SLC26A4 – Pendred syndrome

Pendred syndrome is an autosomal recessive disorder characterized by congenital sensorineural hearing loss and thyroid dyshormonogenesis due to biallelic variants in SLC26A4. Pendrin, the chloride/iodide exchanger encoded by SLC26A4, is expressed in the inner ear and thyroid follicular cells. Diagnosis integrates audiometry, inner ear imaging showing enlarged vestibular aqueduct (EVA), and perchlorate discharge testing to confirm defective iodide organification.

Early reports identified key pathogenic alleles. A seminal case described homozygosity for c.1151A>G (p.Glu384Gly) in a child with progressive bilateral hearing loss and EVA (PMID:9604973). Multi-ethnic cohorts have since revealed a broad allelic spectrum, including recurrent splice-site mutations (c.919-2A>G) and founder missense alleles (p.His723Arg) in East Asian populations (PMID:11502831).

Autosomal recessive inheritance is supported by biallelic SLC26A4 mutations identified in over 200 probands across diverse families. Compound heterozygous and homozygous states involving missense, splice, frameshift, and large deletion alleles consistently co-segregate with Pendred syndrome, confirming strong genetic evidence (PMID:22429511).

Segregation studies in consanguineous kindreds demonstrate clear co-segregation of pathogenic variants with the phenotype. For example, a frameshift c.451del (p.Val151LeufsTer3) variant was homozygous in five affected relatives showing sensorineural deafness and goiter, with obligate carrier parents unaffected (PMID:22429511).

Functional assays reveal that pathogenic pendrin variants are mislocalized to the endoplasmic reticulum and lack Cl⁻/I⁻ exchange activity. In vitro expression of nine disease-causing missense mutants showed defective trafficking and abolished iodide efflux in HEK293 cells (PMID:11932316); corresponding studies confirmed ER retention for L236P, T416P, and G384 mutants (PMID:12354788).

Integrating genetic and experimental data yields a Definitive gene–disease association. The autosomal recessive inheritance, extensive segregation in multiple families, diverse case series, and concordant functional impairments satisfy ClinGen criteria for a definitive link between SLC26A4 and Pendred syndrome.

Key Take-home: Biallelic SLC26A4 variants are a definitive cause of autosomal recessive Pendred syndrome; comprehensive genetic testing of SLC26A4 is essential for accurate diagnosis and management.

References

• Archives of otolaryngology--head & neck surgery • 1998 • Progressive sensorineural hearing loss and a widened vestibular aqueduct in Pendred syndrome PMID:9604973
• The Journal of clinical endocrinology and metabolism • 2001 • Two Chinese families with Pendred's syndrome--radiological imaging of the ear and molecular analysis of the pendrin gene PMID:11502831
• International journal of pediatric otorhinolaryngology • 2012 • Segregation of a new mutation in SLC26A4 and p.E47X mutation in GJB2 within a consanguineous Tunisian family affected with Pendred syndrome PMID:22429511
• The Journal of clinical endocrinology and metabolism • 2002 • Mutations of the PDS gene, encoding pendrin, are associated with protein mislocalization and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome PMID:11932316
• Human molecular genetics • 2002 • Retention of pendrin in the endoplasmic reticulum is a major mechanism for Pendred syndrome PMID:12354788
• Journal of medical genetics • 2003 • Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness PMID:12676893

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