Novel, de novo dysferlin gene mutations in a patient with Miyoshi myopathy

2018 ◽  
Vol 664 ◽  
pp. 107-109 ◽  
Author(s):  
Yi-Ying Hu ◽  
Ya-Jun Lian ◽  
Hong-Liang Xu ◽  
Ya-Ke Zheng ◽  
Chen-Fei Li ◽  
...  
Keyword(s):  
De Novo ◽  
Gene Mutations ◽  
Miyoshi Myopathy

scholarly journals Genomic insights into the origin, domestication and diversification of Brassica juncea

2021 ◽  
Vol 53 (9) ◽  
pp. 1392-1402
Author(s):  
Lei Kang ◽  
Lunwen Qian ◽  
Ming Zheng ◽  
Liyang Chen ◽  
Hao Chen ◽  
...  
Keyword(s):  
Brassica Juncea ◽  
De Novo ◽  
Gene Mutations ◽  
Sequencing Analysis ◽  
Genome Wide ◽  
Long Read ◽  
History Of ◽  
Crop Types ◽  
Allotetraploid Species ◽  
New Crop

AbstractDespite early domestication around 3000 BC, the evolutionary history of the ancient allotetraploid species Brassica juncea (L.) Czern & Coss remains uncertain. Here, we report a chromosome-scale de novo assembly of a yellow-seeded B. juncea genome by integrating long-read and short-read sequencing, optical mapping and Hi-C technologies. Nuclear and organelle phylogenies of 480 accessions worldwide supported that B. juncea is most likely a single origin in West Asia, 8,000–14,000 years ago, via natural interspecific hybridization. Subsequently, new crop types evolved through spontaneous gene mutations and introgressions along three independent routes of eastward expansion. Selective sweeps, genome-wide trait associations and tissue-specific RNA-sequencing analysis shed light on the domestication history of flowering time and seed weight, and on human selection for morphological diversification in this versatile species. Our data provide a comprehensive insight into the origin and domestication and a foundation for genomics-based breeding of B. juncea.

Poster #T152 PHENOTYPIC FEATURES OF PATIENTS WITH SCHIZOPHRENIA CARRYING DE NOVO GENE MUTATIONS

2014 ◽  
Vol 153 ◽  
pp. S344
Author(s):  
Pierre J. Malherbe ◽  
J. Louis Roos ◽  
J Louw Roos ◽  
Maria Karayiorgou ◽  
René Ehlers
Keyword(s):  
De Novo ◽  
Gene Mutations ◽  
De Novo Gene ◽  
Phenotypic Features

scholarly journals Seven novel and six de novo PHEX gene mutations in patients with hypophosphatemic rickets

2016 ◽  
Vol 38 (6) ◽  
pp. 1703-1714 ◽  
Author(s):  
Shan-Shan Li ◽  
Jie-Mei Gu ◽  
Wei-Jia Yu ◽  
Jin-Wei He ◽  
Wen-Zhen Fu ◽  
...  
Keyword(s):  
De Novo ◽  
Gene Mutations ◽  
Hypophosphatemic Rickets ◽  
Phex Gene

Mutations in the AML1 Gene Define an Unfavorable Subgroup in Acute Myeloid Leukemia with FAB M0.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4340-4340
Author(s):  
Frank Dicker ◽  
Mirjam Klaus ◽  
Torsten Haferlach ◽  
Wolfgang Kern ◽  
Wolfgang Hiddemann ◽  
...  
Keyword(s):  
High Performance ◽  
De Novo ◽  
Mutation Screening ◽  
Point Mutations ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Runt Domain ◽  
Screening Efficiency ◽  
Genetic Aberration ◽  
Aml1 Gene

