scholarly journals Targeted Next-Generation Sequencing Identifies ABCA4 Mutations in Chinese Families with Childhood-Onset and Adult-Onset Stargardt Disease

2021 ◽  
Author(s):  
Ling-hui Qu ◽  
Xin Jin ◽  
Chao Zeng ◽  
Nian-gou Zhou ◽  
Yan-hong Liu ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Variants ◽  
Chinese Patients ◽  
Macular Dystrophy ◽  
Adult Onset ◽  
Next Generation ◽  
Childhood Onset ◽  
Stargardt Disease ◽  
Chinese Families ◽  
Generation Sequencing

Background: Stargardt disease (STGD) is the most common form of juvenile macular dystrophy associated with progressive central vision loss, and is agenetically and clinically heterogeneous disease. Molecular diagnosis is of great significance in aiding the clinical diagnosis, helping to determine the phenotypic severity and visual prognosis. In this study, we determined the clinical and genetic features of seven childhood-onset and three adult-onset Chinese STGD families. We performed capture next generation sequencing (NGS) of the probands and searched for potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes.  Methods: In all, 10unrelated Chinese families were enrolled. Panel based NGS was performed to identify potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes, including the five known STGD genes (ABCA4, PROM1, PRPH2, VMD2 and ELOVL4). Variant analysis, Sanger validation, and segregation tests were utilized to validate the disease-causing mutations inthese families. Results: Using systematic data analysis with an established bioinformatics pipeline and segregation analysis, 17 pathogenic mutations in ABCA4 were identified in the ten STGD families. Four of these mutations were novel: c.371delG, c.681T > G, c.5509C > T and EX37del. Childhood-onset STGD was associated with severe visual loss, generalized retinal dysfunction and was due to more severe variants in ABCA4 than those found in adult-onset disease. Conclusions: We expand the existing spectrum of STGD and reveal the genotype-phenotype relationships of the ABCA4 mutations in Chinese patients. Childhood-onset STGD lies at the severe end of the spectrum of ABCA4-associated retinal phenotypes.

scholarly journals Targeted next generation sequencing and family survey enable correct genetic diagnosis in CRX associated macular dystrophy – a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Saoud Al-Khuzaei ◽  
Karl A. Z. Hudspith ◽  
Suzanne Broadgate ◽  
Morag E. Shanks ◽  
Penny Clouston ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Genetic ◽  
Age At Onset ◽  
Genetic Diagnosis ◽  
Heterozygous Mutation ◽  
Macular Dystrophy ◽  
Sequence Variant ◽  
Next Generation ◽  
Stargardt Disease ◽  
Generation Sequencing

Abstract Background We present 3 members of a family with macular dystrophy, originally diagnosed as Stargardt disease, with a significantly variable age at onset, caused by a heterozygous mutation in CRX. Case presentation A 43-year-old female with bull’s eye maculopathy, whose sister was diagnosed with Stargardt disease previously at another centre, was found to have a single ABCA4 variant. Further examination of the family revealed that the asymptomatic father was also affected, indicating a dominant pattern of inheritance. In addition, the ABCA4 variant was not identified in the sister originally diagnosed with Stargardt disease. Next generation sequencing identified a heterozygous c.121C > T, p.R41W missense mutation in CRX in all 3 affected members. Conclusions We describe a common phenotype, but with variable age at onset, with autosomal dominant inheritance and reduced penetrance in a family found to have a pathogenic sequence variant in CRX. This illustrates the importance of panel based molecular genetic testing accompanied by family studies to establish a definitive diagnosis.

The novel approach to distinguish primary multiple lung adenocarcinomas from intrapulmonary metastases by next generation sequencing in Chinese patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20506-e20506
Author(s):  
Lin Li ◽  
Naiquan Mao ◽  
Yingcheng Lyu ◽  
Huayue Lin ◽  
Kefeng Wang ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Next Generation Sequencing ◽  
Chinese Patients ◽  
Comparative Genomic ◽  
Genomic Profiling ◽  
Next Generation ◽  
Architectural Patterns ◽  
Chinese Cohort ◽  
Lung Adenocarcinomas ◽  
Generation Sequencing

