scholarly journals Whole Genome Sequencing Identifies Novel Compound Heterozygous Lysosomal Trafficking Regulator Gene Mutations Associated with Autosomal Recessive Chediak-Higashi Syndrome

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Yaqiong Jin ◽  
Li Zhang ◽  
Senfen Wang ◽  
Feng Chen ◽  
Yang Gu ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Autosomal Recessive ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Regulator Gene ◽  
Lysosomal Trafficking ◽  
Chediak Higashi Syndrome

scholarly journals Effective variant filtering and expected candidate variant yield in studies of rare human disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Brent S. Pedersen ◽  
Joe M. Brown ◽  
Harriet Dashnow ◽  
Amelia D. Wallace ◽  
Matt Velinder ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Rare Disease ◽  
Genome Sequencing ◽  
Autosomal Dominant ◽  
De Novo ◽  
Autosomal Dominant Inheritance ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Dominant Inheritance ◽  
Family Based

AbstractIn studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.

scholarly journals Clinical and Genetic Features in 31 Serial Chinese Children With Gitelman Syndrome

2021 ◽  
Vol 9 ◽  
Author(s):  
Lingxia Zhang ◽  
Ke Huang ◽  
Shugang Wang ◽  
Haidong Fu ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Muscle Weakness ◽  
Growth Retardation ◽  
Gitelman Syndrome ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Whole Exome ◽  
Laboratory Test Results

Gitelman syndrome (GS, OMIM 263800) is a genetic congenital tubulopathy associated with salt loss, which is characterized by hypokalemic metabolic toxicity, hypocalciuria, and hypomagnesemia. GS, which is typically detected in adolescence or adulthood, has long been considered a benign tubular lesion; however, the disease is associated with a significant decrease in the quality of life. In this study, we assessed the genotype–phenotype correlations based on the medical histories, clinical symptoms, laboratory test results, and whole-exome sequencing profiles from pediatric patients with GS. Between January 2014 and December 2020, all 31 consecutively enrolled patients complained of fatigue, salt craving, and muscle weakness. Sixteen patients demonstrated growth retardation, and five patients presented with nocturia and constipation. All patients presented with hypokalemic metabolic alkalosis, normal blood pressure, hyperaldosteronism, and a preserved glomerular filtration rate, and 24 of the 31 (77.4%) patients had hypomagnesemia. Homozygous, compound heterozygous, and heterozygous mutations in SLC12A3 were detected in 4, 24, and 3 patients, respectively. GS patients often present with muscle weakness and fatigue caused by hypokalemia and hypomagnesemia. Therefore, early diagnosis of GS is important in young children to reduce the possibility of growth retardation, tetany, and seizures. Next-generation sequencing such as whole-exome or whole-genome sequencing provides a practical tool for the early diagnosis and improvement of GS prognosis. Further whole-genome sequencing is expected to reveal more variants in SLC123A among GS patients with single heterozygous mutations.

Whole-exome and whole-genome sequencing in chronic lymphocytic leukemia: new biomarkers to target

2020 ◽  
Vol 21 (13) ◽  
pp. 957-962
Author(s):  
Charbel Hobeika ◽  
Gaelle Rached ◽  
Alain Chebly ◽  
Eliane Chouery ◽  
Hampig Raphael Kourie
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
High Throughput Sequencing ◽  
Gene Mutations ◽  
Lymphocytic Leukemia ◽  
Whole Genome ◽  
Mutational Status ◽  
Whole Exome ◽  
Worse Prognosis

Many biomarkers indicate prognosis in chronic lymphocytic leukemia; such as fluorescence in situ hybridization testing: 17p or 11q deletions have a worse prognosis than trisomy 12, 13q deletion or normal result, or the mutational status of the immunoglobulin heavy chain (IGHV): unmutated IGHV have a worse prognosis than mutated IGHV. Recently, many gene mutations ( TP53, NOTCH1 etc.,) have been linked to a worse prognosis. With the new era of high-throughput sequencing, it has become easier to study gene mutations and their implication in predicting prognosis. In this review, we aim to review all the studies that performed whole-exome sequencing or whole-genome sequencing on chronic lymphocytic leukemia cells and explore the implication of various genes in disease prognosis.

scholarly journals Germline and Tumor Whole Genome Sequencing as a Diagnostic Tool to Resolve Suspected Lynch Syndrome

2020 ◽  
Author(s):  
Bernard J. Pope ◽  
Mark Clendenning ◽  
Christophe Rosty ◽  
Khalid Mahmood ◽  
Peter Georgeson ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Gene Mutations ◽  
Gene Promoter ◽  
Whole Genome ◽  
Pathogenic Variants ◽  
Tumor Sequencing ◽  
Mmr Deficiency ◽  
Complex Structural

