Investigating TSHR Gene Variants in Consanguineous Families: Novel Insights into Variable Expression in Familial Congenital Hypothyroidism

Zakiye Nadeali ^1,2 Zohreh Mohammadi Zaniani ¹ Sajjad Biglari ¹ Newsha Molavi ³ Khashayar Zardoui ² Sam Mirfendereski ⁴ Mahin Hashemipour ^5,6* Mohammad Amin Tabatabaiefar ^1* Constantin Polychronakos ^2,7*

• ¹ Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Isfahan, Iran
• ² Montreal Children’s Hospital and the Endocrine Genetics Laboratory, Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Canada, Montréal, Canada
• ³ Immunodeficiency Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran, Isfahan, Iran
• ⁴ Department of Radiology, Isfahan University of Medical Sciences, Isfahan, Iran, Isfahan, Iran
• ⁵ Metabolic Liver Disease Research Center, Isfahan University of Medical Sciences, Isfahan, Iran, Isfahan, Iran
• ⁶ Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran, Isfahan, Iran
• ⁷ McGill University, Montreal, Canada

The defective thyroid stimulating hormone receptor (TSHR) gene is one of the main known genetic factors leading to congenital hypothyroidism (CH). However, the relationship between TSHR genotypes and phenotype and the underlying reason for the broad spectrum of phenotypes in the patients carrying TSHR gene defects have not yet been clearly established. This study aimed to investigate the genetics of patients with CH to identify TSHR defects and to explore the specific extrathyroidal defects and other phenotypic features in these patients to establish a genotype-phenotype correlation. Methods:Consanguineous families with primary CH and a history of non-autoimmune acquired hypothyroidism were included in this study. The causative variants in the TSHR gene were identified using exome sequencing.Multiple in silico analysis tools were employed to interpret the variants. Results: Five TSHR variants including two novel variants were identified in patients with thyroid dysgenesis from 5 families. Some patients presented inter-and intra-familial variable expression and different ages of onset. The data suggest the possibility that the clinical phenotype of CH patients caused by TSHR variants can be influenced by the coexistence of other gene defects. Conclusions: This study investigated the variants of the TSHR gene contributing to CH for the first time in Iran. Our study on multiplex consanguineous families could help provide further evidence for the elucidation of the oligogenic inheritance in CH, possibly leading to variable expressivity in CH patients. These data could have implications for genetic diagnosis and counseling to identify deleterious variants for possible diagnostics, clinical management, and preventive aims.