FOXI1 – Autosomal Recessive Nonsyndromic Hearing Loss 4

Genetic studies in patients with DFNB4 (autosomal recessive nonsyndromic hearing loss 4) and enlarged vestibular aqueduct (EVA) have identified rare heterozygous FOXI1 variants in small cohorts but no definitive biallelic or familial segregation. A novel FOXI1 c.519C>A (p.His173Gln) was found in 1/46 EVA probands (PMID:27997596), and c.677C>T (p.Thr226Ile) in 1/29 DFNB4/Pendred probands (PMID:24860705). Large sequencing panels attribute most diagnoses to biallelic SLC26A4 or other loci, with FOXI1 variants accounting for <2% of cases and lacking evidence of recurrence or segregation.

Functional assays show that FOXI1 missense variants do not significantly impair transcriptional activation of SLC26A4 or its promoter in vitro (PMID:22285650), and comprehensive promoter screens reveal no pathogenic FOXI1 alleles in EVA or DFNB4 cohorts. No animal or rescue models support a haploinsufficiency or dominant-negative mechanism. These data together support a Limited gene–disease association for FOXI1 in DFNB4.

Key Take-home: FOXI1 mutations have limited clinical utility in DFNB4 genetic diagnosis due to the absence of biallelic cases, segregation evidence, and functional impact.

References

• PLoS One • 2016 • A New Genetic Diagnostic for Enlarged Vestibular Aqueduct Based on Next-Generation Sequencing. PMID:27997596
• PeerJ • 2014 • Mutation analysis of the SLC26A4, FOXI1 and KCNJ10 genes in individuals with congenital hearing loss. PMID:24860705
• Molecular and Cellular Endocrinology • 2012 • Molecular and functional studies of 4 candidate loci in Pendred syndrome and nonsyndromic hearing loss. PMID:22285650

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