AbstractBackgroundPeople who develop mismatch repair (MMR) deficient cancer in the absence of a germline MMR gene pathogenic variant or hypermethylation of the MLH1 gene promoter in their tumor are classified as having suspected Lynch syndrome (SLS). We applied germline whole genome sequencing (WGS) and targeted and genome-wide tumor sequencing approaches to identify the underlying cause of tumor MMR-deficiency in SLS.MethodsGermline WGS was performed on 14 cancer-affected people with SLS, including two sets of first-degree relatives. Tumor tissue was sequenced for somatic MMR gene mutations by targeted, whole exome sequencing or WGS. Germline pathogenic variants, including complex structural rearrangements and non-coding variants, were assessed for the MMR genes. Tumor mutation burden and mutational signatures.ResultsGermline WGS identified pathogenic MMR variants in 3 of the 14 (21.4%) SLS cases including a 9.5Mb inversion disrupting exons 1-7 of MSH2 in a mother and daughter. Excluding these 3 MMR carriers, tumor sequencing identified at least two somatic MMR gene mutations in 8/11 (72.7%) tumors tested, supporting a non-inherited cause of tumor MMR-deficiency. In the second mother-daughter pair, the combined analysis of germline and tumor by WGS supported a somatic rather than inherited cause of their tumor MMR-deficiency, through presence of double somatic MSH2 mutations in their respective tumors.ConclusionGermline WGS of people with SLS improved the identification of Lynch syndrome. When coupled with tumor sequencing, >70% of the people with SLS were resolved as having double somatic MMR mutations and a non-inherited cause for their tumor MMR-deficiency.

Identification of New Leukemia Associated Gene Mutations by Whole Genome Sequencing of DNA From Two Siblings with Congenital Neutropenia and Secondary AML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 12-12
Author(s):  
Maksim Klimiankou ◽  
Siarhei Kandabarau ◽  
Marlene Reuter ◽  
Anna-Lena Hagemann ◽  
Cornelia Zeidler ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Gene Mutations ◽  
Leukemic Cells ◽  
Severe Neutropenia ◽  
Whole Genome ◽  
Congenital Neutropenia ◽  
Runx1 Gene ◽  
Healthy Siblings ◽  
Complete Genomics

Abstract Abstract 12 To identify the pattern of genetic aberrations, which may promote leukemia development in patients with severe congenital neutropenia (CN), we have performed a whole genome sequencing (WGS) of DNA samples from myeloid leukemic cells of two affected siblings suffering from CN. Both children harbored ELANE gene mutations. The father of the children demonstrates somatic mosaicism for the ELANE mutation and has no severe neutropenia. For WGS we used Complete Genomics technology (Complete Genomics. Inc, Mountain View, CA.). More than 90 % of genomes were sequenced at high quality with minimum coverage of at least 20-fold. As an example, 3.355.399 single nucleotide variants (SNVs) were identified in DNA isolated from leukemia blasts of one CN patient. The following filters were used to identify mutations in the leukemic cells from the two patients: 1) Non-synonymous SNVs in coding sequences only (9288 SNVs), 2) 54 healthy individuals sequenced by Complete Genomics (557 SNVs), 4) five members of one family from the same ethnic area (healthy parents, one cyclic neutropenia patient and her healthy brother, 471 SNVs), 5) five family members of the affected two children: parents and three healthy siblings (two healthy sisters and one heatlthy brother). Remaining SNVs presented in the two affected children were subsequently analysed using in silico prediction software Polyphen 2, which predicts possible impact of an amino acid substitution on the structure and function of human proteins. Fourteen SNVs with predicted damaging effects on the protein function were used for further analysis. All candidate SNVs were validated by Sanger sequencing. We detected nine inherited candidate SNVs presented in the two affected children but not in healthy siblings. The SNV in the ELANE gene (c.452G>A p.C151Y, dbsnp.129:rs57246956) was inherited from the father. Novel SNVs inherited from the father were as follows: in the TCTE1, FAM135A, M6PR, C20orf144 and PTPN23 genes. Only three SNVs were inherited from the healthy mother (in BLOC1S1, DUS3L and KIAA1543 genes). All SNVs were heterozygous. We also found 5 sporadic SNVs presented in leukemia sample of one CN patient only, but absent in his DNA sample from an earlier time point of CN diagnosis. These are heterozygous SNVs in the CSF3R, ACAP2, GRM1, LASS3, and RUNX1 gene. All five gene mutations might be involved in leukemogenesis. Interestingly, both affected patients had somatic mutation in the RUNX1 gene at the same nucleotide position (c.415C>G, p.R139G in sick brother and c.415C>T, p.R139* in sick sister). In summary, we identified candidate genes that may be relevant for leukemogenesis in CN patients. Our study also establishes WGS as an unbiased method for discovering leukemia-initiating mutations in previously unidentified genes that may respond to targeted therapies Disclosures: No relevant conflicts of interest to declare.

scholarly journals Identification of a Rare Case With Nagashima-Type Palmoplantar Keratoderma and 18q Deletion Syndrome via Exome Sequencing and Low-Coverage Whole-Genome Sequencing

2021 ◽  
Vol 12 ◽  
Author(s):  
Qianqian Li ◽  
Xiaofan Zhu ◽  
Conghui Wang ◽  
Jingjing Meng ◽  
Duo Chen ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Exome Sequencing ◽  
Genome Sequencing ◽  
Deletion Syndrome ◽  
Compound Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Palmoplantar Keratoderma ◽  
18Q Deletion Syndrome ◽  
Low Coverage