Abstract The AML1/RUNX1 gene is the most frequent target for chromosomal translocations in leukemia. Recently point mutations in the AML1 gene have been demonstrated as another mode of genetic aberration. AML1 mutations have been reported in de novo MDS and AML, as well as in therapy related MDS and AML. The AML M0 subtype has been found to be most frequently affected by sporadic AML1 gene mutations. We analysed AML1 gene mutations in a cohort of 49 M0 patients. Mutation screening was performed either with SSCP (n=21) and/or denaturating High Performance Liquid Chromatography (dHPLC) (n=33), 5 cases were analyzed by both methods. SSCP screening of exons 3–5 of the AML1 gene was carried out at the genomic level. These exons cover the socalled Runt domain, which is most frequently mutated. Fragments with aberrant mobility were sequenced. With this method 5 cases were found to be mutated. Subsequently, to improve the screening efficiency an assay using dHPLC was established. Hereby, we screened the cDNA of patient samples for mutations in amino acid codons 1–277 of the AML1b transcript, where the Runt domain is located between codons 49 and 178. All 5 cases detected by SSCP were confirmed by dHPLC. Nine mutations were detected in the cohort of 28 cases (32%) which had not been analyzed by SSCP. In total, 14 of the 49 samples (29%) tested were identified to be mutated, which is a slightly higher frequency than previously reported. In the cohort of 35 AML1 non-mutated cases 20 (57%) had a normal karyotype and 15 (43%) an aberrant karyotypes, whereas only 6 of the 14 AML1 mutated cases (43%) had a normal karyotype (p=0.001). Three of the AML1 mutated cases (21%) also had FLT3 mutations. One had an FLT3-LM, one an FLT3-TKD mutation, and one case both LM and TKD mutations. Clinical follow up data were available for 33 patients (22 AML1 non- mutated, 11 AML1 mutated). The median OS and EFS of the AML1 non-mutated versus the mutated group was 276 days versus 63 days (p = 0.0679) and 276 vs. 63 days (p=0.0630) respectively. Thus the AML1 mutated cases tend to have a worse clinical outcome. When other AML subtypes were screened for AML1 mutations, i.e. M1 (n=26), M2 (n=21) and M4 (n=3), only 1 additional AML1 mutation was detected, confirming the highest prevalence of AML1 mutations in M0. In conclusion, 1) we established a new assay to screen for AML1 mutations. 2) We confirmed the high incidence of AML1 gene mutations in AML M0, both in cases with normal and aberrant karyotype. 3) For the first time we demonstrated that AML1 mutations define an unfavorable subentity in AML M0.

Mutational Spectrum Analysis of Interesting Correlation and Interrelationship Between RNA Splicing Pathway and Commonly Targeted Genes in Myelodysplastic Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 273-273 ◽  
Author(s):  
Yasunobu Nagata ◽  
Masashi Sanada ◽  
Ayana Kon ◽  
Kenichi Yoshida ◽  
Yuichi Shiraishi ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Genetic Basis ◽  
De Novo ◽  
Gene Mutations ◽  
Myeloid Neoplasms ◽  
Disease Subtypes ◽  
The Difference ◽  
De Novo Aml ◽  
Insight Into ◽  
Splicing Machinery

Abstract Abstract 273 Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms showing a frequent transition to acute myeloid leukemia. Although they are discriminated from de novo AML by the presence of a preleukemic period and dysplastic cell morphology, the difference in molecular genetics between both neoplasms has not been fully elucidated because of the similar spectrum of gene mutations. In this regards, the recent discovery of frequent pathway mutations (45∼90%) involving the RNA splicing machinery in MDS and related myeloid neoplasm with their rare mutation rate in de novo AML provided a novel insight into the distinct molecular pathogenesis of both neoplasms. Thus far, eight components of the RNA splicing machinery have been identified as the targets of gene mutations, among which U2AF35, SF3B1, SRSF2 and ZRSR2 show the highest mutation rates in MDS and CMML. Meanwhile, the frequency of mutations shows a substantial variation among disease subtypes, although the genetic/biological basis for these differences has not been clarified; SF3B1 mutations explain >90% of the spliceosome gene mutations in RARS and RCMD-RS, while mutations of U2AF35 and ZRSR2 are rare in these categories (< 5%) but common in CMML (16%) and MDS without increased ring sideroblasts (20%). On the other hand, SRSF2 mutations are most frequent in CMML (30%), compared with other subtypes (<10 %) (p<0.001) (Yoshida K, et al, unpublished data). So to obtain an insight into the genetic basis for these difference, we extensively explored spectrums of gene mutations in a set of 161 samples with MDS and related myeloid neoplasms, in which mutations of 10 genes thus far identified as major targets in MDS were examined and their frequencies were compared with regard to the species of mutated components of the splicing machinery. The mutation status of the 161 specimens was determined using the target exon enrichment followed by massively parallel sequencing. In total, 86 mutations were identified in 81(50%) in the 8 components of the splicing machinery. The mutations among 4 genes, U2AF35 (N = 20), SRSF2 (N = 31), SF3B1 (N = 15) and ZRSR2 (N = 10), explained most of the mutations with a much lower mutational rate for SF3A1 (N = 3), PRPF40B (N = 3), U2AF65 (N = 3) and SF1 (N = 1). Conspicuously, higher frequency 4 components of the splicing machinery were mutated in 76 out of the 161 cases (47.2%) in a mutually exclusive manner. On the other hand, 172 mutations of the 10 common targets were identified among 117, including 41 TET2 (25%), 32 RUNX1 (20%), 26 ASXL1 (16%), 24 RAS (NRAS/KRAS) (15%), 22 TP53 (14%), 17 IDH1/2 (10%), 10 CBL (6%) and 10 EZH2 (6%) mutations. We examined the difference between the major spliceosome mutations in terms of the number of the accompanying mutations in the 10 common gene targets. The possible bias from the difference in disease subtypes was compensated by multiple regressions. The SRSF2 mutations are more frequently associated with accompanying gene mutations with a significantly higher number of those mutations (N=29; OR 6.2; 95%CI 1.1–35) compared with that of the U2AF35 mutations (N=14) (p=0.038). Commonly involving the E/A splicing complexes, these splicing pathway mutations lead to compromised 3' splice site recognition. However, individual mutations may still have different impacts on cell functions, which could contribute to the determination of discrete disease phenotypes. It was demonstrated that SRSF2 was involved in the regulation of DNA stability and that depletion of SRSF2 can lead to DNA hypermutability, which may explain the higher number of accompanying gene mutation in SRSF2-mutated cases than cases with other spliceosome gene mutations. In conclusion, it may help to disclosing the genetic basis of MDS and related myeloid neoplasms that highly paralleled resequencing was confirmed SRSF2 mutated case significantly overlapped common mutations. Disclosures: No relevant conflicts of interest to declare.

