{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:08:57Z","timestamp":1787504937356,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T00:00:00Z","timestamp":1665014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Taipei Veterans General Hospital","award":["VGH V110C-052"],"award-info":[{"award-number":["VGH V110C-052"]}]},{"name":"Taipei Veterans General Hospital","award":["V111C-099"],"award-info":[{"award-number":["V111C-099"]}]},{"name":"Taipei Veterans General Hospital","award":["MOST 110-2314-B-075-054-MY3"],"award-info":[{"award-number":["MOST 110-2314-B-075-054-MY3"]}]},{"name":"Taipei Veterans General Hospital","award":["MOST 111-2324-B-075-42"],"award-info":[{"award-number":["MOST 111-2324-B-075-42"]}]},{"name":"Ministry of Science and Technology of Taiwan","award":["VGH V110C-052"],"award-info":[{"award-number":["VGH V110C-052"]}]},{"name":"Ministry of Science and Technology of Taiwan","award":["V111C-099"],"award-info":[{"award-number":["V111C-099"]}]},{"name":"Ministry of Science and Technology of Taiwan","award":["MOST 110-2314-B-075-054-MY3"],"award-info":[{"award-number":["MOST 110-2314-B-075-054-MY3"]}]},{"name":"Ministry of Science and Technology of Taiwan","award":["MOST 111-2324-B-075-42"],"award-info":[{"award-number":["MOST 111-2324-B-075-42"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Leber\u2019s hereditary optic neuropathy (LHON) is a maternally transmitted disease caused by mitochondria DNA (mtDNA) mutation. It is characterized by acute and subacute visual loss predominantly affecting young men. The mtDNA mutation is transmitted to all maternal lineages. However, only approximately 50% of men and 10% of women harboring a pathogenic mtDNA mutation develop optic neuropathy, reflecting both the incomplete penetrance and its unexplained male prevalence, where over 80% of patients are male. Nuclear modifier genes have been presumed to affect the penetrance of LHON. With conventional genetic methods, prior studies have failed to solve the underlying pathogenesis. Whole exome sequencing (WES) is a new molecular technique for sequencing the protein-coding region of all genes in a whole genome. We performed WES from five families with 17 members. These samples were divided into the proband group (probands with acute onset of LHON, n = 7) and control group (carriers including mother and relative carriers with mtDNSA 11778 mutation, without clinical manifestation of LHON, n = 10). Through whole exome analysis, we found that many mitochondria related (MT-related) nuclear genes have high percentage of variants in either the proband group or control group. The MT genes with a difference over 0.3 of mutation percentage between the proband and control groups include AK4, NSUN4, RDH13, COQ3, and FAHD1. In addition, the pathway analysis revealed that these genes were associated with cofactor metabolism pathways. Family-based analysis showed that several candidate MT genes including METAP1D (c.41G &gt; T), ACACB (c.1029del), ME3 (c.972G &gt; C), NIPSNAP3B (c.280G &gt; C, c.476C &gt; G), and NSUN4 (c.4A &gt; G) were involved in the penetrance of LHON. A GWAS (genome wide association study) was performed, which found that ADGRG5 (Chr16:575620A:G), POLE4 (Chr2:7495872T:G), ERMAP (Chr1:4283044A:G), PIGR (Chr1:2069357C:T;2069358G:A), CDC42BPB (Chr14:102949A:G), PROK1 (Chr1:1104562A:G), BCAN (Chr 1:1566582C:T), and NES (Chr1:1566698A:G,1566705T:C, 1566707T:C) may be involved. The incomplete penetrance and male prevalence are still the major unexplained issues in LHON. Through whole exome analysis, we found several MT genes with a high percentage of variants were involved in a family-based analysis. Pathway analysis suggested a difference in the mutation burden of MT genes underlining the biosynthesis and metabolism pathways. In addition, the GWAS analysis also revealed several candidate nuclear modifier genes. The new technology of WES contributes to provide a highly efficient candidate gene screening function in molecular genetics.<\/jats:p>","DOI":"10.3390\/ijms231911891","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T23:39:31Z","timestamp":1665272371000},"page":"11891","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Candidate Modifier Genes for the Penetrance of Leber\u2019s Hereditary Optic Neuropathy"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1542-5832","authenticated-orcid":false,"given":"Hui-Chen","family":"Cheng","sequence":"first","affiliation":[{"name":"Program in Molecular Medicine, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Department of Ophthalmology, Taipei Veterans General Hospital, 201 Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan"},{"name":"Department of Ophthalmology, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Department of Life Sciences and Institute of Genome Sciences, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Brain Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2544-2353","authenticated-orcid":false,"given":"Sheng-Chu","family":"Chi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Taipei Veterans General Hospital, 201 Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiao-Ying","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Taichung Veterans General Hospital, Taichung 40705, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenn-Yah","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Brain Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2709-3086","authenticated-orcid":false,"given":"An-Guor","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Taipei Veterans General Hospital, 201 Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan"},{"name":"Department of Ophthalmology, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.preteyeres.2006.05.002","article-title":"Leber\u2019s hereditary optic neuropathy: A multifactorial disease","volume":"25","author":"Yen","year":"2006","journal-title":"Prog. 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