scholarly journals Whole Exome Sequencing Reveals Novel and Recurrent Disease-Causing Variants in Lens Specific Gap Junctional Protein Encoding Genes Causing Congenital Cataract

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 512
Author(s):  
Vanita Berry ◽  
Alex Ionides ◽  
Nikolas Pontikos ◽  
Ismail Moghul ◽  
Anthony T. Moore ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Sequence Variant ◽  
Whole Exome ◽  
Protein Encoding ◽  
Novel Variant ◽  
Junctional Protein ◽  
Autosomal Dominant Congenital Cataract ◽  
Gap Junctional ◽  
Encoding Genes

Pediatric cataract is clinically and genetically heterogeneous and is the most common cause of childhood blindness worldwide. In this study, we aimed to identify disease-causing variants in three large British families and one isolated case with autosomal dominant congenital cataract, using whole exome sequencing. We identified four different heterozygous variants, three in the large families and one in the isolated case. Family A, with a novel missense variant (c.178G>C, p.Gly60Arg) in GJA8 with lamellar cataract; family B, with a recurrent variant in GJA8 (c.262C>T, p.Pro88Ser) associated with nuclear cataract; and family C, with a novel variant in GJA3 (c.771dupC, p.Ser258GlnfsTer68) causing a lamellar phenotype. Individual D had a novel variant in GJA3 (c.82G>T, p.Val28Leu) associated with congenital cataract. Each sequence variant was found to co-segregate with disease. Here, we report three novel and one recurrent disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract. Our study further extends the mutation spectrum of these genes and further facilitates clinical diagnosis. A recurrent p.P88S variant in GJA8 causing isolated nuclear cataract provides evidence of further phenotypic heterogeneity associated with this variant.

scholarly journals Mutations in PIKFYVE cause autosomal dominant congenital cataract

2021 ◽  
Author(s):  
Shaoyi Mei ◽  
Yi Wu ◽  
Yan Wang ◽  
Yubo Cui ◽  
Miao Zhang ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Kinase Domain ◽  
Dominant Negative ◽  
Chinese Family ◽  
Bafilomycin A1 ◽  
Atpase Inhibitor ◽  
Causative Gene ◽  
Whole Exome ◽  
Autosomal Dominant Congenital Cataract

Congenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. Through whole exome sequencing of a Chinese family with congenital cataract, we identified a disease-causing mutation (p.G1943E) in PIKFYVE, which affecting the PIP kinase domain of the PIKfyve protein. We demonstrated that heterozygous/homozygous disruption of PIKfyve kinase domain, instead of overexpression of PIKFYVEG1943E in zebrafish mimicked the cataract defect in human patients, suggesting that haploinsufficiency, rather than dominant-negative inhibition of PIKfyve activity caused the disease. Phenotypical analysis of pikfyve zebrafish mutants revealed that loss of Pikfyve caused aberrant vacuolation (accumulation of Rab7+Lc3+ amphisomes) in lens cells, which was significantly alleviated by treatment with the V-ATPase inhibitor bafilomycin A1 (Baf-A1). Collectively, we identified PIKFYVE as a novel causative gene for congenital cataract and demonstrated the potential application of Baf-A1 in treatment of congenital cataract.

scholarly journals Partial duplication of the CRYBB1-CRYBA4 locus is associated with autosomal dominant congenital cataract

2016 ◽  
Author(s):  
Owen M. Siggs ◽  
Shari Javadiyan ◽  
Shiwani Sharma ◽  
Emmanuelle Souzeau ◽  
Karen M. Lower ◽  
...  
Keyword(s):  
Conflict Of Interest ◽  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Copy Number Variant ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Autosomal Dominant Congenital Cataract ◽  
Variant Analysis ◽  
Short Indels

AbstractCongenital cataract is a rare but severe paediatric visual impediment, often caused by variants in one of several crystallin genes that produce the bulk of structural proteins in lens. Here we describe a pedigree with autosomal dominant isolated congenital cataract and linkage to the crystallin gene cluster on chromosome 22. No rare single nucleotide variants or short indels were identified by whole-exome sequencing, yet copy number variant analysis revealed a duplication spanning both CRYBB1 and CRYBA4. While the CRYBA4 duplication was complete, the CRYBB1 duplication was not, with the duplicated CRYBB1 product predicted to create a gain of function allele. This association suggests a new genetic mechanism for the development of isolated congenital cataract.Grant informationSupported by the National Health and Medical Research CouncilConflict of interestthe authors declare no conflict of interest.

