The Genetics and the Genomics of Primary Congenital Glaucoma

Abstract

The sight is one of the five senses allowing an autonomous and high-quality life, so that alterations of any ocular component may result in several clinical phenotypes (from conjunctivitis to severe vision loss and irreversible blindness). Most parts of clinical phenotypes have been significantly associated with mutations in genes regulating the normal formation and maturation of the anterior segments of the eye. Among the eye anterior segment disorders, special attention is given to Glaucoma as it represents one of the major causes of bilateral blindness in the world, with an onset due to Mendelian or multifactorial genetic-causative traits. This review will point out the attention on the Primary Congenital Glaucoma (PCG), which is usually transmitted according to an autosomal-recessive inheritance pattern. Taking into consideration the genetic component of the PCG, it is possible to observe a strong heterogeneity concerning the disease-associated loci (GLC3), penetrance defects, and expressivity of the disease. Given the strong PGC heterogeneity, pre- and posttest genetic counseling plays an essential role in the achievement of an appropriate management of PCG, in terms of medical, social, and psychological impact of the disease.

Understanding mutational effects in digenic diseases

“…Both lead to autosomal glaucoma (OMIM: #231300, #137750), an eye disease characterized by damage to the optic nerve. It is one of the major causes of bilateral blindness in the world, and interestingly it exhibits variable onset because of Mendelian or multifactorial traits ( 38 ). The digenic combinations dd026 and dd027 share a common variant (R368H) in the gene CYP1B1, but have different variants in MYOC, as shown in Table 3 .…”

Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

“…In family 2 ( Figure 1A), we screened for TEK variants by Sanger sequencing and identified an inconsistency in father-toson transmission for a known SNP (see Sanger sequencing traces in Figure 1B) that suggested the presence of a deletion. Copy number variation analysis was performed on the family trio using Affyan increase in aqueous humor (AH) production (5,6,14). Ocular anterior chamber fluid (AH) is produced by the ciliary body and drained mainly through Schlemm's canal (SC) and uveoscleral pathways (21,22).…”

“…PCG occurs in all ethnic groups, but the disease incidence varies according to ethnic background, ranging from 1:1,250 in inbred populations to 1:30,000 in populations with heterogeneous ethnicity (6,(8)(9)(10)(11)(12). Families can exhibit autosomal recessive or dominant inheritance, although the majority of cases appear to be sporadic (5,6,(10)(11)(12)(13)(14).…”

“…The molecular etiology of PCG is only partially understood, as only a few genes responsible for PCG have been identified (6,(10)(11)(12)(13)(14). Mutations in CYP1B1, which encodes a cytochrome P450 enzyme, is the most common cause of autosomal recessive PCG worldwide, accounting for up to 87% of familial cases in some inbred populations but only 25%-27% in populations with heterogeneous ethnicity (5, 9, 15-18).…”

Loss of PRSS56 function leads to ocular angle defects and increased susceptibility to high intraocular pressure

“…Primary congenital glaucoma (PCG) is a neonatal or early infancy autosomal recessive disease characterized by abnormal development of ocular angle structures, including the TM. Collectively, mutations in CYP1B1, LTBP2, MYOC, FOXC1 and GPATCH3 constitute a major cause of PCG worldwide [16][17][18][19][20][21][22][23]. However, mutations in these genes account for less than 50% of all PCG cases, suggesting that additional genes contribute to the etiology of PCG.…”