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Biochemistry and Molecular Biology  |   February 2015
Evaluation of 12 Myopia-Associated Genes in Chinese Patients With High Myopia
Author Notes
  • State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China 
  • Correspondence: Qingjiong Zhang, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China; zhangqji@mail.sysu.edu.cn, qingjiongzhang@yahoo.com
Investigative Ophthalmology & Visual Science February 2015, Vol.56, 722-729. doi:10.1167/iovs.14-14880
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      Jiali Li, Dan Jiang, Xueshan Xiao, Shiqiang Li, Xiaoyun Jia, Wenmin Sun, Xiangming Guo, Qingjiong Zhang; Evaluation of 12 Myopia-Associated Genes in Chinese Patients With High Myopia. Invest. Ophthalmol. Vis. Sci. 2015;56(2):722-729. doi: 10.1167/iovs.14-14880.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: Two recent large-scale genome-wide association studies identified significant associations between myopia and single nucleotide polymorphisms (SNPs) near the PRSS56, BMP3, KCNQ5, LAMA2, TOX, TJP2, RDH5, ZIC2, RASGRF1, GJD2, RBFOX1, and SHISA6 genes. Our study is to examine whether rare variants in these genes contribute to high myopia.

Methods.: Whole-exome sequencing was performed on samples of 298 probands with early-onset high myopia (eoHM; spherical refraction in each meridian ≤ −6.00 [diopters] D in both eyes; age of onset < 7 years) and 195 controls (different forms of retinal degeneration including Leber congenital amaurosis, cone-rod dystrophy, and familial exudative vitroretinopathy). Potential variations in these genes were selected for further validation and comparison to the controls. Moreover, Sanger sequencing was used to evaluate the coding regions and the upstream 800 bps of GJD2 in 395 additional subjects with late-onset moderate to high myopia (loMHM; spherical refraction in each meridian ≤ −4.00 D; age of onset ≥ 7 years) and 403 healthy controls (−0.50 D ± 1.00 D).

Results.: Exome sequencing of the 298 probands with eoHM identified 25 rare variants that were predicted to affect coding residues. The segregation analysis and the distribution of rare variants between patients and controls did not provide evidence to support their involvement in myopia. Sanger sequencing of GJD2 in an additional 395 subjects with loMHM and 403 healthy controls did not identify myopia-associated variants.

Conclusions.: We did not find evidence to support the association of myopia with rare variants in these genes, probably due to our limited sample size. Additional studies are expected to validate these results.

