Articles de revues : « Novel mutation »

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Matsutani, Taro, Yuki Ueno, Tsukasa Fukunaga et Michiaki Hamada. « Discovering novel mutation signatures by latent Dirichlet allocation with variational Bayes inference ». Bioinformatics 35, n^o 22 (16 avril 2019) : 4543–52. http://dx.doi.org/10.1093/bioinformatics/btz266.

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Abstract Motivation A cancer genome includes many mutations derived from various mutagens and mutational processes, leading to specific mutation patterns. It is known that each mutational process leads to characteristic mutations, and when a mutational process has preferences for mutations, this situation is called a ‘mutation signature.’ Identification of mutation signatures is an important task for elucidation of carcinogenic mechanisms. In previous studies, analyses with statistical approaches (e.g. non-negative matrix factorization and latent Dirichlet allocation) revealed a number of mutation signatures. Nonetheless, strictly speaking, these existing approaches employ an ad hoc method or incorrect approximation to estimate the number of mutation signatures, and the whole picture of mutation signatures is unclear. Results In this study, we present a novel method for estimating the number of mutation signatures—latent Dirichlet allocation with variational Bayes inference (VB-LDA)—where variational lower bounds are utilized for finding a plausible number of mutation patterns. In addition, we performed cluster analyses for estimated mutation signatures to extract novel mutation signatures that appear in multiple primary lesions. In a simulation with artificial data, we confirmed that our method estimated the correct number of mutation signatures. Furthermore, applying our method in combination with clustering procedures for real mutation data revealed many interesting mutation signatures that have not been previously reported. Availability and implementation All the predicted mutation signatures with clustering results are freely available at http://www.f.waseda.jp/mhamada/MS/index.html. All the C++ source code and python scripts utilized in this study can be downloaded on the Internet (https://github.com/qkirikigaku/MS_LDA). Supplementary information Supplementary data are available at Bioinformatics online.

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Kapoor, Ritika R., Sarah E. Flanagan, Piers Fulton, Anupam Chakrapani, Bernadette Chadefaux, Tawfeg Ben-Omran, Indraneel Banerjee, Julian P. Shield, Sian Ellard et Khalid Hussain. « Hyperinsulinism–hyperammonaemia syndrome : novel mutations in the GLUD1 gene and genotype–phenotype correlations ». European Journal of Endocrinology 161, n^o 5 (novembre 2009) : 731–35. http://dx.doi.org/10.1530/eje-09-0615.

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BackgroundActivating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion.ObjectivesTo study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA.Patients and methodsTwenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed.ResultsHeterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 μmol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified.ConclusionPatients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations.

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Haynes, Alison. « Novel DOCK8 Mutation ». LymphoSign Journal 2, n^o 1 (1 mars 2015) : 39–46. http://dx.doi.org/10.14785/lpsn-2014-0023.

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Background: Hyper IgE syndrome (HIES) is a primary immunodeficiency with sporadic, autosomal dominant (STAT3 mutation) and autosomal recessive (DOCK8 and TYK2 mutations) inheritance patterns. HIES secondary to DOCK8 mutation is characterized by extensive cutaneous viral and staphylococcal infections, recurrent sinopulmonary infections, severe allergic diseases, increased susceptibility to malignancy with lymphopenia, eosinophilia, and elevated immunoglobulin E (IgE). Methods: This case report highlights the clinical presentation and immune investigations of a male patient with a novel DOCK8 mutation. Results: Our patient presented with cutaneous viral infections including severe molluscum contagiosum and herpes simplex virus plus skin abscesses and acute otitis media. In addition to infections, he developed intermittent diarrhea, eczematous lesions, abnormal fingernails, oral ulcers, and Bell's palsy. Immune evaluation revealed lymphopenia, in particular low CD8 cells, low mitogen stimulation response, and poor specific antibody production requiring immunoglobulin replacement. Genetic sequencing confirmed a novel mutation in DOCK8. Conclusion: Patients with significant cutaneous viral and bacterial infections, recurrent sinopulmonary infections, severe allergic diseases, and lymphopenia with associated elevated IgE should be investigated for DOCK8 mutation. This case report highlights a novel mutation in the DOCK8 exon 45 aa1970, c.5908 G>C change alanine to proline homozygous change A1970 to P1970 Statement of novelty: This case reports on a novel mutation in DOCK8

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Kim, Youn Jung, Hong Zhang, Yejin Lee, Figen Seymen, Mine Koruyucu, Yelda Kasimoglu, James P. Simmer, Jan C. C. Hu et Jung-Wook Kim. « Novel WDR72 Mutations Causing Hypomaturation Amelogenesis Imperfecta ». Journal of Personalized Medicine 13, n^o 2 (14 février 2023) : 326. http://dx.doi.org/10.3390/jpm13020326.

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Amelogenesis imperfecta (AI) is a heterogeneous collection of hereditary enamel defects. The affected enamel can be classified as hypoplastic, hypomaturation, or hypocalcified in form. A better understanding of normal amelogenesis and improvements in our ability to diagnose AI through genetic testing can be realized through more complete knowledge of the genes and disease-causing variants that cause AI. In this study, mutational analysis was performed with whole exome sequencing (WES) to identify genetic etiology underlying the hypomaturation AI condition in affected families. Mutational analyses identified biallelic WDR72 mutations in four hypomaturation AI families. Novel mutations include a homozygous deletion and insertion mutation (NM_182758.4: c.2680_2699delinsACTATAGTT, p.(Ser894Thrfs*15)), compound heterozygous mutations (paternal c.2332dupA, p.(Met778Asnfs*4)) and (maternal c.1287_1289del, p.(Ile430del)) and a homozygous 3694 bp deletion that includes exon 14 (NG_017034.2:g.96472_100165del). A homozygous recurrent mutation variant (c.1467_1468delAT, p.(Val491Aspfs*8)) was also identified. Current ideas on WDR72 structure and function are discussed. These cases expand the mutational spectrum of WDR72 mutations causing hypomaturation AI and improve the possibility of genetic testing to accurately diagnose AI caused by WDR72 defects.

