Combinational analysis of linkage and exome sequencing identifies the causative mutation in a Chinese family with congenital cataract

Congenital cataract is the most common cause of the visual disability and blindness in childhood. This study aimed to identify gene mutations responsible for autosomal dominant congenital cataract (ADCC) in a Chinese family using next-generation sequencing technology. This family included eight unaffected and five affected individuals. After complete ophthalmic examinations, the blood samples of the proband and two available family members were collected. Then the whole exome sequencing was performed on the proband and Sanger sequencing was applied to validate the causal mutation in the two family members and control samples. After the whole exome sequencing data were filtered through a series of existing variation databases, a heterozygous mutation c.499T<G (p.E167X) in CRYBB2 gene was found. And the results showed that the mutation cosegregated with the disease phenotype in the family and was absolutely absent in 1000 ethnicity-matched control samples. Thus, the heterozygous mutation c.499T<G (p.E167X) in CRYBB2 was the causal mutation responsible for this ADCC family. In conclusion, our findings revealed a novel stopgain mutation c.499T<G (p.E167X) in the exon 6 of CRYBB2 which expanded the mutation spectrum of CRYBB2 in Chinese congenital cataract population and illustrated the important role of CRYBB2 in the genetics research of congenital cataract.

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Novel SOX2 Mutation in Autosomal Dominant Cataract-Microcornea Syndrome

10.21203/rs.3.rs-1085640/v1 ◽

2021 ◽

Author(s):

Zhi-Bo Lin ◽

Jin Li ◽

Hai-Sen Sun ◽

A-Yong Yu ◽

Shi-Hao Chen ◽

...

Keyword(s):

Exome Sequencing ◽

Missense Mutation ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Congenital Cataract ◽

Autosomal Dominant ◽

Family Members ◽

High Mobility ◽

Chinese Family ◽

Whole Exome

Abstract Background: Congenital cataract-microcornea syndrome (CCMC) is characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Although several causative genes have been reported in patients with CCMC, the genetic etiology of CCMC is yet to be clearly understood. Purpose: To unravel the genetic cause of autosomal dominant family with CCMC.Methods: All patients and available family members underwent a comprehensive ophthalmologic clinical examination in the hospital by expert ophthalmologists and carried out to clinically diagnosis. All the patients were screened by whole-exome sequencing and then validated using co-segregation by Sanger sequencing. Results: Four CCMC patients from a Chinese family, and five unaffected family members were enrolled in this study. Using whole-exome sequencing, missense mutation c.295G>T (p.a99s, NM_003106.4) in the SOX2 gene was identified and validated by segregation analysis. In addition, this missense mutation was predicted to be damaging by multiple predictive tools. Variant p.Ala99Ser was located in a conservation high mobility group (HMG)-box domain in SOX2 protein, with a potential pathogenic impact of p.Ala99Ser on protein level.Conclusions: A novel missense mutation (c.295G>T, p.Ala99Ser) in the SOX2 gene was found in this Han Chinese family with congenital cataract and microcornea. Our study firstly determined that mutations in SOX2 were associated with CCMC, warranting further investigations on the pathogenesis of this disorder. This result expands the mutation spectrum of SOX2 and provides useful information to study the molecular pathogenesis of CCMC.

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A novel missense mutation of CRYBB1 causes congenital cataract in a Chinese family

European Journal of Ophthalmology ◽

10.1177/1120672120914497 ◽

2020 ◽

pp. 112067212091449

Author(s):

Yanan Ji ◽

Xiangyu Zhao ◽

Juanmei Zhang ◽

Dan Zhang ◽

Chunliu Tian ◽

...

Keyword(s):

Missense Mutation ◽

Protein Function ◽

Congenital Cataract ◽

Family Members ◽

Causative Mutation ◽

Chinese Family ◽

Heterozygous Mutation ◽

Nuclear Cataract ◽

Mutation Site ◽

The Family

Objective of the study: To identify the pathogenic gene and mutation site of a Chinese family with congenital cataract. Methods: Eight family members and 100 controls were employed, and targeted exome sequencing was used to identify the genetically pathogenic factor of the proband. Results: Targeted next-generation sequencing identified a novel missense mutation c.209A>C (p.Q70P) of CRYBB1 gene in the family. Sanger sequencing results showed that this heterozygous mutation was a causative mutation, which was not found in unaffected family members and healthy controls. Bioinformatics predicts that the effect of this mutation on protein function is probably harmful. Conclusion: We demonstrate that c.209A>C of CRYBB1 gene is a pathogenic mutation in the family of congenital nuclear cataract in this study. This is the first report that this mutation leads to congenital nuclear cataract, which broadens the mutation spectrum of CRYBB1 gene in congenital nuclear cataract.

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Use of high-throughput targeted exome sequencing in genetic diagnosis of Chinese family with congenital cataract

International Journal of Ophthalmology ◽

10.18240/ijo.2016.05.02 ◽

2016 ◽

Keyword(s):

Exome Sequencing ◽

High Throughput ◽

Congenital Cataract ◽

Genetic Diagnosis ◽

Chinese Family ◽

Targeted Exome Sequencing

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A novel TLE6 mutation, c.541+1G>A, identified using whole‐exome sequencing in a Chinese family with female infertility

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.1743 ◽

2021 ◽

Author(s):

Bin Mao ◽

Xueling Jia ◽

Hongfang Liu ◽

Xiaojuan Xu ◽

Xiaodong Zhao ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Female Infertility ◽

Chinese Family ◽

Whole Exome

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A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy

Translational Stroke Research ◽

10.1007/s12975-021-00926-0 ◽

2021 ◽

Author(s):

Qing Li ◽

Chengfeng Wang ◽

Wei Li ◽

Zaiqiang Zhang ◽

Shanshan Wang ◽

...

Keyword(s):

Basement Membrane ◽

Skin Biopsy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Dominant ◽

Chinese Family ◽

Heterozygous Mutation ◽

Collagen Type Iv ◽

Lacunar Infarcts ◽

Whole Exome

AbstractPontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

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