High Incidence of RAS Signalling Pathway Mutations in MLL–rearranged Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 539-539
Author(s):  
Vera Grossmann ◽  
Susanne Schnittger ◽  
Alexander Kohlmann ◽  
Christiane Eder ◽  
Annette Fasan ◽  
...  
Keyword(s):  
Survival Data ◽  
De Novo ◽  
Gene Mutations ◽  
Signalling Pathway ◽  
Melting Curve Analysis ◽  
Prognostic Impact ◽  
Tp53 Mutations ◽  
Equity Ownership ◽  
Ras Signalling ◽  
Acute Myeloid

Abstract Abstract 539 Background: Chromosomal translocations of the MLL gene on chromosome 11q23 are associated with a unique subset of acute lymphoblastic or acute myeloid leukemias (AML). In adults, MLL rearrangements are detected in 3% of de novo AML and in 10% of therapy-related AML (t-AML) cases and are associated with poor prognosis. In addition to disease defining mutations recent high-throughput sequencing studies had shown that almost all myeloid malignancies accumulate a large number of cooperating gene mutations. Aim: Determination of somatic mutations occurring in cases harboring MLL rearrangements and investigation of the prognostic impact of molecular and additional chromosomal aberrations. Patients and Methods: We investigated a cohort of 110 adult AML (80 de novo, 30 t-AML) cases harboring an 11q23 translocation. The cohort was composed of 66 females and 44 males; median age: 55.8 years. MLL translocation partners were as follows: MLLT3 (n=46), MLLT4 (n=15), ELL (n=15); MLLT10 (n=8), others (n=26). Chromosome banding analysis data was available in all cases and survival data in 78 cases (median overall survival (OS) was 10.1 months). Patients were screened for mutations in ASXL1 (n=98), CBL (n=62), CEBPA (n=61), FLT3-ITD (n=103), FLT3-TKD (n=95), IDH1 (n=96), IDH2 (n=84), KRAS (n=107), NPM1 (n=101), NRAS (n=106), PTPN11 (n=99), RUNX1 (n=110), and TP53 (n=110) using amplicon deep-sequencing (454 Roche Life Sciences, Branford, CT), direct Sanger sequencing or melting curve analysis. Results: Overall, mutations were detected in 59/110 (53.6%) cases. We discovered that 42/110 (38.2%) MLL-translocated AML cases harbored mutations within the RAS signalling pathway (KRAS mut: 23/107; 21.5%; NRAS mut: 22/106; 20.8%; PTPN11 mut: 3/99, 3.0%) or alterations in the RAS regulating FLT3 gene (FLT3-ITD: 4/103, 3.9%, and FLT3-TKD: 10/95, 10.5%). Additional mutations were detected in the tumor suppressor gene TP53 (8/110; 7.3%), ASXL1 (6/98; 6.1%), RUNX1 (4/110; 3.6%), and IDH1 (1/96). No mutation was detected in IDH2, CBL, CEBPA, and NPM1. Most cases showed only one mutation (n=39, 66.1%), whereas 17 cases (28.8%) showed two and 3 cases (5.1%) three mutations in different genes. No difference of mutation distribution was seen between de novo and t-AML. In this cohort, no associations amongst gene mutations were observed, however, FLT3-ITD was associated with MLL-ELL (3/14 vs 1/89, P=0.008) and PTPN11 mutations with MLLT10-MLL (2/8 vs 1/91, P=0.017) alterations. In addition, KRAS mut and NRAS mut correlated with high WBC count (KRAS mut: 103.0±79 vs 59.2±67 x109/L, P=0.016; NRAS mut: 94.7±57 vs 60.4±72 x109/L, P=0.080). Further, we were interested in the prognostic impact of single gene mutations. NRAS mut and TP53 mut showed both a non-significant inferior impact on OS, i.e. OS after 2 years: 19.1% vs 46.4%, P=0.62; 0% vs 41.3%, P=0.114. Further, TP53 mutations were correlated with shorter event-free survival (EFS) (EFS after 2 years: 0% vs 20.0%, P=0.029). No associations with prognosis were observed for the remaining genes and translocation partners. In contrast, age was associated with OS and EFS (<60 years, n=59 vs ≥60 years, n=51: OS after 2 years: 51.4% vs 26.3%, P=0.003, EFS after 2 years: 28.0% vs 7.7%, P=0.004). Within the cohort of cases ≥60 years, TP53 mutations (n=5) were associated with worse EFS and OS in comparison to TP53 wild-type cases (n=45) (EFS after 2 years: 8.4% vs 0%, P= 0.006; OS after 2 years: 28.5% vs 0%, P=0.045). Of note, no correlations between mutation frequency and age were observed. We next focused on whether the number of mutations showed any impact on survival. This analysis revealed that cases with more than one mutation (n=20) showed shorter EFS (EFS after 2 years: 10.0% vs 27.3%, P=0.020). Finally, we concentrated on AML with t(9;11)(p22;q23)/MLLT3-MLL, recognized as a distinct WHO-entity. We neither detected an association of MLLT3-MLL (n=46) with OS (P=0.445) or EFS (P=0.644) in comparison to the remaining translocation partners nor a distinct gene mutation profile. However, NRAS mutations correlated with shorter OS and EFS in cases with MLLT3-MLL (after 2 years OS: 17.8% vs 48.3%, P=0.045; after 2 years EFS: 17.8% vs 35.2%, P=0.056). Conclusions: In patients with MLL-translocations a high number of secondary alterations (53.6%), predominantly in RAS pathway components (38.2%), were detected. This may have implication on novel therapeutic options in this unfavorable AML subset. Disclosures: Grossmann: MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Fasan:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

