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meha kabra, Goutham Pyatla, Anil K Mandal, Sirisha Senthil, Inderjeet Kaur, Subhabrata Chakrabarti; Landscape of Mutations in 25 Glaucoma, Anterior Segment Dysgenesis, Myopia and Optic Atrophy-Associated Genes in Primary Congenital Glaucoma. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3820. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Primary congenital glaucoma (PCG) is attributed to mutations, largely in the CYP1B1 and to a lesser extent in the LTBP2 and TEK genes. Digenic inheritance of heterozygous alleles of CYP1B1 with MYOC and FOXC1 have been observed in some cases. Herein, we explored the contributions of 25 genes, previously implicated in glaucoma (BAX, COCH, CAV1, CAV2, FBLN5, HSF4, LOXL1, MMP9, OPTN, TBK1, TGFB2, TMEM126A, WDR36), anterior segment dysgenesis (FOXO1, PAX6, PITX2, PITX3, WT1), myopia (LUM, DCN) and optic atrophy (ACO2, NBAS, OAT, OPA1, OPA3) in PCG cases (n=236) that did not harbor any variations in the known PCG-associated genes.
Screening of these genes were accomplished by deep sequencing using a customized gene panel (Ion Proton). The raw data were analyzed using the GATK and imported to the ION Reporter software (version 5.2) and aligned to the hg19 sequence. Bioinformatic analysis (SIFT, PolyPhen and Grantham) for individual variations and threshold quality scores with a depth of coverage between 100-500X were considered. The mutations were validated by Sanger sequencing (ABI 3130 XL) using BigDye chemistry.
Forty heterozygous mutations were observed in 36/236 PCG cases in 15 different genes. Among them, 5 cases also exhibited digenic pattern of inheritance, namely, PCGID49 (WDR36 [C655G], DCN [A352T]), PCGID114 (OPA1 [E524K], OPA3 [H128Y]), PCGID159 (NBAS [S1047P], WT1 [P264R]), PCGID286 (NBAS [K1169E], HSF4 [S243W]), PCGID291 (NBAS [N2335Q], OPTN [P292L]) and one proband (PCGID383) harbored multiple heterozygous alleles (OPTN [E135K], COCH [R91X], WDR36 [D658G], NBAS [G550C]). None of these mutations were found in the ethnically matched controls (n=500). The clinical manifestations between the patients harboring single or multiple copies of the affected alleles were not significantly different either at presentation or follow-up visits.
The overall contributions of these genes accounted for 15.25% (95%CI,11.23%-20.39%) PCG cases that clustered under a common molecular function of catalytic activity and cellular processes based on pathway analysis (Panther Classification system). The present data expands the mutation spectrum and provides novel insights into the role of these genes in PCG pathogenesis.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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