Prevalence of pendrin defects in sudanese families with congenital hypothyroidism

Abstract

Purpose: Pendred syndrome (PDS) is an autosomal recessive disease caused by variants in SLC26A4 manifesting thyroid dyshormonogenesis. Patients typically present with goiter and sensorineural hearing loss (SNHL). The prevalence of PDS in non-African populations is estimated to be between 7.5 and 10 per 100,000, while its occurrence in African populations has not been reported with molecular analysis.

Methods: This study, conducted at a university research center in Miami, USA and Khartoum, Sudan, to investigate PDS in Sudanese families with congenital hypothyroidism (CH). It involved 32 Sudanese families with children diagnosed with CH between 2016 and 2023. Patients underwent clinical evaluation, thyroid function tests, and genetic sequencing.

Results: Two disease-causing SLC26A4 variants were identified in two consanguineous families with first-cousin parents. One homozygous nonsense variant causing premature termination, p.Trp482*, previously reported as part of a compound heterozygous defect together with p.Gly102Arg, while the other homozygous defect was a previously reported missense variant, p.Thr410Met. In 32 families (72 individuals) whole exome sequencing data revealed 56.3% of families or 45.8% individuals harbored the SLC26A4 variants either in hetero or homozygous state. Of the 33 subjects who tested positive for the variants, 12 (36.4%) harbored more than one SLC26A4 variant.

Conclusions: This report extends our understanding of the severity of the phenotypes caused by deleterious bi-allelic variants in SLC26A4. Recurrent SLC26A4 variants observed in our cohort likely reflect high consanguinity rather than a founder effect. SLC26A4 screening could be a part of the molecular testing for children presenting with congenital or early-onset SNHL in Sudan.

Supplementary Information: The online version contains supplementary material available at 10.1007/s12020-025-04423-4.

Keywords: SLC26A4; Dyshormonogenesis; Goiter; Hearing loss; Pendred syndrome.

Fig. 1

Pedigrees and thyroid function tests of 2 families with CH caused by SLC26A4 variants. Family 1 (c.1446G > A, p.Trp482*) and Family 2 (c.1229 C > T, p.Thr410Met). Generations are denoted by roman numerals. Each subject is identified by the number just above the corresponding symbol. Results of thyroid function tests are aligned below each symbol. Diamond shape with inside number indicates the number of additional subjects of either sex. Abnormal values are in bold and underlined. The Asterisk (*) symbol indicates the stop codon. Slanted “T” on the upper left of the symbol indicates the individuals tested in Miami. A double horizontal line between individuals indicates consanguinity. Abbreviations: FT4, free thyroxine; TBG, thyroxine-binding globulin; TG, thyroglobulin; TG Ab, thyroglobulin antibody; TPO Ab, TPO antibody; TSH, thyroid-stimulating hormone; TT3, total triiodothyronine; TT4, total thyroxine; UK, unknown

Fig. 2

SCL26A4 variants. (A) Prevalence of SLC26A4 variants in 32 Sudanese families with CH. 56.3% families or, 45.8% individuals harbored SLC26A4 variants. Of the 33 subjects who tested positive for the variants, 12 (36.4%) harbored more than one SLC26A4 variant (B) Schematic representation of the SLC26A4 gene and location of variants identified. Amino acid numbers are denoted by numbers spanning schematic. SLC26A4 exons are denoted by roman numerals. All SLC26A4 variants identified in the Sudanese individuals in this report are noted at their approximate locations in the SLC26A4 exons. Variants in red are observed in family 1 and 2