A FGF3 mutation associated with differential inner ear malformation, microtia, and microdontia

Area of Science:

• Genetics
• Otolaryngology
• Developmental Biology

Background:

• Autosomal recessive inheritance patterns can lead to complex syndromic phenotypes.
• Fibroblast growth factor 3 (FGF3) plays a crucial role in embryonic development, including inner and outer ear formation.
• Mutations in FGF3 have been implicated in hearing impairment and craniofacial abnormalities.

Purpose of the Study:

• To investigate the genetic basis of a hearing impairment and microdontia syndrome in a Somali family.
• To identify the specific gene and mutation responsible for the observed phenotype.
• To analyze the association between genotype and phenotype in affected individuals.

Main Methods:

• Prospective genetic study involving auditory investigations, computed tomography (CT) scans, and genetic sequencing.
• Analysis of the fibroblast growth factor 3 (FGF3) gene in affected family members.
• Phenotypic assessment including outer ear morphology and inner ear malformations via CT imaging.

Main Results:

• Computed tomography revealed variable inner ear malformations, including labyrinth aplasia and Mondini malformation, in affected individuals.
• Genetic sequencing identified a novel p.R95W missense mutation in the FGF3 gene, segregating with the observed pathology.
• The p.R95W mutation affects a highly conserved region of FGF3, suggesting a disruption of FGF3/FGFR2 signaling.

Conclusions:

• This study identifies homozygous inheritance of a novel FGF3 p.R95W mutation as the cause of variable inner ear malformations and outer ear dysplasia with constant microdontia.
• The findings establish a genotype-phenotype correlation, linking specific FGF3 mutations to a distinct set of developmental abnormalities.
• The observed phenotypes in humans mirror those seen in mouse models with disrupted FGF3/FGFR2 signaling, validating the role of this pathway in ear development.