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Delineation of Novel Compound Heterozygous Variants in LTBP2 Associated with Juvenile Open Angle Glaucoma.

ABSTRACT: Juvenile open angle glaucoma (JOAG), which is an uncommon form of primary open angle glaucoma, is a clinically and genetically heterogeneous disorder. We report on a family with a recessively inherited form of JOAG. The proband has a superior and an inferior never fiber layer thinning in both the eyes and the nasal visual field (VF) defects in the left eye, which are clinical findings consistent with glaucomatous optic neuropathy. Whole exome sequencing revealed two novel compound heterozygous variants [c.2966C>G, p.(Pro989Arg); c.5235T>G, p.(Asn1745Lys)] in latent transforming growth factor-beta-binding protein 2 (LTBP2) segregating with the phenotype. Both these variants are predicted to replace evolutionary conserved amino acids, have a pathogenic effect on the encode protein, and have very low frequencies in the control databases. Mutations in LTBP2 are known to cause the Weill-Marchesani syndrome and a Weill-Marchesani-like syndrome, which include glaucoma in their clinical presentation. However, to our knowledge, this is the first published case of a JOAG subject associated with recessively inherited variants of LTPB2 and, thus, expands the repertoire of the known genetic causes of JOAG and the phenotypic spectrum of LTBP2 alleles.

SUBMITTER: Saeedi O

PROVIDER: S-EPMC6266624 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Delineation of Novel Compound Heterozygous Variants in LTBP2 Associated with Juvenile Open Angle Glaucoma.

Saeedi Osamah O Yousaf Sairah S Tsai Joby J Palmer Kathleen K Riazuddin Saima S Ahmed Zubair M ZM

Genes 20181030 11

Juvenile open angle glaucoma (JOAG), which is an uncommon form of primary open angle glaucoma, is a clinically and genetically heterogeneous disorder. We report on a family with a recessively inherited form of JOAG. The proband has a superior and an inferior never fiber layer thinning in both the eyes and the nasal visual field (VF) defects in the left eye, which are clinical findings consistent with glaucomatous optic neuropathy. Whole exome sequencing revealed two novel compound heterozygous v ...[more]

PMID: 30380740

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Project description:PURPOSE: Glaucoma is a heterogeneous group of optic neuropathies with a complex genetic basis. To date, only the following four genes have been identified: viz. myocilin (MYOC), optineurin (OPTN), WD repeat domain 36 (WDR36), and neurotrophin 4 (NTF4). However, there are conflicting reports regarding the involvement of WDR36 in the pathogenesis of primary open-angle glaucoma (POAG). In the Asian population, mutations in WDR36 appear to play a minor role in POAG pathogenesis but polymorphic variants have been found to be associated with POAG, especially in patients with high tension glaucoma (HTG). The purpose of this study is to determine the role of WDR36 in East Indian POAG patients. To date, no other studies have yet examined this role. METHODS: Ten single nucleotide polymorphisms (SNPs; rs1971050, rs1993465, rs13153937, rs10038177, rs11241095, rs10043631, rs10038058, rs10491424, rs17553936, and rs13186912) spanning almost the entire WDR36 gene were selected and their association with eastern Indian POAG patients was evaluated. Our study pool consisted of 323 POAG patients. Of these 116 were patients who had HTG with intraocular perssure (IOP) >21mmHg and 207 were found to be non-HTG patients (presenting IOP<21mmHg). The study also included 303 participants as controls. The polymorphisms were genotyped in both the patients and the controls using the PCR-RFLP method. Moreover, the SNP that showed significant association was validated by DNA sequencing. The haplotypes were obtained using Haploview 4.1 software. The allele and haplotype frequencies were compared between the patient group and the control group using Pearson's ?(2) test. RESULTS: First, we genotyped the selected SNPs in the 323 POAG patients and 119 of the participants in the control group, in which only rs10038177 (c.710+30C>T) was found to be strongly associated with the HTG cases (OR=2.186; 95% CI=1.458-3.277; p=1.4×10(-4)). To increase the significance of the study, the SNP was genotyped in an additional 184 of the participants in the control group and it was observed that the SNP retained the association (OR=1.216; 95% CI=1.064-2.306; p=0.002). However, no haplotype was found to have any sustainable association with POAG. Based on the LD pattern and location of rs10038177, exon 5 of WDR36 was sequenced but no suspected disease-causing variant was detected. CONCLUSIONS: Our study suggests a possible association between WDR36 SNP in a cohort of eastern Indian POAG patients who also have high intraocular pressure (IOP). This study needs to be further validated in a larger patient cohort.

Dataset Information

Delineation of Novel Compound Heterozygous Variants in LTBP2 Associated with Juvenile Open Angle Glaucoma.

Publications

Delineation of Novel Compound Heterozygous Variants in LTBP2 Associated with Juvenile Open Angle Glaucoma.

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