Strabismus has been known to have a significant genetic component, but the mode of inheritance and the identity of the relevant genes have been enigmatic. This paper reports linkage analysis of nonsyndromic strabismus. The principal results of this study are: (i) the demonstrated feasibility of identifying and recruiting large families in which multiple members have (or had) strabismus; (ii) the linkage in one large family of a presumptive strabismus susceptibility locus to 7p22.1 with a multipoint logarithm of odds score of 4.51 under a model of recessive inheritance; and (iii) the failure to observe significant linkage to 7p in six other multiplex families, consistent with genetic heterogeneity among families. These findings suggest that it will be possible to localize and ultimately identify strabismus susceptibility genes by linkage analysis and mutation screening of candidate genes.linkage ͉ whole genome scan ͉ complex trait ͉ ophthalmic genetics S trabismus (misalignment of the eyes; also referred to as ''squint'') is one of the most common ocular disorders in humans, affecting 1-4% of the population (1). It is frequently associated with amblyopia (uniocular visual neglect), a leading cause of visual impairment in children and young adults. The familial clustering of strabismus has been recognized since antiquity. For example, Hippocrates stated that ''children of parents having distorted eyes squint also for the most part'' (1).Numerous twin and family studies point to a significant genetic component in the etiology of strabismus (summarized in refs. 1-4). Summing the data from 11 published twin studies shows that, among 206 monozygotic and 130 dizygotic twin pairs in which one member of the twin pair had strabismus, 73% of monozygotic twin pairs were concordant for strabismus, whereas only 35% of dizygotic twin pairs were concordant for strabismus. We note that the degree of concordance among dizygotic twin pairs is higher than the Ϸ10-15% typically reported for siblings; this may reflect the overall higher incidence of strabismus among premature and low-birth-weight infants.The overall incidence of strabismus and the incidence of specific types of strabismus show appreciable differences between racial groups, further supporting the relevance of genetic factors. Two studies have documented a lower incidence of all types of strabismus among Africans or African Americans (0.5% and 0.6%, respectively) relative to Americans of European ancestry (2.5%; refs. 5 and 6). Moreover, the majority of African, African American, and Asian strabismics are exotropes, whereas the majority of Caucasian strabismics are esotropes (5-7).With respect to overall heritability, the relative risk for first degree relatives of an affected individual is estimated to be between 3 and 5. Crone and Vezeboer (8) found that 13% of parents of strabismic probands had strabismus vs. a 3% incidence in the general population. Hu (9) found a 9% incidence among first-degree relatives and a 2.2% incidence among second degree relatives, versus ...

The decision to probe early in the office or continue medical management and probe beyond a year of age in a facility with a general anesthetic is at the discretion of the ophthalmologist. Failed probings should be treated in a facility under general anesthesia with a balloon catheter or intubation. Children with congenital nasolacrimal duct obstruction need to be followed to make certain they do not develop anisometropic amblyopia.

BackgroundCongenital fibrosis of the extraocular muscles types 1 and 3 (CFEOM1/CFEOM3) are autosomal dominant strabismus disorders that appear to result from maldevelopment of ocular nuclei and nerves. We previously reported that most individuals with CFEOM1 and rare individuals with CFEOM3 harbor heterozygous mutations in KIF21A. KIF21A encodes a kinesin motor involved in anterograde axonal transport, and the familial and de novo mutations reported to date predictably alter one of only a few KIF21A amino acids – three within the third coiled-coil region of the stalk and one in the distal motor domain, suggesting they result in altered KIF21A function. To further define the spectrum of KIF21A mutations in CFEOM we have now identified all CFEOM probands newly enrolled in our study and determined if they harbor mutations in KIF21A.ResultsSixteen CFEOM1 and 29 CFEOM3 probands were studied. Three previously unreported de novo KIF21A mutations were identified in three CFEOM1 probands, all located in the same coiled-coil region of the stalk that contains all but one of the previously reported mutations. Eight additional CFEOM1 probands harbored three of the mutations previously reported in KIF21A; seven had one of the two most common mutations, while one harbored the mutation in the distal motor domain. No mutation was detected in 5 CFEOM1 or any CFEOM3 probands.ConclusionAnalysis of sixteen CFEOM1 probands revealed three novel KIF21A mutations and confirmed three reported mutations, bringing the total number of reported KIF21A mutations in CFEOM1 to 11 mutations among 70 mutation positive probands. All three new mutations alter amino acids in heptad repeats within the third coiled-coil region of the KIF21A stalk, further highlighting the importance of alterations in this domain in the etiology of CFEOM1.