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

Jin, Zi‐Bing; Wu, Jinyu; Huang, Xiu‐Feng; Feng, Chun-Yun; Cai, Xue‐Bi; Mao, Jian-Yang; Xiang, Lan; Wu, Kun; Xiao, Xueshan; Kloss, Bethany A Volkmann; Li, Zhongshan; Liu, Zhenwei; Huang, Shenghai; Shen, Meixiao; Cheng, Feifei; Cheng, Xuewen; Zheng, Zhili; Chen, Xuejiao; Zhuang, Wenjuan; Zhang, Qingjiong; Young, Terri L.; Xie, Ting; Liu, Fan; Qu, Jia

doi:10.1073/pnas.1615970114

Cited by 82 publications

(75 citation statements)

References 63 publications

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“…In this study, we identified a nonsense mutation (c.562C>T, p.R188*) in CEP250 in a consanguineous family with nonsyndromic RP by whole‐exome sequencing, which has been highly efficient in uncovering genetic defects (Jin et al, , , ). To further elucidate the functional relevance of the human CEP250 mutation, we generated knockin (KI) mouse models to investigate the roles of Cep250 in the retina in vivo .…”

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confidence: 99%

Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa

et al. 2019

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Retinitis pigmentosa (RP) is the most common manifestation of inherited retinal diseases with high degree of genetic, allelic, and phenotypic heterogeneity. CEP250 encodes the C‐Nap1 protein and has been associated with various retinal phenotypes. Here, we report the identification of a mutation (c.562C>T, p.R188*) in the CEP250 in a consanguineous family with nonsyndromic RP. To gain insights into the molecular pathomechanism underlying CEP250 defects and the functional relevance of CEP250 variants in humans, we conducted a functional characterization of CEP250 variant using a novel Cep250 knockin mouse line. Remarkably, the disruption of Cep250 resulted in severe impairment of retinal function and significant retinal morphological alterations. The homozygous knockin mice showed significantly reduced retinal thickness and ERG responses. This study not only broadens the spectrum of phenotypes associated with CEP250 mutations, but also, for the first time, elucidates the function of CEP250 in photoreceptors using a newly established animal model.

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Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa

et al. 2019

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“…Epidemiological studies show that gout incidence increases with age until the age of 70 years and that onset before the age of 40 years is unusual [40,41]. A few studies have demonstrated that complex disease with earlyonset age could be caused by monogenic inheritance of mutated genes [42][43][44]. erefore, aiming to investigate potential causal gene in this pedigree, we used WES which has proven to be highly robust and efficient in the identification of disease-causing genes in monogenic conditions or complex disorders [45].…”

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confidence: 99%

Whole-Exome Sequencing Reveals a Rare Missense Variant in SLC16A9 in a Pedigree with Early-Onset Gout

Huang

Sun

Zhang

et al. 2020

BioMed Research International

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Gout is a common inflammatory arthritis triggered by monosodium urate deposition after longstanding hyperuricemia. In the general community, the disease is largely polygenic in genetic architecture, with many polymorphisms having been identified in gout or urate-associated traits. In a small proportion of cases, rare high penetrant mutations associated with monogenic segregation of the disease in families have been demonstrated to be disease causative. In this study, we recruited a two-generation pedigree with early-onset gout. To elucidate the genetic predisposition, whole-exome sequencing (WES) was performed. After comprehensive variant analyses and cosegregation testing, we identified a missense variant (c.277C>A, p.L93M) in SLC16A9, an extremely rare variant in genetic databases. Moreover, in silico assessments showed strong pathogenicity. This variant cosegregated with the disease phenotype perfectly in the family and is located in a highly conserved functional domain. A few studies supported our results of the association between SLC16A9 and gout and serum urate levels. In conclusion, we provide the first evidence for the association of rare missense in SLC16A9 with early-onset gout. These findings not only expand our current understanding of gout but also may have further implications for the treatment and prevention of gout.

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“…EoHM, defined as a high myopia onset before school age, is considered to be predominantly determined by genetic factors with minimal environmental effects. Mutations in at least 13 genes have been reported to cause eoHM, including ZNF644 (OMIM 614159), 8 SCO2 (OMIM 604272), 9 LRPAP1 (OMIM 104225), 10 SLC39A5 (OMIM 608730), 11 P4HA2 (OMIM 600608), 12 LEPREL (OMIM 610341), 13 ARR3 (OMIM 301770), 14 OPN1LW , 15 LOXL3 , 16 BSG , 17 CPSF1 , 18 NDUFAF7 , 19 and TNFRSF21 20 . However, mutations in these genes may only explain a small portion of patients with eoHM 21,22,23 .…”

Section: Introductionmentioning

confidence: 99%

A novel deep intronic COL2A1 mutation in a family with early‐onset high myopia/ocular‐only Stickler syndrome

Sun

Xiao

et al. 2020

Ophthalmic Physiologic Optic

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Citation information: Sun W, Xiao X, Li S, Jia X, & Zhang Q. A novel deep intronic COL2A1 mutation in a family with early-onset high myopia/ ocular-only Stickler syndrome. Ophthalmic Physiol Opt 2020; 40: 281-288. https://doi. AbstractPurpose: To identify the genetic defect causing early-onset high myopia (eoHM)/ ocular-only Stickler syndrome (ocular-STL) in a large Chinese family. Methods: Genomic DNA and clinical data from a four-generation family with eoHM/ocular-STL were collected. Whole-exome sequencing was performed on one affected member in initial screening. Linkage scan based on microsatellite markers was carried out initially from candidate loci associated with autosomal dominant eoHM and Stickler syndrome. Sanger sequencing was used to detect potential variants. The pathogenicity of candidate variants was evaluated using mini genes ex vivo. Results: Eight patients and five unaffected members in the family participated in the study, in which the patients had high myopia with other variable ocular phenotypes but without extraocular abnormalities. Whole exome sequencing did not detect any potential pathogenic variant in all genes known to associate with the disease. The eoHM/ocular-STL in the family was mapped to markers around COL2A1 by candidate loci linkage scan, with a maximum lod score of 3.31 for D12S1590 at θ = 0. A novel deep intronic variant, c.86-50C > G in intron 1 of COL2A1, was detected by Sanger sequencing and co-segregated with eoHM/ocular-STL in the family. Ex vivo splicing test using mini genes confirmed that the variant created a new splicing acceptor 49 bp before the canonical splicing site of exon 2, resulted in addition of 49 bp fragment in the transcript (from c.86-49 to c.86-1) and premature termination. Conclusions: Linkage study, bioinformatics prediction, and ex vivo transcript analysis suggest a novel deep intronic variant adjacent to 5-prime of exon 2 of COL2A1, affecting exon 2 splicing, as a potential cause of ocular-STL in a large family. To our knowledge, this is the first report of an intronic variant around exon 2 as a cause of ocular-STL while a series of variants in the coding region of exon 2, a dispensable alternative-splicing exon for extraocular tissues, in COL2A1 have been reported to cause Stickler syndrome-related ocular phenotype alone.

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

Cited by 82 publications

References 63 publications

Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa

Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa

Whole-Exome Sequencing Reveals a Rare Missense Variant in SLC16A9 in a Pedigree with Early-Onset Gout

A novel deep intronic COL2A1 mutation in a family with early‐onset high myopia/ocular‐only Stickler syndrome

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