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SLC26A7 – Congenital Hypothyroidism due to Thyroid Dyshormonogenesis

The solute carrier family 26 member 7 (SLC26A7) gene, encoding an anion transporter expressed in the thyroid gland, has been implicated in congenital hypothyroidism due to thyroid dyshormonogenesis (MONDO:0018612). Variants in SLC26A7 follow an autosomal recessive inheritance pattern with homozygous or compound heterozygous alleles leading to deficient iodide transport and impaired thyroid hormone synthesis.

Two independent case reports describe affected individuals harboring homozygous truncating SLC26A7 variants. A girl presented with congenital hypothyroidism and dyshormonogenesis caused by c.1432_1433delGT (p.Val478LysfsTer11), leading to a premature stop codon and predicted nonfunctional protein (PMID:32486989). A 19-year-old Tunisian man developed late-onset goitrous hypothyroidism associated with p.Pro628GlnfsTer11; his heterozygous brother remained euthyroid, supporting recessive segregation (PMID:38812002).

In a cohort of 55 Saudi Arabian patients from 47 families with congenital hypothyroidism, exome sequencing revealed biallelic SLC26A7 mutations in 2 of 30 individuals with dyshormonogenesis (6.7%), establishing SLC26A7 as a recurrent contributor in this subgroup (PMID:29546359). These data place SLC26A7 alongside TG and TPO as genetic causes of thyroid dyshormonogenesis in consanguineous populations.

All reported SLC26A7 alleles are predicted loss-of-function truncating variants consistent with autosomal recessive inheritance. No recurrent or population-specific founder variants have been described. Segregation analyses in available pedigrees align with biallelic transmission exclusively in affected individuals with no observed de novo events.

Functional characterization is currently limited to in silico pathogenicity predictions and the established role of SLC26A7 in iodide exchange; no direct in vitro or in vivo assays in thyroid models have been reported. The proposed mechanism involves impaired anion transport leading to defective thyroid hormone biosynthesis.

Taken together, multiple unrelated cases with homozygous truncating SLC26A7 variants and corroborative cohort data support a moderate level of clinical validity for SLC26A7 in dyshormonogenic congenital hypothyroidism. Additional functional studies are needed to confirm pathogenic mechanisms. Key take-home: Include SLC26A7 in genetic testing panels for congenital hypothyroidism with thyroid dyshormonogenesis.

References

  • Thyroid • 2020 • A Novel Homozygous Mutation in the Solute Carrier Family 26 Member 7 Gene Causes Thyroid Dyshormonogenesis in a Girl with Congenital Hypothyroidism. PMID:32486989
  • Italian Journal of Pediatrics • 2024 • Late-onset dyshormonogenic goitrous hypothyroidism due to a homozygous mutation of the SLC26A7 gene: a case report. PMID:38812002
  • The Journal of Clinical Endocrinology and Metabolism • 2018 • Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis. PMID:29546359

Evidence Based Scoring (AI generated)

Gene–Disease Association

Moderate

Four unrelated probands with homozygous truncating SLC26A7 variants ([PMID:32486989], [PMID:38812002]) plus two additional cases in a multi-patient cohort ([PMID:29546359]); predicted loss-of-function mechanism consistent with thyroid dyshormonogenesis.

Genetic Evidence

Moderate

Six individuals from diverse populations harbor biallelic truncating SLC26A7 alleles in unrelated families under an autosomal recessive model, meeting moderate genetic evidence criteria.

Functional Evidence

Limited

Variant pathogenicity is supported by in silico predictions and known transporter role of SLC26A7, but lacks direct in vitro or in vivo functional validation in thyroid models.