A strabismus susceptibility locus on chromosome 7p

Abstract

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 ...

Heritability of Strabismus: Genetic Influence Is Specific to Eso-Deviation and Independent of Refractive Error

“…Genome-wide linkage analysis of comitant strabismus has yielded relatively few chromosomal susceptibility loci. An initial study found loci at chromosomes 7p22.1 (Parikh et al, 2003) and a more recent study (Shaaban et al, 2009), extending previous work by Fujiwara et al (2003), identified loci at 4q28.3 and 7q3.1. This second study, conducted in 55 Japanese families with at least two cases of comitant strabismus, did not distinguish these cases based on the direction of their deviation.…”

Replication of the Recessive STBMS1 Locus but with Dominant Inheritance

“…Subjects were considered to be affected if they had obvious strabismus, underwent strabismus surgery, occlusion, or orthoptic exercises, or received a diagnosis of strabismus or amblyopia. This study, 8 like the previous one, 36 did not distinguish between esotropia and exotropia. DNA of seven large families of European ancestry was sampled, with phenotypes recorded primarily by self-report, and family members underwent whole genome linkage analysis.…”

“…However, the STBMS1 locus was reported under a recessive mode of inheritance. 8 Multipoint analyses were therefore undertaken under both recessive and dominant models. To define appropriate parameters for dominant and recessive inheritance for PNCE, we made the assumption that STBMS1 accounted for approximately 20% of PNCE but that mutations at other unidentified loci accounted for the reminder of the trait.…”

“…6,7 In contrast, for the more common comitant strabismus, only one recessive susceptibly locus has been identified, in a single family, on chromosome 7p. 6,8 Nevertheless, there is considerable evidence of a genetic basis for comitant strabismus. Clinically, it is readily observed that strabismus clusters within families.…”

“…However, this study was underpowered and revealed only a series of insignificant linkage peaks with no definite linkage. The second study, undertaken by Parikh et al, 8 identified potential strabismic families with multiple affected members. Strabismus status was construed from telephone conversations and retrospective analyses of medical records.…”