Strabismus, i.e. misalignment of the visual axes of the eyes, is a fairly common condition that affects up to 4% of the population.
The form of strabismus most common among children is concomitantcharacterised by a more or less constant angle of deviation of the two eyes in all directions of gaze, this is mainly convergent (exotropy) rather than divergent (exotropy).
Concomitant strabismus is associated with a poor binocular vision and amblyopia, and can influence normal interpersonal interactions leading to low self-esteem, social anxiety, phobias and limited employment opportunities with, subtle but significant, productivity losses in the population. The glasses and surgery are the standard treatments for concomitant strabismus, but many patients require several procedures during their lifetime. In any case, treatments do not address the root causes of strabismus, which experts believe are neurological.
The pathogenesis of concomitant strabismus remains largely unknownand several, often opposing, theories have been formulated to explain the infant form of exotropy. There is certainly a significant hereditary component the basis of concomitant strabismus, familial clustering was in fact described as early as around 400 BC by Hippocrates, and confirmed by more modern studies conducted on families and twins. It has been estimated that the relative risk for first-degree relatives of a proband with strabismus is approximately between 3 and 5Heredity remains significant even after correction for environmental risk factors.
A paper, recently published in Investigative Ophthalmology & Visual Sciencefocused attention on esotropia by investigating the genetic variants that confer greater susceptibility to this form of strabismuswhich is believed to be inherited as a complex stretch and has its highest incidence in European populations.
The study enrolled approximately 1,200 patients, Americans of white European descent and mostly seen at Boston Children's Hospital. The researchers conducted on these patients a genome-wide association study (GWAS), never previously used to investigate exotropy. GWAS, a relatively recent technique, investigates cohort genomes or large populations using known genetic markers such as SNPs (Single Nucleotide Polymorphism). This type of analysis can be useful to detect genetic variants that influence common traits such as height, obesity, diabetes or hypertension.
Normally the data obtained with GWAS are of the order of tens of hundreds of results, the analysis on exotropy conducted in this study produced only one. In fact, it was highlighted an association of exotropy with a single polymorphismdifferentially methylated, located within intron 1 (non-coding genetic region) of the WRB gene (tryptophan rich basic protein) located on chromosome 21. WRB is an 'imprinted' gene, i.e. the its expression varies depending on the parent from which it is inherited. Â In this respect, the study showed a statistically significant bias towards paternal inheritance, i.e. patients with strabismus were more likely to have inherited the WRB genetic variant from their father. Furthermore, WRB is located on chromosome 21, and children with trisomy 21 (or Down syndrome) have a higher incidence of squinting, a connection the researchers found interesting.
Although it is difficult at present to establish the precise role of WRB in strabismus, this first genome-wide association study (GWAS) suggests the involvement of a parent-of-origin inheritance effect in the occurrence of exotropia. To replicate and extend these findings, and provide information on the pathophysiological mechanisms underlying concomitant strabismus, however, further population analyses are required.
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Sources:
-Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect. Sherin Shaaban et al.  Investigative Opthalmology & Visual Science, 2018; 59 (10).
Dr. Carmelo Chines
Direttore responsabile
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