Variants in PAX6, PITX3 and HSF4 Causing 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.

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

Eye ◽

10.1038/s41433-021-01711-x ◽

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.

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The genetic landscape of crystallins in congenital cataract

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01613-3 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Vanita Berry ◽

Alex Ionides ◽

Nikolas Pontikos ◽

Michalis Georgiou ◽

Jing Yu ◽

...

Keyword(s):

Congenital Cataract ◽

Rare Variants ◽

Large Family ◽

Crystalline Lens ◽

Missense Variant ◽

Sequence Variants ◽

Nuclear Cataract ◽

Whole Exome ◽

Novel Variants ◽

Genetic Landscape

Abstract Background The crystalline lens is mainly composed of a large family of soluble proteins called the crystallins, which are responsible for its development, growth, transparency and refractive index. Disease-causing sequence variants in the crystallins are responsible for nearly 50% of all non-syndromic inherited congenital cataracts, as well as causing cataract associated with other diseases, including myopathies. To date, more than 300 crystallin sequence variants causing cataract have been identified. Methods Here we aimed to identify the genetic basis of disease in five multi-generation British families and five sporadic cases with autosomal dominant congenital cataract using whole exome sequencing, with identified variants validated using Sanger sequencing. Following bioinformatics analysis, rare or novel variants with a moderate to damaging pathogenicity score, were filtered out and tested for segregation within the families. Results We have identified 10 different heterozygous crystallin variants. Five recurrent variants were found: family-A, with a missense variant (c.145C>T; p.R49C) in CRYAA associated with nuclear cataract; family-B, with a deletion in CRYBA1 (c.272delGAG; p.G91del) associated with nuclear cataract; and family-C, with a truncating variant in CRYGD (c.470G>A; W157*) causing a lamellar phenotype; individuals I and J had variants in CRYGC (c.13A>C; T5P) and in CRYGD (c.418C>T; R140*) causing unspecified congenital cataract and nuclear cataract, respectively. Five novel disease-causing variants were also identified: family D harboured a variant in CRYGC (c.179delG; R60Qfs*) responsible for a nuclear phenotype; family E, harboured a variant in CRYBB1 (c.656G>A; W219*) associated with lamellar cataract; individual F had a variant in CRYGD (c.392G>A; W131*) associated with nuclear cataract; and individuals G and H had variants in CRYAA (c.454delGCC; A152del) and in CRYBB1 (c.618C>A; Y206*) respectively, associated with unspecified congenital cataract. All novel variants were predicted to be pathogenic and to be moderately or highly damaging. Conclusions We report five novel variants and five known variants. Some are rare variants that have been reported previously in small ethnic groups but here we extend this to the wider population and record a broader phenotypic spectrum for these variants.

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Mutations in PIKFYVE cause autosomal dominant congenital cataract

10.1101/2021.06.25.449865 ◽

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.

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

Genes ◽

10.3390/genes11050512 ◽

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.

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Mutation Analysis of Families with Autosomal Dominant Congenital Cataract: A Recurrent Mutation in the CRYBA1/A3 Gene Causing Congenital Nuclear Cataract

Current Eye Research ◽

10.1080/02713683.2017.1406527 ◽

2018 ◽

Vol 43 (3) ◽

pp. 304-307 ◽

Cited By ~ 3

Author(s):

Kai Jie Wang ◽

Xu Zha ◽

Dou Dou Chen ◽

Si Quan Zhu

Keyword(s):

Mutation Analysis ◽

Congenital Cataract ◽

Autosomal Dominant ◽

Recurrent Mutation ◽

Nuclear Cataract ◽

Autosomal Dominant Congenital Cataract

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

10.1101/042515 ◽

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.

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Novel mutations associated with autosomal dominant congenital cataract are identified in Chinese families

10.1101/367516 ◽

2018 ◽

Author(s):

Zhenyu Wang ◽

Chen Huang ◽

Yanxiu Sun ◽

Huibin Lv ◽

Mingzhou Zhang ◽

...

Keyword(s):

Congenital Cataract ◽

Autosomal Dominant ◽

Bioinformatics Analysis ◽

Genetic Defect ◽

Hereditary Disease ◽

The Other ◽

Novel Mutations ◽

Chinese Families ◽

Functional Changes ◽

Autosomal Dominant Congenital Cataract

AbstractPurposeAs the leading cause of the impairment of vision of children, congenital cataract is considered as a hereditary disease, especially autosomal dominant congenital cataract (ADCC). The purpose of this study is to identify the genetic defect of six Chinese families with ADCC.Subjects and MethodsSix Chinese families with ADCC were recruited in the study. (103 members in total, 96 members alive, 27 patients in total) Genomic DNA samples extracting from probands’ peripheral blood cells were captured the mutations using a specific eye disease enrichment panel with next generation sequencing. After initial pathogenicity prediction, sites with specific pathogenicity were screened for further validation. Sanger sequencing was conducted in the other individuals in the families and other 100 normal controls. Mutations definitely related with ADCC will then be analyzed by bioinformatics analysis. The pathogenic effect of the amino acid changes and structural and functional changes of the proteins were finally analyzed by bioinformatics analysis.ResultsSeven mutations in six candidate genes associated with ADCC of six families were detected (MYH9 c.4150G>C, CRYBA4 c.169T>C, RPGRRIP1 c.2669G>A, WFS1 c.1235T>C, CRYBA4 c.26C>T, EPHA2 c.2663+1G>A, and PAX6 c.11–2A>G). All the seven mutations were only detected on affected individuals in the families. Among them there are three novel mutations (MYH9 c.4150G>C, CRYBA4 c.169T>C, RPGRRIP1 c.2669G>A) and four that have been reported (WFS1 c.1235T>C, CRYBA4 c.26C>T, EPHA2 c.2663+1G>A, and PAX6 c.11–2A>G). RPGRIP1 (c.2669G>A) mutation and CRYBA4 (c.26C>T) mutation are predicted to be benign according to bioinformatics analysis while the other five mutations (EPHA2, PAX6, MYH9, CRYBA4 c.169T>C, WFS1) are thought to be pathogenic.ConclusionWe report two novel heterozygous mutations (MYH9 c.4150G>C and CRYBA4 c.169T>C) in six Chinese families supporting their vital roles in causing ADCC.

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