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      Clinical and genetic characteristics of Chinese patients with familial or sporadic pediatric cataract

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          Abstract

          Background

          Pediatric cataract is a clinically and genetically heterogeneous disease which is a significant cause of lifelong visual impairment and treatable blindness. Our study aims to investigate the genotype spectrum in a group of Chinese patients with pediatric cataract.

          Methods

          We enrolled 39 families with pediatric cataract from October 2015 to April 2016. DNA samples of the probands were analyzed by target next-generation sequencing. Variants were validated using Sanger sequencing in the probands and available family members.

          Results

          In our cohort of 39 cases with different types of pediatric cataract, 23 cases were found to harbor putative pathogenic variants in 15 genes: CRYAA, CRYBA1, CRYBA4, CRYBB1, CRYGC, CRYGD, MIP, GCNT2, IARS2, NHS, BCOR, BFSP2, FYCO1, MAF, and PAX6. The mutation detection rates in the familial and sporadic cases were 75 and 47.8%, respectively. Of the 23 causative variants, over half were novel.

          Conclusions

          This is a rare report of systematic mutation screening analysis of pediatric cataract in a comparably large cohort of Chinese patients. Our observations enrich the mutation spectrum of pediatric cataract. Next-generation sequencing provides significant diagnostic information for pediatric cataract cases, especially when considering sporadic and subtle syndromal cases.

          Electronic supplementary material

          The online version of this article (10.1186/s13023-018-0828-0) contains supplementary material, which is available to authorized users.

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          Congenital cataracts and their molecular genetics.

          J. Hejtmancik (2008)
          Cataract can be defined as any opacity of the crystalline lens. Congenital cataract is particularly serious because it has the potential for inhibiting visual development, resulting in permanent blindness. Inherited cataracts represent a major contribution to congenital cataracts, especially in developed countries. While cataract represents a common end stage of mutations in a potentially large number of genes acting through varied mechanisms in practice most inherited cataracts have been associated with a subgroup of genes encoding proteins of particular importance for the maintenance of lens transparency and homeostasis. The increasing availability of more detailed information about these proteins and their functions and is making it possible to understand the pathophysiology of cataracts and the biology of the lens in general.
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            Crystallin gene mutations in Indian families with inherited pediatric cataract

            Ramachandran Ramya Devi, Wenliang Yao, Perumalsamy Vijayalakshmi … (2008)
            Purpose Pediatric cataract is the most common form of treatable childhood blindness and is both clinically and genetically heterogeneous. Autosomal dominant and recessive forms of cataract have been reported to be caused by mutations in 22 different genes so far. Of the cataract mutations reported to date, about half the mutations occur in crystallins, a quarter of the mutations in connexins, and the remainder is evenly divided between intrinsic membrane proteins, intermediate filament proteins, and transcription factors. This study is aimed at identification of the spectrum and frequency of crystallin gene mutations in cataractous patients in an Indian population. Methods Genetic analysis was extended to screen the entire coding region of the CRYAA, CRYAB, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, CRYGC, CRYGD, and CRYGS genes using single stranded conformational polymorphism (SSCP) analysis as a screening technique followed by direct sequencing of all subjects that displayed an electrophoretic shift. Results This report describes the first simultaneous mutation analysis of 10 crystallin genes in the same population, represented by 60 south Indian families. The analysis allowed the identification of causative mutations in 10 of the families (three novel and six reported). This includes six missense mutations (CRYAA-R12C, R21W, R54C, CRYAB- A171T, CRYGC-R168W, CRYGS- S39C), two nonsense mutations (CRYBB2- Q155X, CRYGD- R140X), and one splice mutation, which was identified in two families (CRYBA1-IVS3+1G>A). Conclusions Crystallin mutations are responsible for 16.6% of the inherited pediatric cataract in this population. As causative mutations have not been found in many of the families analyzed, this study suggests the presence of further novel genes or sequence elements involved in the pathogenesis of cataract in these families.
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              Genetic heterogeneity in microcornea-cataract: five novel mutations in CRYAA, CRYGD, and GJA8.