COL4A1 is a Novel Causative Gene Responsible for Congenital Hemolytic Anemia, Representing Characteristic Clinical Course in Infants

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 934-934
Author(s):  
Hiromi Ogura ◽  
Shouichi Ohga ◽  
Takako Aoki ◽  
Taiju Utsugisawa ◽  
Hidehiro Takahashi ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Small Vessel Disease ◽  
Gene Mutations ◽  
Basement Membranes ◽  
Red Cell ◽  
Missense Mutations ◽  
Causative Gene ◽  
Congenital Hemolytic Anemia

Abstract We have been working on the differential diagnosis of congenital hemolytic anemia, but even with extensive analysis of hemoglobin, red cell membrane and enzymes, approximately 40% of patients remained to be diagnosed. In this study, we analyzed 17 undiagnosed hemolytic anemia subjects under the age of 1 by whole-exome sequencing, and identified COL4A1 gene mutations in 5 cases (29.4%). All patients were de novo cases without family histories and exhibited moderate to severe neonatal hemolytic anemia: Hgb, 5.2-9.3 g/dl; MCV, 90.0-126.9; MCHC, 29.9-32.7; and reticulocyte count, 9.2-33.0%. Either schizocytes or poikilocytes were observed in peripheral blood smears of 3 cases, suggesting that the microangiopathy was attributable to hemolysis. Previous reports showed that mutation of COL4A1 accounts for brain small-vessel disease characterized by stroke and eye abnormalities and the most characteristic complications of the present cases were congenital anomaly in the central nervous system, such as porencephaly, schizencephaly, congenital hydrocephalus, cataracts or paraventricular calcification, as reported previously. Hemolytic anemia became less severe within 2 months after birth, and all cases no longer required red cell transfusion after Day 50. COL4A1 encodes subtype 1 of type IV collagen, which is most abundantly expressed in basement membranes, including the vasculature. The COL4A1 gene mutations identified in the cases were all novel missense mutations except one, located in exons 26, 27, 37, 38 and 51. Although the pathophysiological significance of the mutations remains unclear, COL4A1 is the first identified causative gene responsible for congenital hemolytic anemia without intrinsic defects of red blood cells, and mutation of COL4A1 is the most prevalent cause of neonatal hemolytic anemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Role of Transcription Factor and Signaling Gene Mutations in the Clonal Evolution of MDS to Secondary AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4338-4338
Author(s):  
Andrew E Menssen ◽  
Christopher A Miller ◽  
Ajay J Khanna ◽  
Gue Su Chang ◽  
Jin J Shao ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Disease Progression ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Clonal Evolution ◽  
Gene Mutations ◽  
Blast Count ◽  
Tumor Clonality ◽  
Serial Samples ◽  
Skin Samples