Introduction
Genetic factors play an important role in the development of high myopia. Up to now, 22 myopia loci have been documented in Online Mendelian Inheritance in Man (OMIM),132 16 of which are high myopia loci. However, the exact genes in most of the myopia loci remain unknown. Recently, two large-scale genome-wide association studies (GWASs) identified a number of loci associated with myopia based on the analysis of refractive error33 and age of myopia onset.34 One study was a GWAS meta-analysis involving 37,382 individuals from 27 studies of European ancestry and 8376 individuals from five Asian cohorts.33 The other study was a GWAS of 45,771 participants in US population of European ancestry.34 Both GWASs identified significant associations of refractive error with single nucleotide polymorphisms (SNPs; P < 5 × 10−8) near the following 12 genes: protease, serine, 56 (PRSS56, MIM 613858); bone morphogenetic protein 3 (BMP3, MIM 112263); potassium voltage-gated channel, KQT-like subfamily, member 5 (KCNQ5, MIM 607357); laminin, alpha 2 (LAMA2, MIM 156225); thymocyte selection-associated high mobility group box (TOX, MIM 606863 ); tight junction protein 2 (TJP2, MIM 607709); retinol dehydrogenase 5 (11-cis/9-cis) (RDH5, MIM 601617); zinc family member 2 (ZIC2, MIM 603073); ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1, MIM 606600); gap junction protein, delta2 (GJD2, MIM 607058); RNA binding protein, fox-1 homolog (Caenorhabditis elegans) 1 (RBFOX1, MIM 605104); and shisa family member 6 (SHISA6, HGNC 34491). It would be interesting to know whether rare variants in the coding regions of these genes contribute to early-onset high myopia (eoHM). In order to identify the genetic defects associated with eoHM, we performed whole-exome sequencing on samples of 298 probands from unrelated families with eoHM. In this study, the available data for these 12 genes were selected from the whole-exome sequencing results and analyzed. 
Previously, SNPs near GJD2 have been frequently reported to be associated with myopia in a number of studies,3444 including our analysis based on 396 individuals with late-onset moderate to high myopia (loMHM) and 404 healthy controls.37 To further explore the molecular basis of this association, the coding regions and 800 bp upstream region of GJD2 were analyzed using Sanger sequencing in the same cohorts of subjects. 
Materials and Methods
Subjects
This analysis is part of our project in study of genetic defects associated with eoHM, some of which have been demonstrated to be Mendelian traits that more likely to be caused by monogenic defects, as shown in our previous studies, which mapped myopia loci (MYP1, MYP11, and MYP13) in four unrelated Chinese families (two families demonstrated MYP13 associations) using linkage analysis.2,10,14,15 Whole-exome sequencing was performed on samples of 298 Chinese probands from unrelated families with eoHM as well as those from 195 controls. The criteria for patients with eoHM were as follows: (1) spherical refraction in each meridian less than or equal to −6.00 (diopters) D in both eyes, (2) high myopia developed before the age of 7 years, and (3) no other known ocular or related systemic diseases. All patients were recruited from the clinic of the Zhongshan Ophthalmic Center (Sun Yat-sen University, Guangzhou, China). Among the 298 unrelated families with eoHM, 155 cases had a family history of eoHM, while 143 were sporadic. Only the probands were included for analysis regardless of whether they had a family history or not. Refractive errors were measured using an auto refractometer (KR-8000; Topcon, Paramus, NJ, USA) after cycloplegia (Mydrin-P; Santen Pharmaceutical Co., Ltd., Osaka, Japan). Ophthalmologic examinations, including a slit-lamp examination, a direct ophthalmoscope, and a best-vision acuity test, were performed to exclude other ocular diseases. The 195 controls were unrelated probands and exhibited different forms of retinal degeneration, including Leber congenital amaurosis, cone-rod dystrophy, and familial exudative vitroretinopathy. None of them was associated with eoHM. The results of whole-exome sequencing of 195 subjects with other conditions were used as controls. The inclusion criteria for the 396 loMHM and 404 healthy controls were described previously37: (1) late-onset moderate to high myopia including a spherical equivalent less than or equal to −4.0 D and a best aided visual acuity of 0.8 or better without other known eye or systemic diseases, (2) all control individuals have bilateral refraction between −0.50 D and +1.0 D spherical equivalent without a family history of high myopia and have a best unaided visual acuity of 1.0 or better without other known eye or systemic diseases, and (3) the cases and healthy control individuals must have received a minimum of 12 years of education. All individuals mentioned above, including the 298 eoHM patients, 195 controls with other forms of retinal degeneration, 396 loMHM patients, and 404 healthy controls, were recruited from Chinese population at the Zhongshan Ophthalmic Center. Written informed consent was obtained from the participants or their guardians, following the tenets of the Declaration of Helsinki. This study was approved by the institutional review board of Zhongshan Ophthalmic Center. 
Whole-Exome Sequencing
