Increased Prevalence of TG and TPO Mutations in Sudanese Children With Congenital Hypothyroidism

Abstract

Context: Congenital hypothyroidism (CH) is due to dyshormonogenesis in 10% to 15% of subjects worldwide but accounts for 60% of CH cases in the Sudan.

Objective: To investigate the molecular basis of CH in Sudanese families.

Design: Clinical phenotype reporting and serum thyroid hormone measurements. Deoxyribonucelic acid extraction for whole-exome sequencing and Sanger sequencing.

Setting: University research center.

Patients: Twenty-six Sudanese families with CH.

Intervention: Clinical evaluation, thyroid function tests, genetic sequencing, and analysis. Our samples and information regarding samples from the literature were used to compare TG (thyroglobulin) and TPO (thyroid peroxidase) mutation rates in the Sudanese population with all populations.

Results: Mutations were found in dual-oxidase 1 (DUOX1), dual-oxidase 2 (DUOX2), iodotyrosine deiodinase (IYD), solute-carrier (SLC) 26A4, SLC26A7, SLC5A5, TG, and TPO genes. The molecular basis of the CH in 7 families remains unknown. TG mutations were significantly higher on average in the Sudanese population compared with the average number of TG mutations in other populations (P < 0.05).

Conclusions: All described mutations occur in domains important for protein structure and function, predicting the CH phenotype. Genotype prediction based on phenotype includes low or undetectable thyroglobulin levels for TG gene mutations and markedly higher thyroglobulin levels for TPO mutations. The reasons for higher incidence of TG gene mutations include gene length and possible positive genetic selection due to endemic iodine deficiency.

Keywords: TG; TPO; congenital hypothyroidism; goiter.

Figure 1.

Generations are denoted by roman numeral. Each subject is identified by the number just above the corresponding symbol. Laboratory thyroid function tests are aligned below each symbol. Abnormal values are in bold and underlined. Abbreviations: FT₄, free thyroxine; TBG, thyroxine binding globulin; TG, thyroglobulin; TG Ab, anti-thyroglobulin antibody; TPO Ab, anti-TPO antibody; TSH, thyroid-stimulating hormone; TT₃, total triiodothyronine; TT₄, total thyroxine.

Figure 2.

Amino acid numbers are denoted by numbers spanning schematic. Important domains are denoted by roman numerals or by their name for each gene. For the TPO gene, the Myeloperoxidase (MPO) domain is denoted by the black box from amino acid position 142 to 737. Catalytic site necessary for proper TPO function is within MPO Domain. The TPO Transmembrane domain is also marked along the gene approximately between amino acid 846 and 872. Each of the documented mutations in this report and previously reported by our lab is noted by boxes in their approximate locations. *, a novel mutation. Abbreviations: CCP-L, Complement control protein-like; ChEL, Cholinesterase-like; DUOX1, Dual oxidase 1; DUOX2, Dual oxidase 2; EGF-L, Epidermal growth factor-like; IYD, Iodotyrosine Deiodinase; MPO, Myeloperoxidase; SLC26A4, Solute-carrier family 26 member 4; SLC26A7, Solute-carrier family 26 member 7; SLC5A5, Solute-carrier family 5 member 5; TG, Thyroglobulin; TPO, Thyroid peroxidase.

Figure 3.

Relationship of unique mutations in 19 Sudanese families compared with the gene’s amino acid length. Mutations were only counted once in the instance of the same mutation being present in 2 different families. Trend line is denoted by the dotted line and the r2 is noted next to the line. Abbreviations: DUOX1, Dual oxidase 1; DUOX2, Dual oxidase 2; IYD, Iodotyrosine Deiodinase; SLC26A4, Solute-carrier family 26 member 4; SLC26A7, Solute-carrier family 26 member 7; SLC5A5, Solute-carrier family 5 member 5; TG, Thyroglobulin; TPO, Thyroid peroxidase.