Main Outcome Measures
Abbreviations and Acronyms:ACMG (American College of Medical Genetics and Genomics), AD (autosomal dominant), CC (congenital cataract)
|Participant||Age (yrs)/Gender||Eye||Visual Acuity||Best-Corrected Visual Acuity||Lens||Nystagmus||Axial Length (mm)||Cornea Diameter (mm)||B-mode US Findings||Surgery and Trauma History|
|1 Proband||30/F||OU||0.02||0.02||CC (Nuclear)||Yes||21.79/20.94||10.8/10.9||Vitreous bodies opaque||No|
|2 Proband’s son||5/M||OU||0.2||0.3||IOL (PS:CC Nuclear)||Yes||22.53/21.74||10.3/10.2||NA||Phacoemulsification + IOL|
|3 Proband’s daughter||2/F||OU||NA||NA||CC (Nuclear)||Yes||NA||8/8||NA||No|
|4 Proband’s husband||33/M||No||1.0/1.0||1.0/1.0||Transparent||No||23.53/24.01||12.7/12.8||Vitreous bodies opaque||No|
|5. Proband’s grandfather||67/M||OU||0.5/0.6||0.8/0.8||SC||No||23.97/23.99||12.6/12.7||Vitreous bodies opaque||No|
|6. Proband’s grandmother||66/F||OU||0.7/0.6||1.0/1.0||SC||No||23.76/23.88||12.5/12.8||Vitreous bodies opaque||No|
Whole-Exome Sequencing Analysis
Reads Mapping and Variants Analysis
- Richards S.
- Aziz N.
- Bale S.
- et al.
Sanger Sequencing for Verification
- 1.One disease-associated variant was identified using Exomiser analysis by matching the proband’s phenotype and the inheritance pattern. The variant was determined to be pathogenic according to ACMG guidelines (Table 2).13
ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-423Table 2Explanations
- Richards S.
- Aziz N.
- Bale S.
- et al.
Genotype Proband CRYGC 2q33. 3 NM_020989:exo n3:c.389_390i
p.C130fs Frameshift mutation MutationTaster pred (D) Heterozygous Proband’s son CRYGC 2q33. 3 NM_020989:exo n3:c.389_390i
p.C130fs Frameshift mutation MutationTaster pred (D) Heterozygous Proband’s daughter CRYGC 2q33. 3 NM_020989:exo n3:c.389_390i
p.C130fs Frameshift mutation MutationTaster pred (D) HeterozygousD = damaged.
- 2.There was no information associated with this variant in the ClinVar database.
- 3.There were no matched variants in 59 genes according to the ACMG SF (secondary findings) v2.0 mutation analysis.
- The Online Mendelian Inheritance in Man database (available at https://www.omim.org/entry/123680) described known mutations in the CRYGC gene that have been shown to cause cataracts (Table 3).Table 3Gene Description of Mutations That Have Been Shown to Cause Cataracts
Cytogenetic Locus Physical Locus Gene Exon/Intron DNA Change Protein Change Inheritance Origin Cataract Phenotype Other Phenotype Reference Comment 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.13A>C p.T5P AD UK Central zonular pulverulent (Coppock-like) Heon et al 1999 25 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.119-123dup5bp p.C42AfsX63 AD USA Variable zonular pulverulent Ren et al 2000 26 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.502C>T p.R168W AD India Lamellar Santhiya et al 2002 27 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.502C>T p.R168W AD Mexico Nuclear Peripupillary iris atrophy, nystagmus, myopia Gonzalez-Huerta et al 2007 28 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.502C>T p.R168W AD India Lamellar Devi et al 2008 33 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.327C>A p.C109X AD China Nuclear Nystagmus Yao et al 2008 29 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.470G>A p.W157X AD China Nuclear Microcornea Zhang et al 2009 32 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.143G>A p.R48H AD India Nuclear pulverulent Kumar et al 2011 34 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.471G>A p.W157X AD China Nuclear Microcornea Guo et al 2012 31 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.385G>T p.G129C AD China Nuclear Li et al 2012 30 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.124delT p.C42AfsX60 AD Korea Congenital Kondo et al 2013 35 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.157_161dupGCGGC p.Q55VfsX50 AD USA congenital Reis et al 2013 12 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.417C>G p.Y139X AD USA congenital Microphthalmia/microcornea, glaucoma, corneal opacity