Whole-exome sequencing was analyzed by a commercial service. Exome capture was performed with an Agilent SureSelect Human All Exon Enrichment Kit V4 (51189318 bps; Agilent, Santa Clara, CA, USA) array. DNA fragments were sequenced using the Illumina HiSeq 2000 system (Illumina, San Diego, CA, USA). The average sequencing depth was 125-fold. Reads were mapped against UCSC hg19 (in the public domain, http://genome.ucsc.edu/) using Burrows-Wheeler Aligner (BWA; in the public domain, http://bio-bwa.sourceforge.net/). Single nucleotide polymorphisms and Indels were detected by SAMTOOLS (in the public domain, http://samtools.sourceforge.net/) based on a Bayesian statistical algorithm.45,46 The default filters of variant calling were previously described.47 The sequence capture performance results of the 298 samples in the current study included the following: (1) the average total yield was 7,462,972,765 bp, (2) the coverage of target regions (more than 10×) in average was 97.0%, and (3) after excluding unmappable reads, redundant reads, multiple mapped reads, and reads out of target, the average depth for the target regions reached 93.9-fold. Whole-exome sequencing, a sequence-based approach, was used to assess variants in previously associated myopia genes with the aim of identifying genetic variants including rare variants. Therefore, variants in PRSS56, BMP3, KCNQ5, LAMA2, TOX, TJP2, RDH5, ZIC2, RASGRF1, GJD2, RBFOX1, and SHISA6 were collected from the whole-exome sequencing data of 298 probands with eoHM and 195 controls. The genomic coordinates for the tested regions were shown in Supplementary Table S1. The observed variants were filtered sequentially as follows: (1) variants in nontranslated regions (UTRs) and introns without a significant effect on splicing sites according to the Berkeley Drosophila Genome Project (BDGP; in the public domain, http://www.fruitfly.org/) were excluded,48 (2) exonic synonymous variants without a significant effect on splicing sites were excluded, (3) variants with a minor allele frequency (MAF) greater than or equal to 0.01 were compared between the 298 patients and 195 controls and were attached as supplementary material for reference, whereas variants with a MAF less than 0.01 were further filtered according to the following two steps, (4) variants shared with the 195 controls were excluded, and (5) variants predicted to be benign according to SIFT (in the public domain, http://sift.jcvi.org/www/SIFT_enst_submit.html),49 PolyPhen-2 (in the public domain, http://genetics.bwh.harvard.edu/pph2/),50 or Condel (in the public domain, http://bg.upf.edu/condel/analysis) were excluded.51 The MAF of each variant was obtained from public databases, including the Single Nucleotide Polymorphism Database (dbSNP; in the public domain, http://www.ncbi.nlm.nih.gov/projects/SNP/), 1000 Genomes (in the public domain, http://www.1000genomes.org/), and the Exome Variation Server (in the public domain, http://evs.gs.washington.edu/EVS/). 
Sanger Sequencing
Variants that passed the above filtering steps from whole-exome sequencing were validated using Sanger sequencing. Segregation analysis was performed on the available family members. Moreover, Sanger sequencing was used to analyze the coding regions and the upstream 800-bp region of the GJD2 gene in an additional 396 individuals with loMHM and 404 healthy controls (DNA samples from one case and one control in these groups were unavailable due to the deletion of stocks, so only 395 individuals with loMHM and 403 controls participated in this study). The primers used to amplify these fragments are listed in Supplementary Table S2 and were designed using the Primer3 online tool (in the public domain, http://bioinfo.ut.ee/primer3-0.4.0/). The methods used for amplification, sequencing, and analysis of the target fragments were previously reported.52 The descriptions of the variants are consistent with the nomenclature for sequence variations Human Genome Variation Society (HGVS; in the public domain, http://www.hgvs.org/mutnomen/).53 
Statistical Analysis
The analysis of common variants: The frequencies of common variants were compared between cases and controls using the χ2 test or likelihood-ratio test (the count of the alternative allele is <10). 
The corrected significant P value for this study should be less than 0.003 (α = 0.05/16) according to the Bonferroni method. Statistical analyses were performed with SPSS software ver. 13 (SPSS Science, Chicago, IL, USA). 
The analysis of rare variants: the number of rare variants across a gene is compared between cases and controls using the Combined Multivariate and Collapsing method with Hotelling T2 test (Golden Helix SVS, ver. 8.3.0; Golden Helix, Bozeman, MT, USA). Corrections for multiple testing were done with the Bonferroni method. 
Results
A total of 561 variants in the 12 genes were detected from the whole-exome sequencing data of 298 probands with eoHM (Supplementary Table S3). After filtering, 16 common variants were compared between cases and controls (Supplementary Table S4), and 27 rare variants were further analyzed using Sanger sequencing and family segregation. For the 27 rare variants, 25 were confirmed by Sanger sequencing (Supplementary Fig. S1), whereas the other two variants were determined to be false positives. Of the 25 confirmed variants, six were available for segregation analysis, four of which did not cosegregate with the phenotype (Table 1; Fig.).54 The P value of the levels of segregation was greater than 0.05. The variant types and the frequencies of rare variants among the 12 genes were similar between the 298 patients with eoHM and the 195 controls (Table 1; Supplementary Table S3), without statistically significant difference. No variant was observed in the linkage disequilibrium (LD) region with the known risk variants identified by the previous two GWASs.33,34 
Table 1.
 
