Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families

Fernández-Alcalde, Celia; Nieves-Moreno, M.; Noval, Susana; Peralta, Jesús; Montaño, Victoria E. F.; Pozo, Ángela del; Santos‐Simarro, Fernando; Vallespín, Elena

doi:10.3390/genes12040580

Cited by 20 publications

(21 citation statements)

References 44 publications

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“…Three variants were identified in connexin genes GJA8 and GJA3 . A GJA8 p.(Gly22Ser) change, observed in family CRCH137, has been previously reported 25 27 28 and is one meiosis short of reclassification as likely pathogenic ( table 1 , figure 3A ). In family CTAS71, the novel p.(Lys131del) change ( table 1 , figure 3B ) is located centrally in the GJA8 protein’s cytoplasmic loop which is a less conserved protein region in general.…”

Section: Resultsmentioning

confidence: 75%

Pathogenic genetic variants identified in Australian families with paediatric cataract

et al. 2022

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ObjectivePaediatric (childhood or congenital) cataract is an opacification of the normally clear lens of the eye and has a genetic basis in at least 18% of cases in Australia. This study aimed to replicate clinical gene screening to identify variants likely to be causative of disease in an Australian patient cohort.Methods and analysisSixty-three reported isolated cataract genes were screened for rare coding variants in 37 Australian families using genome sequencing.ResultsDisease-causing variants were confirmed in eight families with variant classification as ‘likely pathogenic’. This included novel variants PITX3 p.(Ter303LeuextTer100), BFSP1 p.(Glu375GlyfsTer2), and GJA8 p.(Pro189Ser), as well as, previously described variants identified in genes GJA3, GJA8, CRYAA, BFSP1, PITX3, COL4A1 and HSF4. Additionally, eight variants of uncertain significance with evidence towards pathogenicity were identified in genes: GJA3, GJA8, LEMD2, PRX, CRYBB1, BFSP2, and MIP.ConclusionThese findings expand the genotype–phenotype correlations of both pathogenic and benign variation in cataract-associated genes. They further emphasise the need to develop additional evidence such as functional assays and variant classification criteria specific to paediatric cataract genes to improve interpretation of variants and molecular diagnosis in patients.

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Section: Resultsmentioning

confidence: 75%

Pathogenic genetic variants identified in Australian families with paediatric cataract

et al. 2022

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“…The 14th (arginine), 25th (proline), and 150th (arginine) codons were most frequently reported, which are marked in red in Figure 2C . A Spanish author had reported that a missense mutation in c. C232T (p. Ser78Pro) resulted in nuclear cataract ( Fernández-Alcalde et al, 2021 ). Our variant amino acid site (78) was the same as that reported by the Spanish author, but our variant resulted in serine-to-phenylalanine substitution.…”

Section: Resultsmentioning

confidence: 99%

Case Report: A Novel Mutation in the CRYGD Gene Causing Congenital Cataract Associated with Nystagmus in a Chinese Family

Gao

Ren

et al. 2022

Front. Genet.

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Purpose: Congenital cataract (CC) is a common disease resulting in leukocoria and the leading cause of blindness in children worldwide. Approximately 50% of congenital cataract is inherited. Our aim is to identify mutations in a Chinese family with congenital cataract.Methods: A four-generation Chinese family diagnosed with congenital cataract was recruited in West China Hospital of Sichuan University. Genomic DNA was extracted from the peripheral blood of these participants. All coding exons and flanking regions were amplified and sequenced, and the variants were validated using Sanger sequencing. AlphaFold2 was used to predict possible protein structural changes in this variant.Results: The proband had congenital nuclear cataract with nystagmus. A heterozygous variant c.233C > T was identified in exon 2 of the CRYGD gene in chromosome 2. This mutation resulted in a substitution of serine with phenylalanine at amino acid residue 78 (p.S78F). The variant might result in a less stable structure with a looser loop and broken hydrogen bond predicted by AlphaFold2, and this mutation was co-segregated with the disease phenotype in this family.Conclusion: We described cases of human congenital cataract caused by a novel mutation in the CRYGD gene and provided evidence of further phenotypic heterogeneity associated with this variant. Our study further extends the mutation spectrum of the CRYGD gene in congenital cataract.

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“… Ex3/5 c.313T>G p.F105V AR Iraq Presenile, cortical, sutural ( 12 ) 5. Ex4/5 c.385C>T p.R129C AD Spain - ( 13 ) 6. Ex4/5 c.388C>T p.R130C AD UK/Czechia Nuclear pulverulent ( 3 ) 7.…”

Section: Discussionmentioning

confidence: 99%

A recurrent variant in LIM2 causes an isolated congenital sutural/lamellar cataract in a Japanese family

Berry

Fujinami

Mochizuki

et al. 2022

Ophthalmic Genetics

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Background Genetically determined cataract is both clinically and molecularly highly heterogeneous. Here, we have identified a heterozygous variant in the lens integral membrane protein LIM2, the second most abundant protein in the lens, responsible for congenital sutural/lamellar cataract in a three-generation Japanese family. Methods Whole exome sequencing (WES) was undertaken in one affected and one unaffected individual from a family with autosomal dominant congenital cataract to establish the underlying genetic basis. Results A recurrent missense variant LIM2: c.388C>T; p.R130C was identified and found to co-segregate with disease. In addition, one variant COL11A1:c.3788C>T of unknown significance (VUS) was also identified. Conclusions We report a variant in LIM2 causing an isolated autosomal-dominant congenital sutural/lamellar cataract in a Japanese family. This is the first report of a LIM2 variant in the Japanese population. Hence, we expand the mutation spectrum of LIM2 variants in different ethnic groups.

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Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families

Cited by 20 publications

References 44 publications

Pathogenic genetic variants identified in Australian families with paediatric cataract

Pathogenic genetic variants identified in Australian families with paediatric cataract

Case Report: A Novel Mutation in the CRYGD Gene Causing Congenital Cataract Associated with Nystagmus in a Chinese Family

A recurrent variant in LIM2 causes an isolated congenital sutural/lamellar cataract in a Japanese family

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