Primary Congenital Glaucoma via the LTBP2 Gene

Primary congenital glaucoma (PCG) or Trabeculodysgenesis presents in neonates and during the infantile period, with a varying prevalence rate ranging from 1 in 1,250 to 20,000 among different geographic locations and ethnic groups. The highest prevalence is found in the Gypsy population of Slovakia (1 in 1,250) followed by Saudi Arabians (1:2,500), Southern India (1:3,300), and Western nations (1:5000-22,000) (Gencík et al. 1982; Azmanov et al. 2011; Abu-Amero and Edward 2011). PCG is characterized by elevated intraocular pressure (IOP), increased corneal diameter (megalocornea), enlarged globe (buphthalmos), Haab’s striae (opacification of the cornea with ruptures involving Descemet’s membrane), corneal edema and optic nerve head cupping, thinning of the anterior sclera and atrophy of the iris. Symptoms include photophobia, blepharospasm (abnormal contraction of the eyelid), and hyperlacrimation (excessive tearing). Abnormal development of the anterior segment angle or goniodysgenesis are the hallmarks of congenital glaucoma. It is a chronic disease and a major cause of blindness; earlier detection is needed in order to prevent vision loss (Martin et al. 2000; Abu-Amero and Edward 2011).

Currently, mutations in CYP1B1 and LTBP2 have been reported to cause PCG with autosomal recessive inheritance (Abu-Amero et al.2011; Abu-Amero and Edward 2011). LTBP2 is the second gene implicated in PCG after CYP1B1. LTBP2, encoded by LTBP2, is the largest member of the latent transforming growth factor (TGF)-beta binding protein family, that is localized in the anterior segment of the eye at the ciliary body. LTBP2 expression was shown in human eyes, including the trabecular meshwork which is considered to be affected in PCG. LTBP2 was shown to be essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone and its surrounding structures (Ali et al. 2009; Narooie-Nejad et al. 2009). So far, about 10 pathogenic variations in LTBP2 have been associated with PCG and the majority of them are null mutations (Human Gene Mutation Database).

A LTBP2 founder mutation (p.Arg299*), in the Gypsy population, accounts for over 50% of the CYP1B1-negative cases and 40% of overall PCG cases (Ali et al. 2009). In another study, two out of three unrelated CYP1B1-negative PCG affected Iranian families had loss of function mutations in LTBP2, which segregated with the disease and were absent in 400 control individuals (Narooie-Nejad et al. 2009).

This test provides full coverage of all coding exons of the LTBP2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).