Rare Variants Identified in 298 Patients With eoHM and 195 Controls
Table 1.
 
Rare Variants Identified in 298 Patients With eoHM and 195 Controls
Gene Chromosome Position Nucleotide Change Residue Change Status Prediction No. in eoHM MAF in 1000 G/EVS Coseg- regation Note
SIFT Polyphen Condel
Group 1: Patients (n = 298)
PRSS56 chr02 233387809 c.746C>T p.P249L Het T PD NA 1 None NA Jiang et al.*
PRSS56 chr02 233388488 c.1019C>T p.S340F Het T PD NA 2 None NA Jiang et al.*
PRSS56 chr02 233389065 c.1400G>A p.R467H Het NA NA NA 1 None NO Novel
BMP3 chr04 81967440 c.865C>T p.R289C Het D PrD Del 1 None NA Novel
BMP3 chr04 81967678 c.1103G>C p.R368P Het D PrD Del 1 None NA Novel
LAMA2 chr06 129371227 c.277C>A p.P93T Het D B N 1 None YES Novel
LAMA2 chr06 129498874 c.1330T>G p.C444G Het D PrD Del 1 None NA Novel
LAMA2 chr06 129499009 c.1465A>G p.K489E Het D PrD Del 1 None NO Novel
LAMA2 chr06 129634169 c.3338C>T p.T1113I Het D PrD Del 1 None NA Novel
LAMA2 chr06 129691106 c.4930G>A p.V1644M Het T PrD N 1 0.0009/NA NO rs182762857
LAMA2 chr06 129781360 c.6883C>T p.R2295C Het D PrD Del 2 None NA Novel
LAMA2 chr06 129781361 c.6884G>A p.R2295H Het D PrD Del 2 0.001/NA NA rs142164767
LAMA2 chr06 129813143 c.7996C>G p.P2666A Het T PD N 1 None NA Novel
TJP2 chr09 71842683 c.1306_1308del p.I436del Het - - - 1 0.001/NA NA rs35082395
TJP2 chr09 71852043 c.2263C>G p.L755V Het D PrD Del 1 None NA Novel
TJP2 chr09 71854949 c.2545A>G p.R849G Het D B Del 1 None NA Novel
TJP2 chr09 71869243 c.3526C>T p.R1207C Het D PD Del 1 None NA Novel
GJD2 chr15 35044791 c.854G>A p.R285Q Het D PD Del 1 None NA Novel
RASGRF1 chr15 79339292 c.674T>C p.I225T Het D PD Del 1 None NO Novel
RBFOX1 chr16 7568218 c.157C>A p.P53T Het T B Del 1 None NA Novel
RBFOX1 chr16 7647415 c.664G>A p.V222I Het T NA N 1 None NA Novel
SHISA6 chr17 11461295 c.1177G>A p.E393K Het D PrD N 1 None NA Novel
SHISA6 chr17 11461316 c.1351C>T p.R451C Het T NA Del 1 None YES Novel
SHISA6 chr17 11461596 c.1478C>A p.A493D Het T PD Del 1 None NA Novel
SHISA6 chr17 11461536 c.1571G>A p.R524H Het D NA Del 1 None NA Novel
Group 2: Controls (n = 195)
PRSS56 chr02 233388569 c.1100C>G p.A367G Het NA NA NA 1 None - Novel
PRSS56 chr02 233389996 c.1592G>A p.G531D Homo NA NA NA 1 None - Novel
BMP3 chr04 81967641 c.1066C>A p.L356M Het T PrD Del 1 None - Novel
BMP3 chr04 81974641 c.1370T>C p.V457A Het D PrD Del 1 None - Novel
LAMA2 chr06 129635813 c.3425G>C p.G1142A Het D PrD Del 1 None - Novel
LAMA2 chr06 129641781 c.4157A>T p.Y1386F Het T PD N 1 None - Novel
LAMA2 chr06 129712735 c.5171T>C p.M1724T Het T PD N 1 None - rs140373926
LAMA2 chr06 129835657 c.9128G>A p.G3043E Het T PD Del 1 None - Novel
KCNQ5 chr06 73331999 c.80_82ins p.A27dup Het _ _ _ 1 None - Novel
KCNQ5 chr06 73787508 c.816A>G p.I272M Het D PrD Del 1 None - Novel
KCNQ5 chr06 73905120 c.2839C>A p.H947N Het T B Del 1 None - Novel
RDH5 chr12 56115192 c.224G>A p.R75H Het D B Del 1 0.0005/NA - rs140121982
ZIC2 chr13 100634644 c.326C>T p.S109F Het D B Del 1 None - Novel
ZIC2 chr13 100634735 c.417C>A p.F139 Het D D N 1 None - Novel
RASGRF1 chr15 79382812 c.29G>A p.G10D Het D PD Del 1 None - Novel
RASGRF1 chr15 79341870 c.592G>A p.D198N Het T B Del 1 0.0009/NA - rs150981409
RASGRF1 chr15 79339236 c.730G>T p.V244L Het T B Del 1 None - Novel
RASGRF1 chr15 79298594 c.2048C>T p.T683I Het T PD N 1 None - Novel
SHISA6 chr17 11144971 c.232G>T p.A78S Het T PD N 1 None - Novel
SHISA6 chr17 11166826 c.782C>T p.T261M Het T PD N 1 None - Novel
SHISA6 chr17 11461229 c.1264G>T p.V422F Het T NA Del 1 None - Novel
For the additional sequencing analysis of GJD2 in 395 individuals with loMHM and 403 healthy controls, Sanger sequencing was successful in all cases and controls. Five common SNPs (rs193057189, rs2277558, rs651724, rs35174018, and rs3743123) were detected in both the patients and controls and no significant differences in the genotype frequency or allele frequency were detected (Table 2). In addition, a novel c.1-635G>T variant in the promoter region of GJD2 was detected in one of the 395 patients but not in any of the 403 healthy controls. No other variants were identified in the patients or controls. 
Table 2.
 