scholarly journals Variants in PAX6, PITX3 and HSF4 Causing Autosomal Dominant Congenital Cataract

2021 ◽  
Author(s):  
Vanita Berry ◽  
Alex Ionides ◽  
Nikolas Pontikos ◽  
Anthony T Moore ◽  
Roy A Quinlan ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Congenital Cataract ◽  
Target Genes ◽  
Autosomal Dominant ◽  
Bioinformatics Analysis ◽  
Missense Variant ◽  
Nuclear Cataract ◽  
Whole Exome ◽  
Novel Variants ◽  
Autosomal Dominant Congenital Cataract

Abstract Background: Lens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes are associated with congenital cataracts and other eye anomalies.Methods: Using whole exome sequencing, we identified disease-causing variants in two large British families and one isolated case with autosomal dominant congenital cataract. Bioinformatics analysis confirmed these disease-causing mutations as rare or novel variants, with a moderate to damaging pathogenicity score, with testing for segregation within the families using direct Sanger sequencing. Results: Family A had a missense variant (c.184G>A; p.V62M) in PAX6 and affected individuals presented with nuclear cataract. Family B had a frameshift variant (c.470-477dup; p.A160R*) in PITX3 that was also associated with nuclear cataract. A recurrent missense variant in HSF4 (c.341T>C; p.L114P) was associated with congenital cataract in a single isolated case. Conclusions: We have therefore identified novel variants in PAX6 and PITX3 that cause autosomal dominant congenital cataract.

scholarly journals Variants in PAX6, PITX3 and HSF4 causing autosomal dominant congenital cataracts

Eye ◽  
2021 ◽  
Author(s):  
Vanita Berry ◽  
Alex Ionides ◽  
Nikolas Pontikos ◽  
Anthony T. Moore ◽  
Roy A. Quinlan ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Congenital Cataract ◽  
Target Genes ◽  
Autosomal Dominant ◽  
Missense Variant ◽  
Nuclear Cataract ◽  
Congenital Cataracts ◽  
Whole Exome ◽  
Novel Variants ◽  
Autosomal Dominant Congenital Cataract

Abstract Background Lens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes are associated with congenital cataracts and other eye anomalies. Methods Using whole exome sequencing, we identified disease-causing variants in two large British families and one isolated case with autosomal dominant congenital cataract. Bioinformatics analysis confirmed these disease-causing mutations as rare or novel variants, with a moderate to damaging pathogenicity score, with testing for segregation within the families using direct Sanger sequencing. Results Family A had a missense variant (c.184 G>A; p.V62M) in PAX6 and affected individuals presented with nuclear cataract. Family B had a frameshift variant (c.470–477dup; p.A160R*) in PITX3 that was also associated with nuclear cataract. A recurrent missense variant in HSF4 (c.341 T>C; p.L114P) was associated with congenital cataract in a single isolated case. Conclusions We have therefore identified novel variants in PAX6 and PITX3 that cause autosomal dominant congenital cataract.

scholarly journals A missense mutation S228P in the CRYBB1 gene causes autosomal dominant congenital cataract

2007 ◽  
Vol 120 (9) ◽  
pp. 820-824 ◽  
Author(s):  
Jun WANG ◽  
Xu MA ◽  
Feng GU ◽  
Ning-pu LIU ◽  
Xiao-lin HAO ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Autosomal Dominant Congenital Cataract

scholarly journals Connexin46 Mutations in Autosomal Dominant Congenital Cataract

1999 ◽  
Vol 64 (5) ◽  
pp. 1357-1364 ◽  
Author(s):  
Donna Mackay ◽  
Alexander Ionides ◽  
Zoha Kibar ◽  
Guy Rouleau ◽  
Vanita Berry ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Autosomal Dominant Congenital Cataract

scholarly journals A novel missense mutation in LIM2 causing isolated autosomal dominant congenital cataract

2020 ◽  
Vol 41 (2) ◽  
pp. 131-134
Author(s):  
Vanita Berry ◽  
Nikolas Pontikos ◽  
Lubica Dudakova ◽  
Anthony T. Moore ◽  
Roy Quinlan ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Autosomal Dominant Congenital Cataract
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