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

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.

Central Congenital Hypothyroidism Caused by a Novel Mutation, C47W, in the Cysteine Knot Region of TSHß.

BACKGROUND: Isolated central congenital hypothyroidism (ICCH) is a rare form (1:50,000 newborns) of congenital hypothyroidism, which can present with growth and neuropsychological retardation. Unlike the more common primary CH (1:1,500-1:4,000), which presents on newborn screening with elevated serum thyroid-stimulating hormone (TSH) and low thyroxine (T4) and triiodothyronine (T3), ICCH presents with low TSH and low thyroid hormone levels. ICCH, therefore, may be missed in most newborn screens that are based only on elevated TSH. Most cases of ICCH have been associated with mutations in the TSHß gene. PATIENT: We present a consanguineous Sudanese family where the proband was diagnosed with "atypical" CH (serum TSH was low, not high). INTERVENTION AND OUTCOME: The propositus underwent whole-exome sequencing, and the C47W TSHß mutation was identified. Sanger sequencing confirmed the proband to be homozygous for C47W, and both parents were heterozygous for the same mutation. The mutation was predicted by several in silico methods to have a deleterious effect (SIFT 0.0, Damaging; Polyphen2_HDIV 0.973, probably damaging; MutationTaster 1, disease causing; and CADD 3.17, 16.62). C47W affects the first cysteine of the cysteine knot of the TSHß subunit. The cysteine knot region of TSHß is highly conserved across species and is critical for binding to the TSH receptor. Only two other mutations were previously reported along the cysteine knot and showed consistently low or undetectable serum TSH and low T4 and T3 levels. Other TSHß gene mutations causing ICCH have been reported in the "seatbelt" region, necessary for TSHß dimerization with the alpha subunit. CONCLUSIONS: Identification of a mutation in the TSHß gene reinforces the importance of identifying ICCH that can occur in the absence of elevated serum TSH and demonstrates the functional significance of the TSHß cysteine knot.

Congenital Hypothyroidism due to Oligogenic Mutations in Two Sudanese Families.

Dyshormonogenic congenital hypothyroidism (CH) generally results from biallelic defects in thyroid hormone synthesis genes. Whole exome sequencing allows easier identification of multiple gene defects. Two Sudanese families with CH resulting from oligogenic defects identified by whole exome sequencing are presented. In family 1, the proposita with CH and goiter was heterozygous for three TPO, one TG, and one DUOX2 mutations, including three novel variants inherited from both parents. In family 2, two brothers with psychomotor delay and goiter were homozygous for digenic mutations in the DUOX2 and DUOX1 genes, while their asymptomatic parents were heterozygous. Accumulation of pathogenic mutations may contribute to CH.

A Novel Missense Mutation in the SLC5A5 Gene in a Sudanese Family with Congenital Hypothyroidism.

Thyroid hormone synthesis requires the presence of iodide. The sodium-iodide symporter (NIS) is a glycoprotein that mediates the active uptake of iodide from the blood stream into the thyroid grand. NIS defects due to SLC5A5 gene mutations are known to cause congenital hypothyroidism (CH). The proposita is a 28-year-old female whose origin is North Sudan where neonatal screening for CH is not available. She presented with severe constipation and a goiter at the age of 40 days. Laboratory testing confirmed CH, and she was started on levothyroxine. Presumably due to the delayed treatment, the patient developed mental retardation. Her younger sister presented with a goiter, tongue protrusion, and umbilical hernia, and the youngest brother was also diagnosed with CH based on a thyrotropin level >100 µIU/mL at the age of 22 days and 8 days, respectively. The two siblings were treated with levothyroxine and had normal development. Their consanguineous parents had no history of thyroid disorders. Whole-exome sequencing was performed on the proposita. This identified a novel homozygous missense mutation in the SLC5A5 gene-c.1042T>G, p.Y348D-which was subsequently confirmed by Sanger sequencing. All affected children were homozygous for the same mutation, and their unaffected mother was heterozygous. The NIS protein is composed of 13 transmembrane segments (TMS), an extracellular amino-terminus, and an intracellular carboxy-terminus. The mutation is located in the TMS IX, which has the most ß-OH group-containing amino acids (serine and threonine), which is implicated in Na+ binding and translocation. In conclusion, a novel homozygous missense mutation in the SLC5A5 gene was identified in this Sudanese family with CH. The mutation is located in the TMS IX of the NIS protein, which is essential for NIS function. Low iodine intake in Sudan is considered to affect the severity of hypothyroidism in patients.