Allele and Genotype Frequencies of the Five Detected SNPs of the GJD2 Gene Among 395 Individuals With loMHM and 403 Healthy Controls
Table 2.
 
Allele and Genotype Frequencies of the Five Detected SNPs of the GJD2 Gene Among 395 Individuals With loMHM and 403 Healthy Controls
Exon Nucleotide Change Residue Change SNP Allele Frequency P Genotype Frequency P OR 95% CI
loMHM NC loMHM NC
A B A B A/A A/B B/B A/A A/B B/B
E1 c.1_500G>T Intronic rs193057189 786 4 804 2 0.395 391 4 0 401 2 0 0.394 0.489 (0.089, 2.676)
E1 c.1_127A>T Intronic rs2277558 338 452 339 467 0.769 66 206 123 79 181 143 0.122 1.030 (0.846, 1.256)
E2 c.333A>T p.T111T rs651724 450 340 463 343 0.846 123 204 68 141 181 81 0.161 0.981 (0.804, 1.196)
E2 c.369C>T p.S123S rs35174018 699 91 709 97 0.749 312 75 8 315 79 9 0.953 1.051 (0.775, 1.425)
E2 c.588C>T p.S196S rs3743123 589 201 606 200 0.772 214 161 20 227 152 24 0.630 0.967 (0.771, 1.213)
Discussion
Based on the analysis of whole-exome sequencing data for the 298 probands with eoHM and the 195 controls, 25 rare variants were identified in the PRSS56, BMP3, KCNQ5, LAMA2, TOX, TJP2, RDH5, ZIC2, RASGRF1, GJD2, RBFOX1, and SHISA6 genes in the eoHM patients. However, segregation analysis and the distribution of variants between cases and controls do not find clues to support the involvement of these rare variants in high myopia. An additional Sanger sequencing of the GJD2 gene in 395 individuals with loMHM and 403 healthy controls does not identify any myopia-associated variants. 
Investigating the genetic factors associated with myopia has become a hot topic in recent years. A number of loci and genes have been suggested to be associated with myopia, but many of these results come from controversial studies. The loci or genes supported by independent studies are of great interest for further investigation. Moreover, for certain gene for which common variants are associated with diseases, rare variants in the genes may also contribute to the diseases, such as those observed in the CFH gene and AMD.5575 In the current study, we wanted to determine whether myopia is associated with rare variants in the PRSS56, BMP3, KCNQ5, LAMA2, TOX, TJP2, RDH5, ZIC2, RASGRF1, GJD2, RBFOX1, and SHISA6 genes, for which nearby SNPs have been identified as being associated with refractive errors, including myopia, in various studies.34,35,37,4042,44,7678 However, we do not find evidence to support the association of myopia with rare variants in these 12 genes based on the analysis of 298 probands with eoHM. It might be possible that our sample size was limited to detect rare variants and some low-frequency variants; thus, a far greater number of samples may be required to resolve this issue. 
Using individuals with other diseases as controls has been previously reported.40,79,80 As for our current study, we preliminarily used patients with different kinds of retinal degeneration as controls in order to evaluate the potential role of rare variants in high myopia. However, both variants types and the frequencies of the rare variants of these 12 genes were similar between the patients and the controls. Thus, we did not conduct further analysis using healthy controls. However, using controls with other diseases in the current study may be inappropriate if the rare variants detected are potentially associated with both diseases. Therefore, the pathogenicity of these 12 genes in high myopia should be further studied. 
Thus far, the susceptible genetic factors for myopia in the locus 15q14 are still unclear although numerous studies have shown that SNPs within the 15q14 region are significantly associated with myopia. GJD2 is the gene closest to the most significant SNP, rs634900 (P = 2.21 × 10−14) in the 15q14 region.41 GJD2 encodes connexin36, which forms gap junctions that transmit electrical signals in the mammalian retina.81,82 Targeted deletion of mouse connexin36 resulted in the complete elimination of ON-pathway signaling in the rod pathway.83,84 Mice with defective ON-pathway signaling are highly susceptible to myopia.85 These findings suggest that GJD2 is a potential good candidate gene for myopia. However, the systemic evaluation of GJD2 was rarely performed, with direct sequencing of GJD2 in only 47 individuals and no identified variants.41 Our previous study confirmed the association of SNPs within 15q14 with myopia based on an analysis of 396 individuals with loMHM and 404 healthy controls.37 However, in the current study, sequence analysis of GJD2 in the same cohorts does not uncover any causative variants. 
In conclusion, we do not provide evidence that rare variants in these 12 genes are a common cause of high myopia. Due to our limited sample size and the use of controls, further studies are expected to disclose the molecular basis of the significant association between SNPs near these genes and myopia. Meanwhile, only a few variants in six genes recently reported to be associated with high myopia were detected in a very small number of probands with eoHM (9/298), where the pathogenicity of most variants was suggestive, undetermined, or unlikely.86 This study together with the current study suggests that the genetic defects for most probands with eoHM are awaited to be identified. Extensive analysis of the data from whole-exome sequencing is expected to identify additional potential causative variants in other genes.1552 
Figure.
 
Pedigrees of the 27 high-myopia families with variations. +, wild-type.
Figure.
 
