of the study was an identification of genetic factors responsible for thyroid maldevelopment in two siblings with THA.

Methods: We evaluated a three-generation THA family with two sisters presenting the disorder. Proband (Patient II:3) was diagnosed at the age of 45 due to neck asymmetry. Left lobe agenesis and nontoxic multinodular goiter were depicted. Proband's sister (Patient II:6) was euthyroid, showed up at the age of 39 due to neck discomfort and left-sided THA was demonstrated. Affected individuals were subjected to whole-exome sequencing (WES) (Illumina, TruSeq Exome Kit) and all identified variants were evaluated for pathogenicity. Sanger sequencing was used to confirm WES data and check segregation among first-degree relatives.

Results: In both siblings, a compound heterozygous mutations NM_000168.6: c.[2179G>A];[4039C>A] (NP_000159.3: p.[Gly727Arg];[Gln1347Lys]) were identified in the GLI3 gene, affecting exon 14 and 15, respectively. According to the American College of Medical Genetics, variants are classified as of uncertain significance, and were found to be very rare (GnomAD MAF 0.007131 and 0.00003187). The segregation mapping and analysis of relatives indicated causativeness of compound heterozygosity.

Conclusions: We demonstrated for the first time a unique association of THA phenotype and the presence of compound heterozygous mutations p.[Gly727Arg];[Gln1347Lys] of GLI3 gene in two siblings.

Keywords: GLI3 gene; GLIS3 gene; Thyroid dysgenesis; Thyroid hemiagenesis; Whole-exome sequencing.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Tc99m scintiscan (a) and surgical specimen (b) obtained after complete thyroidectomy, depicting agenesis of the left thyroid lobe in the patient II:3. Agenesis of the left lobe in the patient II:6 demonstrated by thyroid ultrasound examination (c). d Pedigree of the THA family. Blackened symbols are presenting affected sisters, symbols with an asterisk indicating individuals who were not examined with US. The remaining patients were confirmed to have bilobed thyroid. Individual I:2—neck asymmetry was reported by family members therefore a question mark regarding THA status was used, II:8—thyroidectomy, multinodular goiter III:1—hypothyroidism, Hashimoto’s thyroiditis
Fig. 2
Fig. 2
A demonstration of the phylogenetic conservation of Gly727 (a) and Gln1347 (b)
See this image and copyright information in PMC

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