Candidate Modifier Genes for the Penetrance of Leber’s Hereditary Optic Neuropathy
Abstract
:1. Introduction
2. Results
2.1. Identification of Nuclear Modifier Genes
2.2. Family-Based Analysis for MT Genes
2.3. GWAS (Genome Wide Association Study) Analysis
3. Discussion
4. Materials and Methods
4.1. Families and Subjects
4.2. Ophthalmic Examinations
4.3. Sample Collection and DNA Extraction
4.4. Whole Exome Sequencing
4.5. Mitochondria-Related Genes Analysis
4.6. GWAS Analysis
4.7. Family-Based Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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LHON Patient (n = 7) | Relative Carrier (n = 10) * | p Value # | |
---|---|---|---|
Age in years, mean (SD) | 30.71 (11.32) | 50.40 (12.87) | 0.005 |
Gender | |||
Male, n (%) | 6 (86%) | 2 (20%) | 0.01 |
Female, n (%) | 1 (14%) | 8 (80%) | |
Best-corrected visual acuity | <0.001 | ||
logMAR, mean (SD) [range] | 1.80 (0.68) [0.6~2.8] | 0.02 (0.08) [−0.18~0.22] | |
Snellen visual acuity [range] | [LP~0.3] | [0.6~1.5] | |
RNFL thickness, mean (SD) | 60.82 (11.69) | 101.43 (5.92) | <0.001 |
GCIPL thickness, mean (SD) | 50.42 (3.15) | 76.33 (8.94) | <0.001 |
MD of VF in dB, mean (SD) | −17.19 (12.52) | −1.11 (2.08) | 0.03 |
Symbol | Chromosome | Variant Percentage | Differences | |
---|---|---|---|---|
Control | Proband | |||
AK4 | chr1 | 0.70 | 0.29 | −0.41 |
NSUN4 | chr1 | 0.60 | 1 | 0.40 |
RDH13 | chr19 | 0.50 | 0.14 | −0.36 |
COQ3 | chr6 | 0.50 | 0.86 | 0.36 |
FAHD1 | chr16 | 0.10 | 0.43 | 0.33 |
CHPT1 | chr12 | 0.70 | 1.00 | 0.30 |
METAP1D | chr2 | 0.70 | 1.00 | 0.30 |
MRM1 | chr17 | 0.30 | 0 | −0.30 |
NCOA6 | chr20 | 0.30 | 0 | −0.30 |
TOP3A | chr17 | 0.30 | 0 | −0.30 |
Pathway | Symbol | Adjusted p Value |
---|---|---|
Biosynthesis of cofactors * | AK4/RDH13/COQ3 | 0.000628845 |
Ubiquinone and other terpenoid-quinone biosynthesis | COQ3 | 0.030532282 |
Thiamine metabolism | AK4 | 0.030532282 |
Gene Symbol | Chromosome | Family | Description |
---|---|---|---|
METAP1D | Chr2 | 1 | Heterozygous c.41G > T in proband |
2 | Homozygous c.41G > T proband, heterozygous in control | ||
ACACB | Chr12 | 1 | Heterozygous c.1029del in 2 probands |
3 | Missense variant found in control | ||
4 | Heterozygous c.1951G > A in proband | ||
ME3 | Chr11 | 2 | Heterozygous c.972G > C in proband |
4 | Homozygous c.972G > C in proband, heterozygous in control | ||
NIPSNAP3B | Chr9 | 3 | Homozygous c.280G > C, c.476C > G in proband, heterozygous in control |
4 | Heterozygous c.280G > C, c.476C > G in proband | ||
NSUN4 | Chr1 | 4 | Homozygous c.4A > G in proband, heterozygous in control |
5 | Heterozygous c.4A > G in proband |
Symbol | Gene ID | SNP | HGVSc | p Value |
---|---|---|---|---|
ADGRG5 | 221188 | chr16:57562087:A:G | NM_001304376.3: c.-7A > G | 0.001 |
POLE4 | 56655 | chr2:74958729:G:T | NM_019896.4: c.50G > T | 0.002 |
ERMAP | 114625 | chr1:42830447:G:A | NM_001017922.2: c.-2G > A | 0.005 |
PIGR | 5284 | chr1:206935771:C:T | NM_002644.4: c.1093G > A | 0.006 |
chr1:206935822:G:A | NM_002644.4: c.1046-4C > T | 0.006 | ||
CDC42BPB | 9578 | chr14:102949759:G:A | NM_006035.4: c.3449 + 6C > T | 0.006 |
PROK1 | 84432 | chr1:110456232:G:A | NM_032414.3: c.199G > A | 0.007 |
BCAN | 63827 | chr1:156658204:T:C | NM_021948.5: c.2370T > C | 0.008 |
NES | 10763 | chr1:156669844:G:A | NM_006617.2: c.4344C > T | 0.008 |
chr1:156670516:C:T | NM_006617.2: c.3672G > A | 0.008 | ||
chr1:156670711:C:T | NM_006617.2: c.3477G > A | 0.008 |
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Cheng, H.-C.; Chi, S.-C.; Liang, C.-Y.; Yu, J.-Y.; Wang, A.-G. Candidate Modifier Genes for the Penetrance of Leber’s Hereditary Optic Neuropathy. Int. J. Mol. Sci. 2022, 23, 11891. https://doi.org/10.3390/ijms231911891
Cheng H-C, Chi S-C, Liang C-Y, Yu J-Y, Wang A-G. Candidate Modifier Genes for the Penetrance of Leber’s Hereditary Optic Neuropathy. International Journal of Molecular Sciences. 2022; 23(19):11891. https://doi.org/10.3390/ijms231911891
Chicago/Turabian StyleCheng, Hui-Chen, Sheng-Chu Chi, Chiao-Ying Liang, Jenn-Yah Yu, and An-Guor Wang. 2022. "Candidate Modifier Genes for the Penetrance of Leber’s Hereditary Optic Neuropathy" International Journal of Molecular Sciences 23, no. 19: 11891. https://doi.org/10.3390/ijms231911891