title: Variable expressivity of FGF3 mutations associated with deafness and LAMM syndrome.
abstract: BACKGROUND
  Recessive mutations of fibroblast growth factor 3 (FGF3) can cause LAMM syndrome (OMIM 610706), characterized by fully penetrant complete labyrinthine aplasia, microtia and microdontia.
  
  
  METHODS
  We performed a prospective molecular genetic and clinical study of families segregating hearing loss linked to FGF3 mutations. Ten affected individuals from three large Pakistani families segregating FGF3 mutations were imaged with CT, MRI, or both to detect inner ear abnormalities. We also modeled the three dimensional structure of FGF3 to better understand the structural consequences of the three missense mutations.
  
  
  RESULTS
  Two families segregated reported mutations (p.R104X and p.R95W) and one family segregated a novel mutation (p.R132GfsX26) of FGF3. All individuals homozygous for p.R104X or p.R132GfsX26 had fully penetrant features of LAMM syndrome. However, recessive p.R95W mutations were associated with nearly normal looking auricles and variable inner ear structural phenotypes, similar to that reported for a Somali family also segregating p.R95W. This suggests that the mild phenotype is not entirely due to genetic background. Molecular modeling result suggests a less drastic effect of p.R95W on FGF3 function compared with known missense mutations detected in fully penetrant LAMM syndrome. Since we detected significant intrafamilial variability of the inner ear structural phenotype in the family segregating p.R95W, we also sequenced FGF10 as a likely candidate for a modifier. However, we did not find any sequence variation, pointing out that a larger sample size will be needed to map and identify a modifier. We also observed a mild to moderate bilateral conductive hearing loss in three carriers of p.R95W, suggesting either a semi-dominant effect of this mutant allele of FGF3, otitis media, or a consequence of genetic background in these three family members.
  
  
  CONCLUSIONS
  We noted a less prominent dental and external ear phenotype in association with the homozygous p.R95W. Therefore, we conclude that the manifestations of recessive FGF3 mutations range from fully penetrant LAMM syndrome to deafness with residual inner ear structures and, by extension, with minimal syndromic features, an observation with implications for cochlear implantation candidacy.
authors.affiliation: Laboratory of Molecular Genetics, Division of Pediatric Otolaryngology Head & Neck Surgery, Cincinnati Children's Hospital Research Foundation, and University of Cincinnati, College of Medicine, Cincinnati, OH, USA.
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.forename: Rashmi S
authors.initials: RS
authors.lastname: Hegde
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.forename: Idrees
authors.initials: I
authors.lastname: Nasir
authors.forename: Uzma
authors.initials: U
authors.lastname: Shaukat
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.forename: John A
authors.initials: JA
authors.lastname: Butman
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Griffith
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.forename: Byung Yoon
authors.initials: BY
authors.lastname: Choi
mesh_terms: D000013:Congenital Abnormalities / Q000235:genetics; D065817:Congenital Microtia; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics*; D004423:Ear / Q000002:abnormalities; D007758:Ear, Inner / Q000002:abnormalities; D005260:Female; D051518:Fibroblast Growth Factor 3 / Q000235:genetics*; D015870:Gene Expression; D034381:Hearing Loss / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D014071:Tooth Abnormalities
chemical_list: C496444:FGF3 protein, human; D051518:Fibroblast Growth Factor 3