Reis et al 2013 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.134T>C p.L45P UK Gillespie et al 2014 36 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.402C>G p.Y134X UK Gillespie et al 2014 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.497C>T p.S166F AD Australia Nuclear Microphthalmia Prokudin et al 2014 37 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.497C>T p.S166F AD Australia Ma et al 2015 38 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.280G>A p.E94K Sporadic China Total (Unilateral) Li et al 2016 39 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.337C>T p.Q113X Sporadic China Nuclear Li et al 2016 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.403G>T p.E135X AD Microcornea Patel et al 2016 40 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.130delA p.M44CfsX59 AD China Pseudophakia Microcornea Sun et al 2017 17 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.143G>A p.R48H AD China Unilateral Optic disc coloboma Sun et al 2017 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.432C>G p.Y144X AD China Aphakia Microcornea, glaucoma Sun et al 2017 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.136T>G p.Y46D AD China Nuclear Zhong et al 2017 41 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.193delG p.D65TfsX38 AD China Nuclear Zhong et al 2017 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.417C>G p.Y139X AD China Nuclear Microcornea Zhong et al 2017 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.423delG p.R142GfsX5 AD China Nuclear Zhong et al 2017 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.423dupG p.R142AfsX22 AD China Nuclear Zhong et al 2017 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.432C>G p.Y144X AD China Nuclear Zhong et al 2017 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.497C>T p.S166F AD China Nuclear Microcornea Zhong et al 2017 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.505A>T p.R169X AD China Nuclear Zhong et al 2017 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.17T>C p.F6S AD Mexico Nuclear Astiazaran et al 2018 42 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.17T>C p.F6S AD Mexico Lamellar Astiazaran et al 2018 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.233C>T p.S78F AD China Nuclear Li et al 2018 43 2q33-q35 2:208,992,861-208,994,554 CRYGC IVS1 c.10-1G>A AD China Zhuang et al 2019 44 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex2 c.192delC p.D65TfsX38 AD China Total Fan et al 2020 45 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.497C>T p.S166F AD China Total Fan et al 2020 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.382G>T p.E128X AD India Nuclear Kandaswamy et al 2020 46 2q33-q35 2:208,992,861-208,994,554 CRYGC Ex3 c.432C>G p.Y144X AD Turkey Sekeroglu et al 2020 47AD = autosomal dominant.This gene encodes a member of the beta/gamma-crystallin family of proteins. Crystallins constitute major proteins of the vertebrate eye lens and are responsible for maintaining the transparency and refractive index of the lens. The Online Mendelian Inheritance in Man represents mutations in this gene that have been shown to cause cataracts. Online Mendelian Inheritance in Man No. 604307.Source: https://www.omim.org/entry/123680.
- DNA analysis of the proband’s son revealed a heterozygous frameshift mutation in CRYGC (NM_020989: exon 3: c.389_390insGCTG: p.C130fs). DNA analysis of the proband’s daughter also showed a heterozygous frameshift mutation in CRYGC (NM_020989: exon 3: c.389_390insGCTG: p.C130fs).
- 4.We identified the heterozygous CRYGC p.C130fs variant, including a frameshift mutation not currently reported in the ClinVar database. Sanger sequencing revealed that not only the proband but also her son and daughter carried this specific frameshift mutation.
- 5.The multiple sequence alignments generated using CLUSTAL X software showed that the p.c130fs of human of CRYGC is highly conserved in Homo sapiens, Mus musculus, Rattus norvegicus, Canis lupus familiaris, Pan troglodytes, and Halichoerus grypus (Fig 3).
