Importance of genetic studies in the diagnosis of glaucoma
Authors: Bifet Meritxell Jodar 
Published: January 2024

Glaucoma is the world's leading cause of irreversible blindness being a known family grouping disease with a strong hereditary component. Based on the age of onset and other clinical characteristics, glaucoma has been classified into primary congenital glaucoma (PCG), juvenile glaucoma (JG), and primary open‐angle glaucoma (POAG), the latter occurring in adulthood. Early‐onset forms of glaucoma such as, PCG and JG, are typically monogenic diseases inherited as Mendelian autosomal dominant or recessive traits, whereas adult glaucoma is a complex trait, with multifactorial inheritance.

Genetic variants causing early‐onset glaucoma are highly penetrant. Some examples include dominant negative pathogenic variants in the MYOC gene accounting for 10% of JG cases or biallelic pathogenic variants in CYP1B1 gene mainly associated with PCG. In our cohort of 32 patients with a diagnosis of PCG or JG, we have identified two JOAG patients with two different pathogenic variants in the olfactomedin/like domain of MYOC gene and one PGC patient with two heterozygote pathogenic variants in CYP1B1 gene. Familiar segregation studies of these genetic variants in the three families confirm their pathogenicity. On the one hand, segregation studies of both variants identified in MYOC gene revealed its presence in those relatives with a clinical diagnosis of glaucoma and its absence in healthy individuals. On the other hand, parental screening of both variants identified in CYP1B1 showed that each parent is an asymptomatic carrier of one of the variants confirming that our patient present both variants in CYP1B1 gene in compound heterozygosis. Furthermore, heterozygote pathogenic variants in FOXC1 and COL2A1 genes associated with Axenfeld‐Rieger syndrome type 3 and Stickler syndrome type 1, respectively, have been identified in two different patients with PGC. In these cases, glaucoma is a phenotypic trait of both syndromes inherited in an autosomal dominant manner.

Family grouping is a known risk factor for glaucoma in the adult, with a risk 7–10 times greater than the observed in general population. The genetic study of adult glaucoma is complex since its transmission mechanisms are sometimes unclear and have variable penetrance and late onset. In our cohort of 65 patients diagnosed with adult glaucoma, we have identified rare genetic variants with uncertain clinic significance in CYP1B1, SIX6, CARD10, MFN1, OPTC, OPTN, and WDR36 glaucoma‐related genes. Some of these variants are classified as hypomorphic alleles that reduce but do not eliminate gene's functionality and they can contribute to late‐onset disorders.

Glaucoma is a treatable disease if detected in early stages and treatment can stop visual loss, however if damage has already occurred it cannot be reverted. Therefore, to identify a genetic cause associated with glaucoma is not only beneficial for the patient but also to detect asymptomatic carriers of the disease in the family‐relatives, which will be susceptible for early treatment. Therefore, proper genetic analysis may provide more accurate information on the prognosis and the adequacy of the therapeutic approach to personalize the treatment of glaucoma.