scholarly journals Molecular Etiology of Isolated Congenital Cataract Using Next-Generation Sequencing: Single Center Exome Sequencing Data from Turkey

2020 ◽  
Vol 11 (5-6) ◽  
pp. 302-308
Author(s):  
Hande Taylan Sekeroglu ◽  
Beren Karaosmanoglu ◽  
Ekim Z. Taskiran ◽  
Pelin O. Simsek Kiper ◽  
Mehmet Alikasifoglu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Sanger Sequencing ◽  
Congenital Cataract ◽  
Family Members ◽  
First Year ◽  
Ophthalmological Examination ◽  
Sequencing Data ◽  
Molecular Etiology ◽  
Bilateral Congenital Cataract ◽  
First Year Of Life

Congenital cataract, which refers to lenticular opacity diagnosed at birth or more commonly during the first year of life, is one of the leading causes of childhood blindness. Molecular understanding of the disease pathogenesis has evolved thanks to many studies based on modern technologies. In this study, we aimed to identify and discuss the molecular etiology of nonsyndromic or nonmetabolic bilateral congenital cataract by whole-exome sequencing (WES). Patients with bilateral congenital cataract presumed to be isolated after metabolic and genetic evaluation were enrolled in the study. All patients underwent detailed ophthalmological examination and bilateral cataract surgery. DNA samples of the probands, parents, and available affected family members were analyzed by WES. Variants were validated and confirmed by Sanger sequencing in all probands and in available affected family members. A total of 4 patients (3 girls and 1 boy) were recruited. Two patients had nuclear, 1 patient had total, and 1 patient had combined lamellar and sutural cataract. One family had consanguinity. A heterozygous c.215+1G&#x3e;A mutation in <i>CRYBA1</i>, heterozygous c.432C&#x3e;G (p.Tyr144Ter) mutation in <i>CRYGC</i>, heterozygous c.70A&#x3e;C (p.Pro24Thr) mutation in <i>CRYGD</i>, and a heterozygous c.466G&#x3e;A (p.Gly156Arg) mutation in <i>CRYBB3</i> were detected. All these mutations were confirmed by Sanger sequencing in selected affected individuals. The current study identified all causative mutations of congenital cataract in the crystalline genes. The results confirmed that WES is a very useful tool in the investigation of the diseases with heterogeneous genetic background.

scholarly journals Whole exome sequencing of a family revealed a novel variant in the CHM gene, c.22delG p.(Glu8Serfs*4), which co-segregated with choroideremia

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Handong Dan ◽  
Tuo Li ◽  
Xinlan Lei ◽  
Xin Huang ◽  
Yiqiao Xing ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Family Members ◽  
Clinical Manifestations ◽  
Complex Form ◽  
Chinese Family ◽  
Sequencing Data ◽  
Whole Exome ◽  
Novel Variant

Abstract Choroideremia is a complex form of blindness-causing retinal degeneration. The aim of the present study was to investigate the pathogenic variant and molecular etiology associated with choroideremia in a Chinese family. All available family members underwent detailed ophthalmological examinations. Whole exome sequencing, bioinformatics analysis, Sanger sequencing, and co-segregation analysis of family members were used to validate sequencing data and confirm the presence of the disease-causing gene variant. The proband was diagnosed with choroideremia on the basis of clinical manifestations. Whole exome sequencing showed that the proband had a hemizygous variant in the CHM gene, c.22delG p. (Glu8Serfs*4), which was confirmed by Sanger sequencing and found to co-segregate with choroideremia. The variant was classified as likely pathogenic and has not previously been described. These results expand the spectrum of variants in the CHM gene, thus potentially enriching the understanding of the molecular basis of choroideremia. Moreover, they may provide insight for future choroideremia diagnosis and gene therapy.

scholarly journals Novel SOX2 Mutation in Autosomal Dominant Cataract-Microcornea Syndrome

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.

Incidence and predictors of glaucoma following surgery for congenital cataract in the first year of life in Victoria, Australia

2013 ◽  
pp. n/a-n/a ◽  
Author(s):  
Jonathan B Ruddle ◽  
Sandra E Staffieri ◽  
Jonathan G Crowston ◽  
Justin C Sherwin ◽  
David A Mackey
Keyword(s):  
Congenital Cataract ◽  
First Year ◽  
First Year Of Life

scholarly journals Excessive Unbalanced Meat Consumption in the First Year of Life Increases Asthma Risk in the PASTURE and LUKAS2 Birth Cohorts

