Compound heterozygous GLI3 variants in siblings with thyroid hemiagenesis

Ewelina Szczepanek-Parulska,Marek Ruchała,Bartłomiej Budny,Katarzyna Zawadzka,Paweł Sztromwasser,Martyna Borowczyk

doi:10.1007/s12020-020-02422-1

Ewelina Szczepanek-Parulska, Marek Ruchała + Show 4 more

Open Access

https://doi.org/10.1007/s12020-020-02422-1

Copy DOI

Abstract

PurposeThyroid 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.MethodsWe 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.ResultsIn 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.ConclusionsWe 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.

Highlights

Thyroid hemiagenesis (THA) is a congenital lack of one thyroid lobe, with an incidence of 0.05–0.5% in population [1]
Sisters were born before the introduction of TSH neonatal screening in Poland, they did not present any features of congenital hypothyroidism (CH) and were diagnosed due to suspicion of goiter at adult age
According to American College of Medical Genetics (ACMG) criteria, variants were classified as uncertain significance because of very rare frequency in population databases

Summary

Introduction

Thyroid hemiagenesis (THA) is a congenital lack of one thyroid lobe, with an incidence of 0.05–0.5% in population [1]. THA was previously considered a benign thyroid maldevelopment, latest data suggest that it might be. In THA patients only a heterozygous mutation in PAX8 gene was documented as genetic cause [6]. Our group has demonstrated that proteasome genes mutations may be associated with THA phenotype [7]. Several uncertain changes, but no Endocrine deleterious mutations in HOXB3, HOXD3, and PITX2, were detected. In another patient with THA, a microduplication of chromosome region 22q11.2 encompassing TBX1 gene was found [1].

Objectives

Methods

Results

Conclusion