Novel homozygous variant in the TPO gene associated with congenital hypothyroidism and mild-intellectual disability

Amir Ullah,Safdar Abbas,Amjad Khan,Farooq Ahamd,Rania Abdulfattah Sharaf,Muhammad Ismail Khan,Nargis Shaheen,Muhammad Bilal,Muhammad Umair

doi:10.1038/s41439-020-00129-3

Abstract

Congenital hypothyroidism (CH) is one of the most common hereditary disorders affecting neonates worldwide. CH is a multifactorial complex disorder and can be caused by either environmental factors or genetic factors. We studied one Pakistani family with segregating mutations in CH inherited in an autosomal recessive manner. Using whole-exome sequencing (WES), we found a novel homozygous missense variant (c.2315A>G; p.Tyr772Cys) in the thyroid peroxidase (TPO) gene. Different bioinformatics prediction tools and Sanger sequencing were performed to verify the identified variant. Our findings highlight the importance of this gene in causing CH and mild-intellectual disability (ID) in two affected brothers. WES is a convenient and useful tool for the clinical diagnosis of CH and other associated disorders.

Highlights

Congenital hypothyroidism (CH) is diagnosed as thyroid hormone deficiency in newborn infants with an incidence of 1:2000 to 1:4000 live births worldwide[1]
80–85% of CH cases are associated with thyroid dysgenesis (TD); either the thyroid gland is absent, reduced in size or versatile[2]
There are a handful of genes known to be Correspondence: Amjad Khan 1Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Science, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia 2Department of Speech Language Pathology and Audiology, National Guard Health Affairs, Ministry of National Guard, Riyadh, Saudi Arabia Full list of author information is available at the end of the article These authors contributed : Amjad Khan, Muhammad Umair responsible for CH associated with both primary thyroid dysgenesis and thyroid dyshormonogenesis (TDH)[4]

Summary

Introduction

Congenital hypothyroidism (CH) is diagnosed as thyroid hormone deficiency in newborn infants with an incidence of 1:2000 to 1:4000 live births worldwide[1]. There are a handful of genes known to be Correspondence: Amjad Khan (amjadkhanqau123@hotmail.com) 1Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Science, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia 2Department of Speech Language Pathology and Audiology, National Guard Health Affairs, Ministry of National Guard, Riyadh, Saudi Arabia Full list of author information is available at the end of the article These authors contributed : Amjad Khan, Muhammad Umair responsible for CH associated with both primary thyroid dysgenesis and thyroid dyshormonogenesis (TDH)[4]. At the age of 26 years, patient IV: 2 had tall forehead, thick eyebrows, deep-set eyes, strabismus, thick lips, protruding ears, and a prominent goiter.

Results

Conclusion