Abstract Background: Expansion of one or more subclone occurs during progression from myelodysplastic syndrome (MDS) to secondary acute myeloid leukemia (sAML). Existing data suggest that acquired mutations in myeloid transcription factor (e.g., RUNX1, CEBPA, WT1) and signaling genes (e.g., receptor tyrosine kinases or RAS pathway genes) contribute to clonal evolution and the rising blast count that defines progression to sAML. While signaling gene (SG) mutations are typically acquired later in disease progression, our understanding of when transcription factor (TF) mutations occur, in what clone they occur (e.g. founding clone or subclone), and whether TF-mutated clones undergo further clonal evolution remains incomplete. This is largely due to the limited number of paired MDS and sAML samples analyzed, the limitation of current sequencing technology and the lack of serial samples, and incomplete characterization of tumor clonality. Methods: We banked paired MDS and sAML (plus skin) samples from 44 patients who progressed from MDS to sAML (median time to progression 306 days, range 21-3568). We sequenced sAML and skin samples for 285 recurrently mutated genes (RMGs) and genotyped the paired MDS sample in patients with TF and/or SG mutations. Twelve patients were selected for enhanced whole genome sequencing (eWGS) of MDS and sAML samples (plus skin) to characterize tumor clonality. Somatic mutations were validated using error-corrected sequencing and clones were identified in MDS and sAML samples using mutation variant allele frequencies (VAFs). We tracked clonal evolution by sequencing serial samples between MDS and sAML. Results: The frequency of both TF and SG mutations were elevated in the 44 sAML patients compared to our previously sequenced cohort of 150 independent de novo MDS patients (signaling: 36% vs. 15%, transcription factor: 30% vs. 11%, respectively, p<0.001). Next, we genotyped the 44 paired MDS samples to address whether TF mutations pre-existed at MDS. While SG mutations were rarely detected at MDS (4/22, 18%), TF mutations typically pre-existed at MDS (13/18, 72%; p<0.001). We next asked if SG mutations occur in the same or separate clone than TF mutations. In all 5 cases that had both a TF and SG mutation, and where we could address clonality, the SG mutations were acquired in a cell already containing a TF mutation. Collectively, the data suggest that TF mutations are usually detected before (median: 217 days, range: 21-1012) the blast count rises above 20%. We next addressed whether TF mutations were present in a founding clone or subclone at MDS. As the accuracy of discriminating founding clones and subclones increases with the number of detected mutations, we performed eWGS on 12 pairs of MDS and sAML samples to determine if TF and SG mutations were subclonal and how subclones evolved during progression. We validated a median of 596 (range: 305-1382) mutations per MDS sample and 582 (range 305-1373) mutations per sample at sAML. Mutation VAFs were used to cluster mutations and identify clones. A median of 4 clones (range: 2-6) were detected at MDS compared to 5 (range: 2-8) at sAML, with no patient showing a decrease in the number of clones at progression. When combined with cytogenetic/copy number alterations, 11/12 cases showed the expansion of a subclone during progression. Nine SG and 8 TF mutations (n=17 total) were detected in the 12 sAML samples. In total, 16/17 (94%) TF or SG mutations occurred in subclones, including 14 in subclones that expanded during progression to sAML. Only 1 TF mutation occurred in a founding clone, and 3/4 TF-mutated subclones gave rise to a new subclone, 2 containing a new RMG. Conclusions: Data from 44 patients shows that nearly half of sAML patients have transcription factor and/or signaling gene mutations. While both are enriched at sAML compared to MDS, TF and SG mutations show different timing of mutation acquisition. TF mutations are often present at MDS in subclones indicating that they may serve as a biomarker at MDS for later progression. In comparison, SG mutations are only rarely detected at MDS and are acquired between MDS and sAML. Additionally, for cells containing both TF and SG mutations, the TF mutation is typically acquired first. Despite these differences in acquisition, both TF and SG mutations occur in subclones that often expand and continue to clonally evolve during disease progression, suggesting that they may contribute to the rise in blast count. Disclosures No relevant conflicts of interest to declare.

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