              Susanne Kjaer, Thomas Rosenberg, Kirsten Baggesen … (2007)
              To unravel the molecular genetic background in families with congenital cataract in association with microcornea (CCMC, OMIM 116150). CCMC families were recruited from a national database on hereditary eye diseases; DNA was procured from a national gene bank on hereditary eye diseases and by blood sampling from one large family. Genomewide linkage analysis, fine mapping, and direct genomic DNA sequencing of nine cataract candidate genes were applied. Restriction enzyme digests confirmed identified mutations. Analyses of 10 Danish families with hereditary congenital cataract and microcornea revealed five novel mutations. Three of these affected the crystallin, alpha-A gene (CRYAA), including two mutations (R12C and R21W) in the crystallin domain and one mutation (R116H) in the small heat shock domain. One mutation (P189L) affected the gap junction protein alpha 8 (GJA8), and one mutation (Y134X) was detected in crystallin gamma-D (CRYGD). The identification of a CRYGD mutation adds another gene to those that may be mutated in CCMC and underscores the genetic heterogeneity of this condition. Three CRYAA mutations at the R116 position, in association with CCMC, suggest that R116 represents a CCMC-mutational hotspot. The CCMC phenotype demonstrates variable expression with regard to cataract morphology and age of appearance. Clinical heterogeneity, including additional malformation of the anterior segment of the eye, confirm that dedicated cataract genes may be involved in the largely unknown developmental molecular mechanisms involved in lens-anterior segment interactions.
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                Author and article information

                Contributors
                Jingyan Li: Jingyan0830@sina.com
                Yunji Leng: Lengyunji0118@163.com
                Shirui Han: Hanshirui2014@163.com
                Lulu Yan: 952235086@qq.com
                Chaoxia Lu: chaoxialu@ibms.pumc.edu.cn
                Yang Luo: yluo@cmu.edu.cn
                Xue Zhang: xuezhang@pumc.edu.cn
                Lihua Cao:
                ORCID: http://orcid.org/0000-0002-0795-0397
                lhcao@cmu.edu.cn
                Journal
                Journal ID (nlm-ta): Orphanet J Rare Dis
                Journal ID (iso-abbrev): Orphanet J Rare Dis
                Title: Orphanet Journal of Rare Diseases
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1750-1172
                Publication date (Electronic): 18 June 2018
                Publication date PMC-release: 18 June 2018
                Publication date Collection: 2018
                Volume: 13
                Electronic Location Identifier: 94
                Affiliations
                [1 ]ISNI 0000 0000 9678 1884, GRID grid.412449.e, The Research Center for Medical Genomics, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, College of Basic Medical Science, , China Medical University, ; No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122 China
                [2 ]ISNI 0000 0000 9889 6335, GRID grid.413106.1, McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, , Chinese Academy of Medical Sciences and Peking Union Medical College, ; Beijing, 100005 China
                Author information
                http://orcid.org/0000-0002-0795-0397
                Article
                Publisher ID: 828
                DOI: 10.1186/s13023-018-0828-0
                PMC ID: 6006596
                PubMed ID: 29914532
                SO-VID: 841e08e0-de46-461b-8163-cd970b1ab0cf
                Copyright © © The Author(s). 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 8 February 2018
                Date accepted : 18 May 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81230015
                Award ID: 81670896
                Award Recipient :
                Funded by: CAMS Innovation Found for Medical Sciences
                Award ID: 2016-I2M-1-002
                Award Recipient :
                Funded by: Beijing Municipal Science and Technology Commission
                Award ID: Z151100003915078
                Award Recipient :
                Funded by: National Key Research and Development Program of China
                Award ID: 2016YFC0905100
                Award Recipient :
                Funded by: Liaoning Provincial Education Department Science and Technology Research Project
                Award ID: LK201653
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: pediatric cataract,next-generation sequencing,variant,nystagmus
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: pediatric cataract, next-generation sequencing, variant, nystagmus

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