Evidence of genetic heterogeneity in autosomal recessive congenital fibrosis of the extraocular muscles

Abstract

PURPOSE: Autosomal recessive congenital fibrosis of the extraocular muscles (CFEOM2) has been described in families from Saudi Arabia. Affected individuals have ptosis and exotropic ophthalmoplegia, and their disease has been mapped to chromosome 11q13. Here, we describe the phenotypic findings in a similarly affected Yemenite family and analyze the family for linkage to the CFEOM2 locus, as well as to the autosomal dominant CFEOM1 and CFEOM3 loci on chromosomes 12cen and 16q24, respectively. METHODS: The family was ascertained through two affected daughters. There are four unaffected siblings, and the parents are consanguineous. Each family member was examined, and linkage analysis was performed using markers from the CFEOM1, CFEOM2, and CFEOM3 loci. RESULTS: Both affected daughters have congenital bilateral ophthalmoplegia. The 15-month-old proband has restrictive exotropia. She fixates with either eye in abduction and with a compensatory head turn to the opposite side. Her 4-year-old sister has a small exotropia and severely limited eye movements. All other family members have normal ophthalmologic examinations. Genetic analysis excluded linkage of the family’s disease to the CFEOM2 and CFEOM3 loci. A lod score of 2.0 (the maximum possible, given the family size and structure), was obtained at the CFEOM1 locus, and the alleles reduced to homozygosity in both affected daughters and none of the other children. CONCLUSIONS: These data establish that there is genetic heterogeneity in autosomal recessive CFEOM and suggest that this second recessive locus may be allelic to the autosomal dominant CFEOM1 locus at 12cen.