A number sign (#) is used with this entry because of evidence that primary congenital glaucoma-3D (GLC3D) is caused by homozygous or compound heterozygous mutation in the LTBP2 gene (602091) on chromosome 14q24.

For a general phenotypic description and a discussion of primary congenital glaucoma (PCG), see GLC3A (231300).

Firasat et al. (2008) identified 2 consanguineous Pakistani families in which PCG mapped to chromosome 14q24.2-q24.3 (GLC3D). Both families were from the Punjab province. Symptoms of PCG in one family appeared in the first 3 years of life. Symptoms in the second family were present either at birth or within the first 6 weeks of life. Visual acuity was confined to light perception and/or counting fingers in both families. Bilateral buphthalmos was present in the second family.

Ali et al. (2009) described 4 unrelated consanguineous Pakistani families with primary congenital glaucoma, including the 2 reported by Firasat et al. (2008). Affected individuals had a history of tearing and photophobia either shortly after birth or within the first 3 years of life. Most had undergone multiple failed surgical procedures and had visual acuity of counting fingers or worse. Increased intraocular pressure was evident since first presentation (up to 56 mm Hg) with corneal enlargement and clouding. Affected individuals from 3 families had mild to moderate osteopenia and high-arched palate. Some affected members had ectopia lentis, and in one family marfanoid habitus with joint hypermobility and tall stature was present in affected individuals. Ali et al. (2009) also reported 8 Gypsy individuals with GLC3D.

Narooie-Nejad et al. (2009) described 2 consanguineous Iranian families with primary congenital glaucoma. The first family had 8 affected members with onset after birth or within the first 2 years of life. Ectopia lentis in both eyes was observed in 1 patient. Ectopia lentis of the right eye and keratectasia of the left eye were observed in another patient. The second family had 2 affected sibs who had onset at birth. The older sib had corneal clouding, and the younger sib had corneal clouding and enlargement.

The transmission pattern of GLC3D in the families reported by Ali et al. (2009) was consistent with autosomal recessive inheritance.

Firasat et al. (2008) identified 2 consanguineous Pakistani families in which PCG mapped to chromosome 14q24.2-q24.3 within a 6.56-cM (approximately 4.2-Mb) genetic interval flanked by D14S289 proximally and D14S85 distally. Maximum lod scores of 5.88 and 6.19 were obtained with markers D14S61 and D14S43 in each family, respectively.

Firasat et al. (2008) and Ali et al. (2009) pointed out that the GLC3D locus on chromosome 14q24.2-q24.3 is adjacent to but does not overlap the GLC3C locus (613085). The GLC3D locus implicated in the Pakistani families contained 97 genes, from which Ali et al. (2009) selected LTBP2 (602091) as a strong candidate based on its high expression in the anterior segment of the eye. Ali et al. (2009) identified a different premature termination mutation in the LTBP2 gene (602091.0001-602091.0004) in each of the 4 Pakistani families reported by them. The mutations segregated with the disorder in each family and were excluded from a panel of 110 ethnically matched control DNAs. Although the 4 Pakistani families all originated from the Punjab province, they each resided in different cities and also belonged to different clans. The lack of a single founder mutation was consistent with the diverse geographic and ethnic origins of these families. Additionally, Ali et al. (2009) found a nonsense mutation in the LTBP2 gene in 8 of 15 Gypsy families; this was the same mutation as that reported in one of the Pakistani families (R299X; 602091.0001).

In 2 consanguineous Iranian families with primary congenital glaucoma, Narooie-Nejad et al. (2009) independently identified respective homozygous 1-bp deletions (602091.0006-602091.0007).

Ali et al. (2009) found the same R299X mutation in a Pakistani family and in 8 Gypsy families with PCG. Affected members of all these families shared an identical haplotype, implying that they shared a distant common ancestor. The Pakistani family belongs to the Jatt (Jat), a clan/ethnic group of Indo-Aryan descent that had been proposed as a possible Gypsy parental population. The findings of Ali et al. (2009) provided support for this hypothesis and suggested that R299X is an ancient founder mutation predating the emergence of European Gypsies from the Jatt. The finding of Ali et al. (2009) of the R299X mutation in 8 of 15 Gypsy individuals with PCG negative for mutations in CYP1B1 (601771) suggested that R299X is the major PCG founder mutation in the Gypsy population, accounting for more than 50% of CYP1B1-negative and nearly 40% of all PCG cases in this ethnic group.

In 37 Roma/Gypsy probands with PCG, Azmanov et al. (2011) performed direct sequencing of the entire coding sequence of the CYP1B1 gene as well as exon 4 of the LTBP2 gene, which harbors the R299X founder mutation. In 25 (approximately 70%) of the 37 patients, they identified homozygosity or compound heterozygosity for 5 different mutations in CYP1B1 or for the R299X mutation in LTBP2. In 14 patients, no mutation was identified. Homozygosity for the R299X LTBP2 mutation resulted in a more severe clinical phenotype and poorer outcome despite a markedly higher number of surgical interventions. The genetically homogeneous group of R299X homozygotes displayed phenotypes varying from PCG with primary dysgenesis of the trabecular meshwork to Marfan syndrome (see 154700)-like zonular disease with ectopia lentis and later-onset secondary glaucoma. Azmanov et al. (2011) stated that preliminary observations on patients with mutations in both CYP1B1 and LTBP2 suggested that the observed combinations were of no clinical significance and that digenic inheritance was unlikely. Genetic drift was suggested as the 'most plausible scenario' for the allelic heterogeneity seen in this Gypsy population.