Pedigrees of the 27 high-myopia families with variations. +, wild-type.
Acknowledgments
The authors thank all of the patients and controls for their participation in this study. 
Supported by grants from the National Natural Science Foundation of China (U1201221; Beijing, China), the Natural Science Foundation of Guangdong (S2013030012978; Guangzhou, Guangdong, China), the Guangdong Department of Science & Technology Translational Medicine Center Grant 2011A080300002 (Guangzhou, Guangdong, China), and the Fundamental Research Funds of the State Key Laboratory of Ophthalmology (Guangzhou, Guangdong, China). 
Disclosure: J. Li, None; D. Jiang, None; X. Xiao, None; S. Li, None; X. Jia, None; W. Sun, None; X. Guo, None; Q. Zhang, None 
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Footnotes
 JL and DJ contributed equally to the work presented here and should therefore be regarded as equivalent authors.
Figure.
 
Pedigrees of the 27 high-myopia families with variations. +, wild-type.
Figure.
 
Pedigrees of the 27 high-myopia families with variations. +, wild-type.
Table 1.
 
Rare Variants Identified in 298 Patients With eoHM and 195 Controls
Table 1.
 
Rare Variants Identified in 298 Patients With eoHM and 195 Controls
Gene Chromosome Position Nucleotide Change Residue Change Status Prediction No. in eoHM MAF in 1000 G/EVS Coseg- regation Note
SIFT Polyphen Condel
Group 1: Patients (n = 298)
PRSS56 chr02 233387809 c.746C>T p.P249L Het T PD NA 1 None NA Jiang et al.*
PRSS56 chr02 233388488 c.1019C>T p.S340F Het T PD NA 2 None NA Jiang et al.*
PRSS56 chr02 233389065 c.1400G>A p.R467H Het NA NA NA 1 None NO Novel
BMP3 chr04 81967440 c.865C>T p.R289C Het D PrD Del 1 None NA Novel
BMP3 chr04 81967678 c.1103G>C p.R368P Het D PrD Del 1 None NA Novel
LAMA2 chr06 129371227 c.277C>A p.P93T Het D B N 1 None YES Novel
LAMA2 chr06 129498874 c.1330T>G p.C444G Het D PrD Del 1 None NA Novel
LAMA2 chr06 129499009 c.1465A>G p.K489E Het D PrD Del 1 None NO Novel
LAMA2 chr06 129634169 c.3338C>T p.T1113I Het D PrD Del 1 None NA Novel
LAMA2 chr06 129691106 c.4930G>A p.V1644M Het T PrD N 1 0.0009/NA NO rs182762857
LAMA2 chr06 129781360 c.6883C>T p.R2295C Het D PrD Del 2 None NA Novel
LAMA2 chr06 129781361 c.6884G>A p.R2295H Het D PrD Del 2 0.001/NA NA rs142164767
LAMA2 chr06 129813143 c.7996C>G p.P2666A Het T PD N 1 None NA Novel