- A novel mutation in the CRYAA gene associated with congenital cataract and microphthalmia in a Chinese family.BMC Med Genet. 2018; 19: 190
- The genetics of cataract: our vision becomes clearer.Am J Hum Genet. 1998; 62: 520-525
- X-linked inheritances recessive of congenital nystagmus and autosomal dominant inheritances of congenital cataracts coexist in a Chinese family: a case report and literature review.BMC Med Genet. 2019; 20: 41
- Genetics of human cataract.Clin Genet. 2013; 84: 120-127
- A novel mutation in the OAR domain of PITX3 associated with congenital posterior subcapsular cataract.BMC Med Genet. 2019; 20: 42
- Molecular genetics of cataract.Prog Mol Biol Transl Sci. 2015; 134: 203-218
- Two human gamma-crystallin genes are linked and riddled with Alu-repeats.Gene. 1985; 38: 197-204
- Lens proteins and their genes.Mol Biol. 1991; 41: 259-281
- Ageing and vision: structure, stability and function of lens crystallins.Prog Biophys Mol Biol. 2004; 86: 407-485
- The genetic and molecular basis of congenital cataract.Arq Bras Oftalmol. 2011; 74: 136-142
- Assignment of the human gamma-crystallin gene cluster (CRYG) to the long arm of chromosome 2, region q33-36.Hum Genet. 1986; 73: 17-19
- Whole exome sequencing in dominant cataract identifies a new causative factor, CRYBA2, and a variety of novel alleles in known genes.Hum Genet. 2013; 132: 761-770
- ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-423
- Genomic sequences of murine gamma B- and gamma C-crystallin-encoding genes: promoter analysis and complete evolutionary pattern of mouse, rat and human gamma-crystallins.Gene. 1993; 136: 145-156
- Lens crystallins: the evolution and expression of proteins for a highly specialized tissue.Annu Rev Biochem. 1988; 57: 479-504
- Genetics of crystallins: cataract and beyond.Exp Eye Res. 2009; 88: 173-189
- Mutations in crystallin genes result in congenital cataract associated with other ocular abnormalities.Mol Vis. 2017; 23: 977-986
- Alteration of protein–protein interactions of congenital cataract crystallin mutants.Invest Ophthalmol Vis Sci. 2003; 44: 1155-1159
- The cataract-associated V41M mutant of human γS-crystallin shows specific structural changes that directly enhance local surface hydrophobicity.Biochem Biophys Res Commun. 2014; 443: 110-114
- The molecular structure and stability of the eye lens: x-ray analysis of gamma-crystallin II.Nature. 1981; 289: 771-777
- Autosomal dominant congenital cataract. Interocular phenotypic variability.Ophthalmology. 1994; 101: 866-871
- Exome sequencing identifies novel and recurrent mutations in GJA8 and CRYGD associated with inherited cataract.Hum Genomics. 2014; 8: 19
- Increased hydrophobicity and decreased backbone flexibility explain the lower solubility of a cataract-linked mutant of γD-crystallin.J Mol Biol. 2011; 412: 647-659
- Identification of sequence similarities among isomerization hotspots in crystallin proteins.J Proteome Res. 2017; 16: 1797-1805
- The gamma-crystallins and human cataracts: a puzzle made clearer.Am J Hum Genet. 1999; 65: 1261-1267
- A 5-base insertion in the gammaC-crystallin gene is associated with autosomal dominant variable zonular pulverulent cataract.Hum Genet. 2000; 106: 531-537
- Novel mutations in the γ-crystallin genes cause autosomal dominant congenital cataracts.J Med Genet. 2002; 39: 352-368
- A family with autosomal dominant primary congenital cataract associated with a CRYGC mutation: evidence of clinical heterogeneity.Mol Vis. 2007; 13: 1333-1338
- A nonsense mutation in CRYGC associated with autosomal dominant congenital nuclear cataract in a Chinese family.Mol Vis. 2008; 14: 1272-1276
- A novel mutation impairing the tertiary structure and stability of γC-crystallin (CRYGC) leads to cataract formation in humans and zebrafish lens.Hum Mutat. 2012; 33: 391-401