e20506 Background: Differentiation of multiple primary lung cancer (MPLC) from intrapulmonary metastasis (IPM) is critical to determine clinical stage. Although clinicopathological features could provide certain evidences, it’s still challenging to identify the tumor malignancy accurately. In General, standard histopathologic approach is adequate in most cases, but has notable limitations in the recognition of IPMs. Herein, we propose an integrated molecular algorithm to facilitate MPLCs and IPMs diagnosis in the clinical practice. Methods: 40 Chinese patients with lung adenocarcinomas were enrolled in the study, 84 tumor samples were collected for next-generation sequencing. Somatic alterations with variant allele fraction (VAF) ≥1% were taken into account for molecular algorithm. A genomic database of 2,471 Chinese lung adenocarcinomas (LUAD) was used to calculate odds of coincidental occurrence, prevalence of individual mutation prevalence. Tumor relatedness diagnosed by histopathologic assessment was contrasted with comparative genomic profiling by subsequent NGS. Moreover, the performance of molecular algorithm prediction was evaluated as well. Results: Firstly, we compared the performance of comprehensive next-generation sequencing (NGS) with standard histopathologic approaches for distinguishing NSCLC subtypes in clinical practice. The genomic profiling was described as following: EGFR alterations occurred more frequently in MPLCs compared to IPMs (77.1% vs 50.0%, P<0.05). Further analysis showed that TP53 alterations occurred less frequently in MPLCs compared to large Chinese cohort (22.9% vs 51.0%, P<0.05). TP53 alterations occurred less frequently in MPLCs compared to large Chinese cohort (P<0.05). The classifications based on the three different methodologies mentioned above were compared. Molecular algorithm prediction was concordant with NGS in 21 cases (52.5%), particularly in the prediction of MPLC. Retrospective review highlighted several histologic challenges, including morphologic progression in some IPMs. For the five undetermined cases, two showed differences in architectural patterns, and remained cases have nodules presented as adenocarcinoma in situ, or minimally invasive adenocarcinoma. Of 28 MPLC cases defined by NGS, 25 cases had unique somatic mutations per pair Based on calculation from the prevalence of EGFR L858R mutation (27%) in large Chinese cohort, the odds of coincidental occurrence of the mutation in two unrelated tumors was 7.3%. Taking together, EGFR alterations occurred more frequently in MPLCs compared to IPMs (77.1% vs 50.0%, P<0.05). Molecular algorithm prediction was concordant with NGS in 21 cases (52.5%). Conclusions: Our results support broad panel NGS to assist differential diagnosis to assist approach in clinical practice. It is necessary to conduct large clinical study to establish comprehensive algorithm models to assist diagnosis and predict clinical outcome.

scholarly journals The genetic analysis of Chinese patients with clonal cytopenias using targeted next-generation sequencing

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lijuan Zhang ◽  
YuYe Shi ◽  
Yue Chen ◽  
Shandong Tao ◽  
Wenting Shi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Myelodysplastic Syndromes ◽  
Rna Splicing ◽  
Myeloproliferative Neoplasms ◽  
Chinese Patients ◽  
Newly Diagnosed ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Significant Difference ◽  
Generation Sequencing

Abstract Background Clonal hematopoiesis (CH) can be found in various myeloid neoplasms (MN), such as myelodysplastic syndromes (MDS), myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN), also in pre-MDS conditions. Methods Cytogenetics is an independent prognostic factor in MDS, and fluorescence in-situ hybridization (FISH) can be used as an adjunct to karyotype analysis. In the past 5 years, only 35 of 100 newly diagnosed MDS and MDS/MPN patients were identified abnormalities, who underwent the FISH panel. In addition, we examined a cohort of 51 cytopenic patients suspected MDS or MDS/MPN with a 20-gene next generation sequencing (NGS), including 35 newly diagnosed MN patients and 16 clonal cytopenias of undetermined significance (CCUS) patients. Results Compared with the CCUS group, the MN group had higher male ratio (22/13 vs 10/6), cytogenetics abnormalities rate (41.4% vs 21.4%) and frequency of a series of mutations, such as ASXL1 (28.6% vs 25%), U2AF1 (25.7% vs 25%), RUNX1 (20% vs 0.0%); also, higher adverse mutations proportion (75% vs 85.2%), and double or multiple mutations (54.3% vs 43.75%). There were 7 MN patients and 4 CCUS patients who experienced cardio-cerebrovascular embolism events demonstrated a significant difference between the two groups (25% vs 20%). Ten of the 11 patients had somatic mutations, half had DNA methylation, while the other half had RNA splicing. Additionally, six patients had disease transformation, and four patients had mutated U2AF1, including two CCUS cases and two MDS-EB cases. Following up to January 2021, there was no significant difference in over survival between the CCUS and MN groups. Conclusion NGS facilitates the diagnosis of unexplained cytopenias. The monitoring and management of CCUS is necessary, also cardio-cerebrovascular embolism events in patients with CH need attention in the clinical practice.