Nagashima-type palmoplantar keratoderma (NPPK) is characterized by non-progressive, diffuse, and cross-gradient hyperkeratosis caused by mutations in the SERPINB7 gene on chromosome 18q21.33. Chromosome 18q deletion syndrome (18q- syndrome) is a terminal deletion or microdeletion syndrome characterized by intellectual disability and congenital malformations. This paper describes an 18-year-old man with palmoplantar keratoderma and diffuse white matter abnormalities in the brain. Trio-based exome sequencing (ES) revealed a suspected mosaic compound heterozygous mutation for c.796C>T (p.Arg266∗) in exon 8 inherited from the mother and a de novo exons 4–6 deletion of SERPINB7. Additional copy number variant (CNV) analysis of the ES data indicated a heterozygous gross deletion of 18q22.3-q23. The two SERPINB7 gene variants were verified by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). Finally, low-coverage whole-genome sequencing (WGS) confirmed the 18q22.3-q23 deletion and additionally detected a mosaic 18q21.33-q22.3 deletion, together explaining NPPK and the neurological phenotypes of the proband. The gross deletion of all exons of SERPINB7 was revealed for the first time. More rarely, c.796C>T (p.Arg266∗) was likely to be mosaic, while the exon deletion was mosaic. In conclusion, the combination of multiple molecular genetic testing methods provides comprehensive informative molecular findings and promotes the diagnosis of complex diseases, as in this case.

scholarly journals A Family with a Novel Mutation and Polycythemia Vera

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4875-4875
Author(s):  
Mayra C. Robinson ◽  
Majd T Ghanim ◽  
Shayla Bergmann
Keyword(s):  
Bone Marrow ◽  
Genetic Testing ◽  
Whole Genome Sequencing ◽  
Polycythemia Vera ◽  
Genome Sequencing ◽  
Gene Mutations ◽  
Gene Sequencing ◽  
Janus Kinase ◽  
Whole Genome ◽  
Hematopoietic Stem

Abstract Background. Chronic myeloproliferative neoplasms are derived from myeloproliferation of a single hematopoietic stem cell and result in either erythrocythemia or thrombocytosis. Polycythemia Vera (PV) is defined by persistent proliferation of red cell mass in the peripheral blood and bone marrow with hemoglobin more than or equal to 16.5 gr/dL (49% Hematocrit) in males and 16 gr/dL (48% Hematocrit) in females. Around 98% of patients with PV harbor an acquired Janus Kinase 2 mutation, namely JAK2V617F. Other well described mutations in PV patients include the EPOR gene, Hypoxia-inducible factor 2 alpha (HIF2A) gene, PHD2 gene mutations and the rare Hemoglobin Tarrant. These mutations and other identified predisposing gene variants have all accounted for familial cases of PV. Presence of specific mutations can be associated with increased risk of myelodysplastic syndrome, progression of disease, and neoplasms which causes a decreased overall survival. Methods: We reviewed the charts and collected clinical information of 3 generations of one family with erythrocythemia, including PV diagnostic testing. Results: The proband, a 3-year-old female, presented to our clinic at 6 months of age with a hemoglobin of 16 gr/dL (upper limit of normal for age is 12.5 gr/dL). Family consisted of 3 generations of related females (maternal grandmother, mother and daughter) with the clinical characteristics of PV as described above, requiring frequent phlebotomy. Genetic testing, for known PV mutations, on the proband revealed no identifiable mutations, similar to the mother's and grandmother's prior genetic testing. The proband had no other laboratory abnormalities, and a bone marrow biopsy and aspirate examination was normal. Now 3 years of age, she has been undergoing phlebotomy every 3 months since diagnosis; further testing with exome gene sequencing showed c.136G>A mutation on EPO gene, a variant of unknown significance. Discussion. Literature review showed 2 previous reports of c.136G>A mutation in the EPO gene. In 2015, Taylor et al described the mutation in two families with erythrocytosis. Their project was aimed at evaluating whole-genome sequencing for diagnosis of families with high suspicion of a genetic component to their clinical presentation with no previously identified pathogenic variants. They concluded that c.136G>A is of autosomal dominant inheritance. Later described in 2016 by Camps et al., the variant was also found in 4 different non-related patients after whole genome sequencing. None of the previous citations demonstrated causality. Determination of predisposing gene mutations, using exome gene sequencing specifically for families with an unknown mutation may help clinicians with prognosis, genetic counseling, and possibly specific treatments. Although an interesting result, a causality between the variant identified and the patient in this report has not yet been verified. Therefore, more testing and reports of this mutation are needed. Further steps in our case will include whole exome sequencing of the proband's family members with idiopathic erythrocytosis to assess the presence of this variant in the whole family. Identification of a specific familial inherited gene mutation resulting in PV can help classify patients based on the mutation. This will help predict disease course, improve quality of life and determine risk of disease transformation. Disclosures No relevant conflicts of interest to declare.

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