TJP2 chr09 71842683 c.1306_1308del p.I436del Het - - - 1 0.001/NA NA rs35082395
TJP2 chr09 71852043 c.2263C>G p.L755V Het D PrD Del 1 None NA Novel
TJP2 chr09 71854949 c.2545A>G p.R849G Het D B Del 1 None NA Novel
TJP2 chr09 71869243 c.3526C>T p.R1207C Het D PD Del 1 None NA Novel
GJD2 chr15 35044791 c.854G>A p.R285Q Het D PD Del 1 None NA Novel
RASGRF1 chr15 79339292 c.674T>C p.I225T Het D PD Del 1 None NO Novel
RBFOX1 chr16 7568218 c.157C>A p.P53T Het T B Del 1 None NA Novel
RBFOX1 chr16 7647415 c.664G>A p.V222I Het T NA N 1 None NA Novel
SHISA6 chr17 11461295 c.1177G>A p.E393K Het D PrD N 1 None NA Novel
SHISA6 chr17 11461316 c.1351C>T p.R451C Het T NA Del 1 None YES Novel
SHISA6 chr17 11461596 c.1478C>A p.A493D Het T PD Del 1 None NA Novel
SHISA6 chr17 11461536 c.1571G>A p.R524H Het D NA Del 1 None NA Novel
Group 2: Controls (n = 195)
PRSS56 chr02 233388569 c.1100C>G p.A367G Het NA NA NA 1 None - Novel
PRSS56 chr02 233389996 c.1592G>A p.G531D Homo NA NA NA 1 None - Novel
BMP3 chr04 81967641 c.1066C>A p.L356M Het T PrD Del 1 None - Novel
BMP3 chr04 81974641 c.1370T>C p.V457A Het D PrD Del 1 None - Novel
LAMA2 chr06 129635813 c.3425G>C p.G1142A Het D PrD Del 1 None - Novel
LAMA2 chr06 129641781 c.4157A>T p.Y1386F Het T PD N 1 None - Novel
LAMA2 chr06 129712735 c.5171T>C p.M1724T Het T PD N 1 None - rs140373926
LAMA2 chr06 129835657 c.9128G>A p.G3043E Het T PD Del 1 None - Novel
KCNQ5 chr06 73331999 c.80_82ins p.A27dup Het _ _ _ 1 None - Novel
KCNQ5 chr06 73787508 c.816A>G p.I272M Het D PrD Del 1 None - Novel
KCNQ5 chr06 73905120 c.2839C>A p.H947N Het T B Del 1 None - Novel
RDH5 chr12 56115192 c.224G>A p.R75H Het D B Del 1 0.0005/NA - rs140121982
ZIC2 chr13 100634644 c.326C>T p.S109F Het D B Del 1 None - Novel
ZIC2 chr13 100634735 c.417C>A p.F139 Het D D N 1 None - Novel
RASGRF1 chr15 79382812 c.29G>A p.G10D Het D PD Del 1 None - Novel
RASGRF1 chr15 79341870 c.592G>A p.D198N Het T B Del 1 0.0009/NA - rs150981409
RASGRF1 chr15 79339236 c.730G>T p.V244L Het T B Del 1 None - Novel
RASGRF1 chr15 79298594 c.2048C>T p.T683I Het T PD N 1 None - Novel
SHISA6 chr17 11144971 c.232G>T p.A78S Het T PD N 1 None - Novel
SHISA6 chr17 11166826 c.782C>T p.T261M Het T PD N 1 None - Novel
SHISA6 chr17 11461229 c.1264G>T p.V422F Het T NA Del 1 None - Novel
Table 2.
 
