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Mariam Lotfy Khaled, Khaled Abu-Amero, Abdulrahman Al-Muammar, Yelena Bykhovskaya, Xiaoyo Gao, Michael A Hauser, R. Rand Allingham, Yaron Rabinowitz, Yutao Liu; Homozygous Mutation in the ELMO3 Gene with Keratoconus. Invest. Ophthalmol. Vis. Sci. 2018;59(9):743. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Keratoconus (KC) is a corneal thinning disorder and a leading cause of corneal transplantation worldwide. Mutations in MIR184 and other genes account for less than 10% KC patients. However, the majority of the mutations remains to be identified. We aimed to identify novel genetic mutations in a Saudi Arabic KC-affected family.
A two-generation consanguineous Saudi Arabic family was found with autosomal recessive inheritance. This family included two unaffected parents, 3 unaffected daughters, 3 affected sons, and one affected daughter. We performed whole exome sequencing (WES) with 5 subjects, including both unaffected parents and three children (two affected males and one unaffected female). WES was done using Roche NimbleGen SeqCap EZ Exome Library 3.0 with a 64 Mb sequence capture with 100bp paired-end sequencing with Illumina HiSeq sequencers. After quality control, sequence alignment was done with the BWA algorithm and variants were annotated using GATK. We used SVS8 software to filter and prioritize variants based on the following criteria: 1) good quality and read depth, 2) show recessive inheritance mode, 3) minor allele frequency (MAF) < 0.1% in publically available variant databases (The Exome Aggregation Consortium (ExAC), NHLBI GO Exome Sequencing Project (ESP), and 1000 Genomes), 4) exonic, non-synonymous variants. PCR-based Sanger sequencing was used to validate selected variants in all family members.
We identified 3 missense single nucleotide variants (SNVs) in 3 genes: MCM6 (rs55660827, c.2428T>C, p.Tyr810His), ELMO3 (rs183146864, c.1009G>A, p.Val337Ile), and MYOCD (rs200094820, c.1234G>C, Val412Leu). In silico functional prediction algorithms (SIFT, Polyphen2, MutationTaster, and MutationAssessor) suggest SNVs in MCM6 and ELMO3 to be pathogenic; however, MYOCD SNV to be benign. In the Greater Middle East (GME) Variome database, MCM6 SNV is common (MAF = 0.094), ELMO3 SNV is uncommon with MAF = 0.015 (one homozygote out of 993 individuals), and MYOCD SNV is rare (MAF = 0.0065). Our RNA-Seq data from normal human corneas (n=9) showed moderate to high expression of ELMO3 and MCM6, but low expression of MYOCD. Mice with homozygous loss of ELMO3 are reported to have corneal opacity, indicating a potential role of ELMO3 in cornea function.
The homozygous mutation in the ELMO3 gene (rs183146864) might be causative in the Saudi Arabic family affected with KC.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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