- A nonsense mutation of CRYGC associated with autosomal dominant congenital nuclear cataracts and microcornea in a Chinese pedigree.Mol Vis. 2012; 18: 1874-1880
- A novel nonsense mutation in CRYGC is associated with autosomal dominant congenital nuclear cataracts and microcornea.Mol Vis. 2009; 15: 276-282
- Crystallin gene mutations in Indian families with inherited pediatric cataract.Mol Vis. 2008; 14: 1157-1170
- Mutation screening and genotype phenotype correlation of α- crystallin, γ-crystallin and GJA8 gene in congenital cataract.Mol Vis. 2011; 17: 693-707
- Pathogenic mutations in two families with congenital cataract identified with whole-exome sequencing.Mol Vis. 2013; 19: 384-389
- Personalized diagnosis and management of congenital cataract by next-generation sequencing.Ophthalmology. 2014; 121: 2124-2137 e1-2
- Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1.Eur J Hum Genet. 2014; 22: 907-915
- Sporadic and familial congenital cataracts: mutational spectrum and new diagnoses using next-generation sequencing.Hum Mutat. 2016; 37: 371-384
- Distribution of gene mutations in sporadic congenital cataract in a Han Chinese population.Mol Vis. 2016; 22: 589-598
- Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract.Hum Genet. 2017; 136: 205-225
- Novel mutations in CRYGC are associated with congenital cataracts in Chinese families.Sci Rep. 2017; 7: 1-7
- Next generation sequencing-based molecular diagnosis in familial congenital cataract expands the mutational spectrum in known congenital cataract genes.Am J Med Genet A. 2018; 176: 2637-2645
- Clinical and genetic characteristics of Chinese patients with familial or sporadic pediatric cataract.Orphanet J Rare Dis. 2018; 13: 1-2
- Mutation screening of crystallin genes in Chinese families with congenital cataracts.Mol Vis. 2019; 25: 427-437
- The mutation spectrum in familial versus sporadic congenital cataract based on next-generation sequencing.BMC Ophthalmol. 2020; 20: 361
- A novel CRYGC E128∗ mutation underlying an autosomal dominant nuclear cataract in a south Indian kindred.Ophthalmic Genet. 2020; 41: 556-562
- Molecular etiology of isolated congenital cataract using next-generation sequencing: single center exome sequencing data from Turkey.Mol Syndromol. 2020; 11: 302-308
- Two Paired Box 6 mutations identified in Chinese patients with classic congenital aniridia and cataract.Mol Med Rep. 2018; 18: 4439-4445
- Identification of a novel MIP frameshift mutation associated with congenital cataract in a Chinese family by whole-exome sequencing and functional analysis.Eye (Lond). 2018; 32: 1359-1364
All authors have completed and submitted the ICMJE disclosures form.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
This research was funded by the Natural Science Foundation of Heilongjiang Province (Surface project), grant number: H2017077
HUMAN SUBJECTS: Human subjects were included in this study. The study and all its protocols were approved by the Ethics Committee of the HongQi Hospital, MuDanJiang Medical University (approval number: 201703). Informed consent was obtained from all participants and their parents/guardians. All research adhered to the tenets of the Declaration of Helsinki.
No animal subjects were used in this study.
Conception and design: Zhou, Zhao, Guo, Zhuang
Data collection: Zhou, Zhao, Guo, Zhuang, Zhuo, Chen, Liu, Wang
Analysis and interpretation: Zhou, Zhao, Guo, Zhuang, Zhuo, Chen, Liu, Wang
Obtained funding: N/A; Study was performed as part of the authors' regular employment duties. No additional funding was provided.
Overall responsibility: Zhou, Zhao
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