Ewelina Szczepanek-Parulska1, Bartłomiej Budny2, Martyna Borowczyk2, Katarzyna Zawadzka3, Paweł Sztromwasser3,4, Marek Ruchała2. 1. Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 49 Przybyszewskiego Street, 60-355, Poznan, Poland. ewelinaparulska@gmail.com. 2. Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 49 Przybyszewskiego Street, 60-355, Poznan, Poland. 3. MNM Diagnostics Sp. z o.o, 64 Macieja Rataja Street, 61-695, Poznan, Poland. 4. Department of Biostatistics and Translational Medicine, Medical University of Lodz, 15 Mazowiecka Street, 92-215, Lodz, Poland.
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.
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.
Authors: U Radhakrishna; D Bornholdt; H S Scott; U C Patel; C Rossier; H Engel; A Bottani; D Chandal; J L Blouin; J V Solanki; K H Grzeschik; S E Antonarakis Journal: Am J Hum Genet Date: 1999-09 Impact factor: 11.025
Authors: P E Macchia; P Lapi; H Krude; M T Pirro; C Missero; L Chiovato; A Souabni; M Baserga; V Tassi; A Pinchera; G Fenzi; A Grüters; M Busslinger; R Di Lauro Journal: Nat Genet Date: 1998-05 Impact factor: 38.330