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

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

Experimental and Therapeutic Medicine ◽

10.3892/etm.2019.7865 ◽

2019 ◽

Author(s):

Zhenyu Wang ◽

Chen Huang ◽

Yanxiu Sun ◽

Huibin Lv ◽

Mingzhou Zhang ◽

...

Keyword(s):

Congenital Cataract ◽

Autosomal Dominant ◽

Novel Mutations ◽

Chinese Families ◽

Autosomal Dominant Congenital Cataract

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Novel mutations identified in Chinese families with autosomal dominant congenital cataracts by targeted next-generation sequencing

BMC Medical Genetics ◽

10.1186/s12881-019-0933-5 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Shan Li ◽

Jianfei Zhang ◽

Yixuan Cao ◽

Yi You ◽

Xiuli Zhao

Keyword(s):

Next Generation Sequencing ◽

Congenital Cataract ◽

Bioinformatics Analysis ◽

Next Generation ◽

Novel Mutations ◽

Congenital Cataracts ◽

Chinese Families ◽

Targeted Next Generation Sequencing ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Abstract Background Congenital cataract is a clinically and genetically heterogeneous visual impairment. The aim of this study was to identify causative mutations in five unrelated Chinese families diagnosed with congenital cataracts. Methods Detailed family history and clinical data were collected, and ophthalmological examinations were performed using slit-lamp photography. Genomic DNA was extracted from peripheral blood of all available members. Thirty-eight genes associated with cataract were captured and sequenced in 5 typical nonsyndromic congenital cataract probands by targeted next-generation sequencing (NGS), and the results were confirmed by Sanger sequencing. Bioinformatics analysis was performed to predict the functional effect of mutant genes. Results Results from the DNA sequencing revealed five potential causative mutations: c.154 T > C(p.F52 L) in GJA8 of Family 1, c.1152_1153insG(p.S385Efs*83) in GJA3 of Family 2, c.1804 G > C(p.G602R) in BFSP1 of Family 3, c.1532C > T(p.T511 M) in EPHA2 of Family 4 and c.356G > A(p.R119H) in HSF4 of Family 5. These mutations co-segregated with all affected individuals in the families and were not found in unaffected family members nor in 50 controls. Bioinformatics analysis from several prediction tools supported the possible pathogenicity of these mutations. Conclusions In this study, we identified five novel mutations (c.154 T > C in GJA8, c.1152_1153insG in GJA3, c.1804G > C in BFSP1, c.1532C > T in EPHA2, c.356G > A in HSF4) in five Chinese families with hereditary cataracts, respectively. NGS can be used as an effective tool for molecular diagnosis of genetically heterogeneous disorders such as congenital cataract, and the results can provide more effective clinical diagnosis and genetic counseling for the five families.

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

10.21203/rs.3.rs-367664/v1 ◽

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.

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