Exome Sequencing on 298 Probands With Early-Onset High Myopia: Approximately One-Fourth Show Potential Pathogenic Mutations in RetNet Genes

Sun, Wenmin; Huang, Li; Xu, Yan; Xiao, Xueshan; Li, Shiqiang; Jia, Xiaoyun; Gao, Bei; Wang, Panfeng; Guo, Xiangming; Zhang, Qingjiong

doi:10.1167/iovs.15-17555

Cited by 76 publications

(78 citation statements)

References 61 publications

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“…Interestingly, HM occurs concomitantly in IRD patients with GRM6 or CACNA1F mutations (32,62). Our findings are consistent with a previous study showing that 23.8% (71/298) of patients with EOHM actually harbor mutations in IRD genes (38).…”

Section: Discussionsupporting

confidence: 91%

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Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Jin

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to −6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in asyet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.early-onset high myopia | de novo mutations | BSG | rare inherited mutations

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Section: Discussionsupporting

confidence: 91%

“…Loss-of-function mutations in this gene are reported to cause autosomal recessive retinitis pigmentosa (36,37). Interestingly, HM is coupled with these diseases in patients (38).…”

Section: Significancementioning

confidence: 99%

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Jin

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Among these seven mutations, three mutations, p.Pro287Leu and p.Arg319Thr in SLC39A5 and p.Lys661Arg in LEPREL1 , have not been previously reported. Our results were consistent with those reported in previous study in that missense mutations accounted for the largest proportion of the four mutation types in reported monogenic high myopia patients 50 .…”

Section: Discussionsupporting

confidence: 93%

“…Mutations identified in the three genes from all subjects with high myopia were filtered by the following criteria 34, 50 :Variants in noncoding region that did not affect splicing sites based on prediction of the Berkeley Drosophila Genome Project (http://www.fruitfly.org/) were excluded;Synonymous mutations in genes that did not alter splicing sites were subtracted;Mutations with minor allele frequency (MAF) less than or equal to 0.01 in the Exome Aggregation Consortium (ExAC) were extracted;Nonsynonymous single nucleotide mutations predicted to be benign by three commonly used silico tools (Mutation Taster, SIFT and Polyphen-2) were excluded;Mutations were verified using dbSNP146 and those without rs number, were regarded as novel rare mutations. …”

Section: Methodsmentioning

confidence: 99%

Mutational screening of SLC39A5, LEPREL1 and LRPAP1 in a cohort of 187 high myopia patients

Feng

Huang

Cheng

et al. 2017

Sci Rep

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High myopia (HM) is a leading cause of mid-way blindness with a high heritability in East Asia. Although only a few disease genes have been reported, a small proportion of patients could be identified with genetic predispositions. In order to expand the mutation spectrum of the causative genes in Chinese adult population, we investigated three genes, SLC39A5, LEPREL1 and LRPAP1, in a cohort of 187 independent Chinese patients with high myopia. Sanger sequencing was used to find possible pathogenic mutations, which were further screened in normal controls. After a pipeline of database and predictive assessments filtering, we, thereby, identified totally seven heterozygous mutations in the three genes. Among them, three novel missense mutations, c.860C > T, p.Pro287Leu and c.956G > C, p.Arg319Thr in SLC39A5, c.1982A > G, p.Lys661Arg in LEPREL1, were identified as potentially causative mutations. Additionally, the two heterozygous mutations (c.1582G > A, p.Ala528Thr; c.1982A > G, p.Lys661Arg) in one patient in LEPREL1 gene were reported in this study. Our findings will not only augment the mutation spectrum of these three genes, but also provide insights of the contribution of these genes to adult high myopia in Chinese. However, further studies are still needed to address the pathogenicity of each of the mutations reported in this study.

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“…Although further studies on the mechanism underlying gain-of-function damages of RPGR mutants are necessary to elucidate molecular functions and interactions at the photoreceptor cilium, in cases of polypeptidic biopolymers, such as RPGR, the presence of cells containing truncated proteins can reliably result in more severe phenotypes than those observed in heterozygous carriers with loss-of-function mutants. This possibility may be also pondered reviewing the data recently reported by Sun et al ., who have described a Chinese, 5-year-old, heterozygous female carrier of RPGR c.139_140insTCTGC mutation as a proband with early-onset PM32. In the vertebrates’ retinas, cell-cell interactions are able to transfer toxic compounds from one cell to an adjacent other via gap junction channels and/or extracellular routes, remodeling the retinal structures in variable patterns of photoreceptors degeneration333435.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia

Parmeggiani

Barbaro

Nadai

et al. 2016

Sci Rep

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The aim of this study was to describe a new pathogenic variant in the mutational hot spot exon ORF15 of retinitis pigmentosa GTPase regulator (RPGR) gene within an Italian family with X-linked retinitis pigmentosa (RP), detailing its distinctive genotype-phenotype correlation with pathologic myopia (PM). All members of this RP-PM family underwent a complete ophthalmic examination. The entire open reading frames of RPGR and retinitis pigmentosa 2 genes were analyzed by Sanger sequencing. A novel frame-shift mutation in exon ORF15 of RPGR gene (c.2091_2092insA; p.A697fs) was identified as hemizygous variant in the male proband with RP, and as heterozygous variant in the females of this pedigree who invariably exhibited symmetrical PM in both eyes. The c.2091_2092insA mutation coherently co-segregated with the observed phenotypes. These findings expand the spectrum of X-linked RP variants. Interestingly, focusing on Caucasian ethnicity, just three RPGR mutations are hitherto reported in RP-PM families: one of these is located in exon ORF15, but none appears to be characterized by a high penetrance of PM trait as observed in the present, relatively small, pedigree. The geno-phenotypic attributes of this heterozygosity suggest that gain-of-function mechanism could give rise to PM via a degenerative cell-cell remodeling of the retinal structures.

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Exome Sequencing on 298 Probands With Early-Onset High Myopia: Approximately One-Fourth Show Potential Pathogenic Mutations in RetNet Genes

Cited by 76 publications

References 61 publications

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Mutational screening of SLC39A5, LEPREL1 and LRPAP1 in a cohort of 187 high myopia patients

Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia

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