Allele and Genotype Frequencies of the Five Detected SNPs of the GJD2 Gene Among 395 Individuals With loMHM and 403 Healthy Controls
Table 2.
 
Allele and Genotype Frequencies of the Five Detected SNPs of the GJD2 Gene Among 395 Individuals With loMHM and 403 Healthy Controls
Exon Nucleotide Change Residue Change SNP Allele Frequency P Genotype Frequency P OR 95% CI
loMHM NC loMHM NC
A B A B A/A A/B B/B A/A A/B B/B
E1 c.1_500G>T Intronic rs193057189 786 4 804 2 0.395 391 4 0 401 2 0 0.394 0.489 (0.089, 2.676)
E1 c.1_127A>T Intronic rs2277558 338 452 339 467 0.769 66 206 123 79 181 143 0.122 1.030 (0.846, 1.256)
E2 c.333A>T p.T111T rs651724 450 340 463 343 0.846 123 204 68 141 181 81 0.161 0.981 (0.804, 1.196)
E2 c.369C>T p.S123S rs35174018 699 91 709 97 0.749 312 75 8 315 79 9 0.953 1.051 (0.775, 1.425)
E2 c.588C>T p.S196S rs3743123 589 201 606 200 0.772 214 161 20 227 152 24 0.630 0.967 (0.771, 1.213)
Supplementary Figure S1
Supplementary Table S1
Supplementary Table S2
Supplementary Table S3
Supplementary Table S4
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