FOXI1 – Hearing Loss Disorder

Pathogenic variants in FOXI1 have been investigated as a cause of autosomal recessive hearing loss with inner ear malformations (DFNB4/EVA), but evidence across multiple cohorts remains limited. In a Siberian series of 165 patients with cochleovestibular anomalies, biallelic SLC26A4 mutations explained 4 of 6 cases, whereas no pathogenic FOXI1 variants were identified (PMID:36499699). In 101 Taiwanese EVA/Pendred families, screening of FOXI1 coding and promoter regions revealed no definite pathogenic alleles despite 24% of families carrying only one SLC26A4 mutation, suggesting FOXI1 does not account for the missing heritability (PMID:19648736). A single novel FOXI1 missense change, c.716C>T (p.Pro239Leu), was functionally neutral in transcriptional activation assays of SLC26A4 (PMID:22285650). In a Chinese EVA cohort, one heterozygous FOXI1 c.214C>A (p.Pro72Thr) carrier lacked a second pathogenic allele, and all definitive diagnoses were driven by SLC26A4 variants (PMID:32447495). No segregation of FOXI1 variants with hearing loss has been documented, and functional studies show no impairment of FOXI1 activity, indicating a limited role in MONDO:0005365.

Key Take-home: Current data do not support FOXI1 as a primary cause of autosomal recessive nonsyndromic hearing loss.

References

• International journal of molecular sciences • 2022 • Analysis of SLC26A4, FOXI1, and KCNJ10 Gene Variants in Patients with Incomplete Partition of the Cochlea and Enlarged Vestibular Aqueduct (EVA) Anomalies PMID:36499699
• Audiology & neuro-otology • 2010 • Phenotypic analyses and mutation screening of the SLC26A4 and FOXI1 genes in 101 Taiwanese families with bilateral nonsyndromic enlarged vestibular aqueduct (DFNB4) or Pendred syndrome. PMID:19648736
• Molecular and cellular endocrinology • 2012 • Molecular and functional studies of 4 candidate loci in Pendred syndrome and nonsyndromic hearing loss. PMID:22285650
• European archives of oto-rhino-laryngology • 2020 • Next-generation sequencing-based mutation analysis of genes associated with enlarged vestibular aqueduct in Chinese families. PMID:32447495

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