CFEOM1, the classic familial form of congenital fibrosis of the extraocular muscles, is genetically heterogeneous but does not result from mutations in ARIX.
BACKGROUND
To learn about the molecular etiology of strabismus, we are studying the genetic basis of 'congenital fibrosis of the extraocular muscles' (CFEOM). These syndromes are characterized by congenital restrictive ophthalmoplegia affecting muscles in the oculomotor and trochlear nerve distribution. Individuals with the classic form of CFEOM are born with bilateral ptosis and infraducted globes. When all affected members of a family have classic CFEOM, we classify the family as a CFEOM1 pedigree. We have previously determined that a CFEOM1 gene maps to the FEOM1 locus on chromosome 12cen. We now identify additional pedigrees with CFEOM1 to determine if the disorder is genetically heterogeneous and, if so, if any affected members of CFEOM1 pedigrees or sporadic cases of classic CFEOM harbor mutations in ARIX, the CFEOM2 disease gene.


RESULTS
Eleven new CFEOM1 pedigrees were identified. All demonstrated autosomal dominant inheritance, and nine were consistent with linkage to FEOM1. Two small CFEOM1 families were not linked to FEOM1, and both were consistent with linkage to FEOM3. We screened two CFEOM1 families consistent with linkage to FEOM2 and 5 sporadic individuals with classic CFEOM and did not detect ARIX mutations.


CONCLUSIONS
The phenotype of two small CFEOM1 families does not map to FEOM1, establishing genetic heterogeneity for this disorder. These two families may harbor mutations in the FEOM3 gene, as their phenotype is consistent with linkage to this locus. Thus far, we have not identified ARIX mutations in any affected members of CFEOM1 pedigrees or in any sporadic cases of classic CFEOM.
Engle
Elizabeth C
EC
Division of Genetics, Childrens Hospital, Boston, MA, USA.
McIntosh
Nathalie
N
Yamada
Koki
K
Lee
Bjorn A
BA
Johnson
Roger
R
O'Keefe
Michael
M
Letson
Robert
R
London
Arnold
A
Ballard
Evan
E
Ruttum
Mark
M
Matsumoto
Naomichi
N
Saito
Nakamichi
N
Collins
Mary Louise Z
ML
Morris
Lisa
L
Del Monte
Monte
M
Magli
Adriano
A
de Berardinis
Teresa
T
D005260:Female; D005355:Fibrosis; D008040:Genetic Linkage; D014644:Genetic Variation; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009801:Oculomotor Muscles / Q000473:pathology*; D009886:Ophthalmoplegia / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype
D018398:Homeodomain Proteins; C491061:PHOX2A protein, human