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexander J. Hose ◽  
Giulia Pagani ◽  
Anne M. Karvonen ◽  
Pirkka V. Kirjavainen ◽  
Caroline Roduit ◽  
...  
Keyword(s):  
16S Rrna ◽  
Meat Consumption ◽  
16S Rrna Sequencing ◽  
Atopic Asthma ◽  
First Year ◽  
Sequencing Data ◽  
Food Items ◽  
Asthma Risk ◽  
Rrna Sequencing ◽  
First Year Of Life

A higher diversity of food items introduced in the first year of life has been inversely related to subsequent development of asthma. In the current analysis, we applied latent class analysis (LCA) to systematically assess feeding patterns and to relate them to asthma risk at school age. PASTURE (N=1133) and LUKAS2 (N=228) are prospective birth cohort studies designed to evaluate protective and risk factors for atopic diseases, including dietary patterns. Feeding practices were reported by parents in monthly diaries between the 4th and 12th month of life. For 17 common food items parents indicated frequency of feeding during the last 4 weeks in 4 categories. The resulting 153 ordinal variables were entered in a LCA. The intestinal microbiome was assessed at the age of 12 months by 16S rRNA sequencing. Data on feeding practice with at least one reported time point was available in 1042 of the 1133 recruited children. Best LCA model fit was achieved by the 4-class solution. One class showed an elevated risk of asthma at age 6 as compared to the other classes (adjusted odds ratio (aOR): 8.47, 95% CI 2.52–28.56, p = 0.001) and was characterized by daily meat consumption and rare consumption of milk and yoghurt. A refined LCA restricted to meat, milk, and yoghurt confirmed the asthma risk effect of a particular class in PASTURE and independently in LUKAS2, which we thus termed unbalanced meat consumption (UMC). The effect of UMC was particularly strong for non-atopic asthma and asthma irrespectively of early bronchitis (aOR: 17.0, 95% CI 5.2–56.1, p &lt; 0.001). UMC fostered growth of iron scavenging bacteria such as Acinetobacter (aOR: 1.28, 95% CI 1.00-1.63, p = 0.048), which was also related to asthma (aOR: 1.55, 95% CI 1.18-2.03, p = 0.001). When reconstructing bacterial metabolic pathways from 16S rRNA sequencing data, biosynthesis of siderophore group nonribosomal peptides emerged as top hit (aOR: 1.58, 95% CI 1.13-2.19, p = 0.007). By a data-driven approach we found a pattern of overly meat consumption at the expense of other protein sources to confer risk of asthma. Microbiome analysis of fecal samples pointed towards overgrowth of iron-dependent bacteria and bacterial iron metabolism as a potential explanation.

scholarly journals Whole-exome Sequencing Reveals the Etiology of the Rare Primary Hepatic Mucoepidermoid Carcinoma

2020 ◽  
Author(s):  
Ping Hou ◽  
Xiaoyan Su ◽  
Wei Cao ◽  
Liping Xu ◽  
Rongguiyi Zhang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Mucoepidermoid Carcinoma ◽  
Sanger Sequencing ◽  
Susceptibility Genes ◽  
Fanconi's Anemia ◽  
Whole Exome ◽  
Fanconi’S Anemia ◽  
Public Data ◽  
Molecular Etiology

Abstract Background Primary hepatic mucoepidermoid carcinoma (HMEC)is extremely rare and the molecular etiology is still unknown.Recently, The CRTC1-MAML2 fusion gene was detected in a primary HMEC which is often associated with MEC of salivary gland in the literature. Methods a 64-year-old male was diagnosed with HMEC based on malignant squamous cells and mucus-secreting cells in immunohistochemical examination. Whole-exome sequencing(WES) and sanger sequencing were used to reveal the molecular characteristics of HMEC,and analysis with public datas among hepatocellular carcinoma, cholangiocarcinoma and salivary MEC. Meanwhile, The susceptibility genes were identified in pedigree investigation.Result Significant somatic mutations in GNAS,KMT2C,ELF3 genes were identified in primary HMEC by WES and sanger sequencing. Meanwhile, through public data analysis, somtatic GNAS gene alterd in 2.1% hepatobiliary tumors, and typically GNAS occur at exon 8, in which Arg201 is converted to either a cysteine (R201C) or a histidine (R201H) related with cholangiocarcinoma associated with parasite infection .Furthermore, heterozygous germline mutations of FANCA, FANCI, FANCJ/BRIP1 and FAN1 genes were also identified. Pedigree investigation verified that mutation of susceptibility genes of Fanconi's anemia were present in the pedigree.Conclusions It was the first time to demonstrate the molecular etiology of the rare HMEC associated with germline Fanconi’s anemia mutations and somatic GNAS R201H mutation.

scholarly journals Glaucoma in aphakic and pseudophakic eyes following surgery for congenital cataract in the first year of life