scholarly journals Assay of frequency and spectrum of genetic variants in TTN in healthy russian population

2021 ◽  
Vol 8 (5) ◽  
pp. 29-37
Author(s):  
Yu. A. Vakhrushev ◽  
A. A. Kozyreva ◽  
S. V. Zhuk ◽  
O. P. Rotar ◽  
A. A. Kostareva
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Variants ◽  
Sanger Sequencing ◽  
Heart Diseases ◽  
Genetic Research ◽  
Russian Population ◽  
Next Generation ◽  
Data Bases ◽  
International Data ◽  
Generation Sequencing

Background. Gene TTN associated with all types of cardiomyopathy, however its large size (294 b.p.) warrants a lot of individual unique genetic variants or variants with low frequency, that aggravates their interpretation. Besides that nowadays there is no data about spectrum of variants in this gene in healthy Russian population. Recognition frequency and spectrum of variants in gene TTN in healthy Russian population will allow us to use it for interpretation results of molecular genetic research for patients with different heart pathology, and define prognosis for different heart diseases.Objective. Recognize frequency and spectrum of single nucleotide and truncating variants in gene TTN in healthy Russian population and compare it with international data bases, and evaluate level of pathogenicity these variants and their distributing across titin structure.Design and methods. 192 men in age 55,8±6,6 years were tested with next-generation sequencing. Identified genetic variants were confirmed by Sanger sequencing. Results. Allele missense variant frequency (with frequency less than 0.1%) in TTN in healthy Russian population amount to 15.1 %, and truncating variants — 0.52 %. 37,9 % of them were variants of unknown significance, 62 % — likely-benign and 0.1 % — benign. There was no pathological and likely-pathological variants. Identified genetic variants distributed throughout the titin structure.Conclusion. Received result is congruent с international data bases and researches. Expended laboratory method (Next generation sequencing and confirmation with Sanger sequencing) can be used both in clinical practice, and in creating data bases of genetic variants in healthy Russian population.

scholarly journals Clinical results and importance of next-generation sequencing (NGS) in detecting targeted mutations in the treatment of metastatic Lung Cancer: Single center initial results

2019 ◽  
Vol 6 (12) ◽  
pp. 327-332
Author(s):  
Cem Mirili ◽  
Çiğdem Kahraman ◽  
Ali Yılmaz ◽  
Mehmet Bilici ◽  
Salim Başol Tekin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Next Generation Sequencing ◽  
Genetic Variants ◽  
Genetic Variant ◽  
Clinical Results ◽  
Clinical Effects ◽  
Next Generation ◽  
Variant Analysis ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Objective:  In Lung cancer (LC), which is one of the most deadly cancers, longer survival has been achieved with targeted agents. For this reason, it is important to find the patients who are suitable for targeted therapies. Next-generation sequencing (NGS) is a method that allows multiple genetic variants to be detected simultaneously by performing massive parallel DNA sequencing at the same time. We wanted to reveal the clinical effects and benefits of genetic variant analysis with NGS for our patients. Material and Methods: Patients with stage 4 non-squamous and not otherwise specified (NOS) Non-small cell LC who underwent genetic variant analysis with NGS were included in the study, retrospectively. Results: Total of the 51 patients, 41 (80.4%) were male and the median age was 64 (35-85) years. According to TNM, 21 (41.2%) patients were stage 4A, 30 (58.8%) patients were stage 4B and 39 (76.5%) patients had adenocarcinoma and 12 (23.5%) had NOS histology. NGS analyzes were performed in median 14 days (8-43) and determined 24 pathogenic variants in 17 (%25) patients: 9EGFR (%17,6), 6PIKC3A (%11,7), 5KRAS (%9,8), 2PTEN (%3,9), 1BRAF (%1,9), 1MET (%1,6) (7 of them concomitantly). Cytotoxic chemotherapy was recommended in 41, anti-EGFR agents in 8 (afatinib in 4, erlotinib in 4 patients) patients and anti-BRAF+MEK inhibitor agent (dabrafenib+trametinib) in 1 patient. Conclusion: With the NGS, in just two weeks, both target and resistance genetic variants of our patients were detected at the same time and individualized treatments were applied. In this way, both time and cost were saved.

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