CFEOM1, the classic familial form of congenital fibrosis of the extraocular muscles, is genetically heterogeneous but does not result from mutations in ARIX

Abstract

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.

Figure 1

Haplotype analysis of pedigrees BJ, CZ, AG, AJ, AH, T, CT, BC, and E at the FEOM1 locus. Black symbols denote those individuals who are clinically affected with classic CFEOM. Genotyping data and schematic segregating haplotype bars for chromosome 12cen markers are shown below the symbol for each study participant. Allele sizes here and in figure 2 were assigned as linkage studies were performed are not equivalent when compared between families. Black bars denote the potential disease-associated region. Diagonally hatched or white bars highlight the inheritance of the non-disease-associated haplotypes. References to specific individuals within the text refer to the generation number (Roman numeral) and position within generation (Arabic numeral). In all 9 pedigrees each family's disease-associated haplotype is inherited by all CFEOM1 individuals and by no asymptomatic individuals.

Figure 2

Haplotype analysis for pedigrees K at the (a)FEOM1 and (b)FEOM3 loci and BT at the (c)FEOM1 and (d)FEOM3 loci. Symbols are defined in the legend to figure 1. In each family the CFEOM1 phenotype is co-inherited with FEOM3 markers and not with FEOM1 markers.