2010 ◽  
Vol 88 (1) ◽  
pp. 53-59 ◽  
Author(s):  
Caitriona Kirwan ◽  
Bernadette Lanigan ◽  
Michael O’Keefe
Keyword(s):  
Congenital Cataract ◽  
First Year ◽  
First Year Of Life

scholarly journals Exome Sequencing Reveals Novel Rare Variants in the Ryanodine Receptor and Calcium Channel Genes in Malignant Hyperthermia Families

2013 ◽  
Vol 119 (5) ◽  
pp. 1054-1065 ◽  
Author(s):  
Jerry H. Kim ◽  
Gail P. Jarvik ◽  
Brian L. Browning ◽  
Ramakrishnan Rajagopalan ◽  
Adam S. Gordon ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Calcium Channel ◽  
Exome Sequencing ◽  
Allele Frequency ◽  
Ryanodine Receptor ◽  
Sanger Sequencing ◽  
Population Sample ◽  
Family Members ◽  
Genetic Diagnosis ◽  
Complementary Dna

Abstract Background: About half of malignant hyperthermia (MH) cases are associated with skeletal muscle ryanodine receptor 1 (RYR1) and calcium channel, voltage-dependent, L type, α1S subunit (CACNA1S) gene mutations, leaving many with an unknown cause. The authors chose to apply a sequencing approach to uncover causal variants in unknown cases. Sequencing the exome, the protein-coding region of the genome, has power at low sample sizes and identified the cause of over a dozen Mendelian disorders. Methods: The authors considered four families with multiple MH cases lacking mutations in RYR1 and CACNA1S by Sanger sequencing of complementary DNA. Exome sequencing in two affecteds per family, chosen for maximum genetic distance, were compared. Variants were ranked by allele frequency, protein change, and measures of conservation among mammals to assess likelihood of causation. Finally, putative pathogenic mutations were genotyped in other family members to verify cosegregation with MH. Results: Exome sequencing revealed one rare RYR1 nonsynonymous variant in each of three families (Asp1056His, Val2627Met, Val4234Leu), and one CACNA1S variant (Thr1009Lys) in the fourth family. These were not seen in variant databases or in our control population sample of 5,379 exomes. Follow-up sequencing in other family members verified cosegregation of alleles with MH. Conclusions: The authors found that using both exome sequencing and allele frequency data from large sequencing efforts may aid genetic diagnosis of MH. In a sample selected by the authors, this technique was more sensitive for variant detection in known genes than Sanger sequencing of complementary DNA, and allows for the possibility of novel gene discovery.

scholarly journals A Novel CRYBB2 Stopgain Mutation Causing Congenital Autosomal Dominant Cataract in a Chinese Family

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yu Zhou ◽  
Yaru Zhai ◽  
Lulin Huang ◽  
Bo Gong ◽  
Jie Li ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Family Members ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Whole Exome ◽  
Causal Mutation ◽  
Control Samples

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.

scholarly journals Transcript-Level Dysregulation of BCL2 Family Genes in Acute Myeloblastic Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3175
Author(s):  
Luiza Handschuh ◽  
Pawel Wojciechowski ◽  
Maciej Kazmierczak ◽  
Krzysztof Lewandowski
Keyword(s):  
Exome Sequencing ◽  
Family Members ◽  
Transcript Level ◽  
Rna Seq ◽  
Sequencing Data ◽  
Bcl2 Family ◽  
Kaplan Meier ◽  
Mutational Status ◽  
Apoptosis Regulation ◽  
Sequencing Data Analysis

The expression of apoptosis-related BCL2 family genes, fine-tuned in normal cells, is dysregulated in many neoplasms. In acute myeloid leukemia (AML), this problem has not been studied comprehensively. To address this issue, RNA-seq data were used to analyze the expression of 26 BCL2 family members in 27 AML FAB M1 and M2 patients, divided into subgroups differently responding to chemotherapy. A correlation analysis, analysis of variance, and Kaplan-Meier analysis were applied to associate the expression of particular genes with other gene expression, clinical features, and the presence of mutations detected by exome sequencing. The expression of BCL2 family genes was dysregulated in AML, as compared to healthy controls. An upregulation of anti-apoptotic and downregulation of pro-apoptotic genes was observed, though only a decrease in BMF, BNIP1, and HRK was statistically significant. In a group of patients resistant to chemotherapy, overexpression of BCL2L1 was manifested. In agreement with the literature data, our results reveal that BCL2L1 is one of the key players in apoptosis regulation in different types of tumors. An exome sequencing data analysis indicates that BCL2 family genes are not mutated in AML, but their expression is correlated with the mutational status of other genes, including those recurrently mutated in AML and splicing-related. High levels of some BCL2 family members, in particular BIK and BCL2L13, were associated with poor outcome.

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