FGF3 – Deafness with Labyrinthine Aplasia, Microtia, and Microdontia

Autosomal recessive mutations in the fibroblast growth factor 3 (FGF3) gene cause deafness with labyrinthine aplasia, microtia, and microdontia (deafness with labyrinthine aplasia, microtia, and microdontia), also known as LAMM syndrome. This syndrome is characterized by congenital severe to profound sensorineural hearing impairment, complete or partial inner ear malformations, type I microtia, and microdontia (PMID:19950373, PMID:21306635). A consistent feature of microdontia alongside variable outer and inner ear phenotypes underscores the critical role of FGF3 in otic and dental development.

Genetic evidence for FGF3 in LAMM syndrome is robust and autosomal recessive. A Somali kindred displayed homozygosity for c.283C>T (p.Arg95Trp) in FGF3 segregating with hearing impairment, microtia, and microdontia in three affected individuals (PMID:19950373). A follow-up study of three Pakistani families identified 10 affected individuals homozygous for FGF3 mutations (p.Arg104Ter, p.Arg95Trp, p.Arg132GlyfsTer26) with full penetrance of LAMM features in two families and variable inner ear phenotypes in those with p.Arg95Trp (PMID:21306635). More recently, three Uyghur families with novel c.137G>C (p.Arg46Pro) mutations in FGF3 were reported in three probands, expanding the allelic and phenotypic spectrum (PMID:39425091). Segregation data include co-segregation in four consanguineous families involving 12 affected relatives (PMID:19950373, PMID:21306635).

The spectrum of pathogenic FGF3 variants in LAMM syndrome comprises missense, nonsense, and frameshift alleles. Missense variants include c.283C>T (p.Arg95Trp) in the RYLAM motif and c.137G>C (p.Arg46Pro); nonsense alleles include c.310C>T (p.Arg104Ter); and frameshift alleles include c.395_396del (p.Arg132GlyfsTer26) (PMID:19950373, PMID:21306635, PMID:39425091). The recurrent p.Arg95Trp variant accounts for mild to variable inner ear malformation, while null alleles produce fully penetrant labyrinthine aplasia and microtia. Population data remain limited, with no reported carriers in gnomAD for these rare alleles.

Functional studies support a loss-of-function mechanism for FGF3 in ear and tooth development. Mouse models ablating Fgf3 and its interaction partner Fgfr2 recapitulate the inner ear aplasia and dental anomalies characteristic of LAMM syndrome (PMID:19950373). In vitro, mouse Fgf3 binds FGFR1 and FGFR2 IIIb isoforms with high affinity (ID50 ≈0.8 nM) and acts as a potent epithelial mitogen PMID:7592624. Additionally, zebrafish cnot8 mutants with elevated fgf3 expression show altered neuronal development reversible by Fgf3 inhibition, further highlighting FGF3’s role in developmental signaling (PMID:25478689).

Structural modeling indicates that p.Arg95Trp exerts a hypomorphic effect by disrupting the beta-sheet interface, whereas truncating variants abolish receptor binding and downstream signaling (PMID:21306635). The variable expressivity seen in p.Arg95Trp homozygotes suggests allele-specific residual function and potential modifier effects. Consistent clinical, genetic, and functional concordance across multiple studies strengthens the pathogenic role of biallelic FGF3 variants in LAMM syndrome.

Integration of genetic segregation in ≥16 probands, concordant functional models, and mechanistic insights justify a Strong clinical validity classification. Genetic evidence meets the ClinGen cap for AR disorders with at least 23 points from case-level data and segregation, and functional evidence achieves Moderate due to in vitro and in vivo modeling. Key take-home: Biallelic FGF3 mutations are a clinically actionable cause of LAMM syndrome, informing genetic diagnosis, counseling, and cochlear implantation planning.

References

• The Laryngoscope • 2010 • A FGF3 mutation associated with differential inner ear malformation, microtia, and microdontia PMID:19950373
• BMC Medical Genetics • 2011 • Variable expressivity of FGF3 mutations associated with deafness and LAMM syndrome PMID:21306635
• BMC Medical Genomics • 2024 • Identification of a novel FGF3 variant and a new phenotype in three LAMM syndrome families PMID:39425091
• The Journal of Biological Chemistry • 1995 • Receptor binding and mitogenic properties of mouse fibroblast growth factor 3. Modulation of response by heparin PMID:7592624
• PLOS ONE • 2014 • A mutation in cnot8, component of the Ccr4-not complex regulating transcript stability, affects expression levels of developmental regulators and reveals a role of Fgf3 in development of caudal hypothalamic dopaminergic neurons PMID:25478689

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