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Lee, Yejin, Hong Zhang, Figen Seymen, Youn Jung Kim, Yelda Kasimoglu, Mine Koruyucu, James P. Simmer, Jan C. C. Hu et Jung-Wook Kim. « Novel KLK4 Mutations Cause Hypomaturation Amelogenesis Imperfecta ». Journal of Personalized Medicine 12, n^o 2 (24 janvier 2022) : 150. http://dx.doi.org/10.3390/jpm12020150.

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Amelogenesis imperfecta (AI) is a group of rare genetic diseases affecting the tooth enamel. AI is characterized by an inadequate quantity and/or quality of tooth enamel and can be divided into three major categories: hypoplastic, hypocalcified and hypomaturation types. Even though there are some overlapping phenotypes, hypomaturation AI enamel typically has a yellow to brown discoloration with a dull appearance but a normal thickness indicating a less mineralized enamel matrix. In this study, we recruited four Turkish families with hypomaturation AI and performed mutational analysis using whole exome sequencing. These analyses revealed two novel homozygous mutations in the KLK4 gene: a nonsense mutation in exon 3 (NM_004917.4:c.170C>A, p.(Ser57*)) was found in families 1, 2 and 3 and a missense mutation in exon 6 (c.637T>C, p.(Cys213Arg)) in family 4. Functional analysis showed that the missense mutation transcript could not translate the mutant protein efficiently or generated an unstable protein that lacked functional activity. The two novel inactivating KLK4 mutations we identified caused a hypomaturation AI phenotype similar to those caused by the four previously described KLK4 nonsense and frameshift mutations. This study improves our understanding of the normal and pathologic mechanisms of enamel formation.

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Helgadottir, Hildur, Paola Ghiorzo, Remco van Doorn, Susana Puig, Max Levin, Richard Kefford, Martin Lauss et al. « Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations ». Journal of Medical Genetics 57, n^o 5 (5 octobre 2018) : 316–21. http://dx.doi.org/10.1136/jmedgenet-2018-105610.

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BackgroundInherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated.MethodsCDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers’ responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load.ResultsEleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001).ConclusionPatients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.

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Wan, Youzhong, Michael S. Lawrence, Lili Wang, Petar Stojanov, Carrie Sougnez, Kristen Stevenson, Lillian Werner et al. « Large-Scale CLL Genome Analysis Reveals Novel Cancer Genes, Including SF3B1 ». Blood 118, n^o 21 (18 novembre 2011) : 463. http://dx.doi.org/10.1182/blood.v118.21.463.463.

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Abstract Abstract 463 The somatic genetic basis of chronic lymphocytic leukemia (CLL), a common and clinically heterogenous adult leukemia, remains poorly understood. Massively parallel sequencing technology provides a method for systematic discovery of genetic alterations that underlie disease, and for uncovering new therapeutic targets and biomarkers. We therefore performed DNA sequencing of 91 CLL samples with matched germline, consisting of 88 exomes and 3 genomes. Samples were collected from patients displaying a range of characteristics representing the broad clinical spectrum of CLL. Libraries were constructed and sequenced on an Illumina GA-II sequencer to deep coverage. Point mutations and indels were detected by comparing sequences of each tumor to its corresponding normal. We detected 1828 non-silent mutations in protein-coding sequences, corresponding to an average somatic mutation rate of 0.72/Mb (range 0.075–2.14). Nine cancer genes were identified, as they were mutated significantly more often than the background rate given their sequence composition across all 91 CLL/normal pairs. Four have been previously described in CLL (TP53, ATM, MYD88 and NOTCH1); the others were novel (SF3B1, ZMYM3, MAPK1, FBXW7 and DDX3X). Strikingly, SF3B1, which functions at the catalytic core of the spliceosome, was mutated the second most frequently (15%). All 14 identified mutations localized to a discrete region (exons 12–18), and 7 were recurrent (K700E). We additionally validated the SF3B1-K700E mutation through genotyping of 101 independent CLL samples. The 9 significantly mutated genes fell into 5 core signaling pathways, in which the genes play established roles: DNA damage repair and cell-cycle control (TP53, ATM), Notch signaling (FBXW7, NOTCH1), inflammatory pathways (MYD88, DDX3X, MAPK1) and RNA splicing/processing (SF3B1, DDX3X). The common cytogenetic aberrations in CLL carry strong prognostic significance, implying that they reflect distinct pathogenesis. Supporting this hypothesis, we discovered strong associations between different driver mutations and key FISH abnormalities. Most TP53 mutations were in samples with del(17p) (p<0.001), resulting in homozygous p53 inactivation. Del(11q) was marginally associated with mutation in ATM which lies in the minimally deleted region of chr. 11q (p=0.09); but clearly associated with SF3B1 mutation (p=0.004), suggesting interaction within this clinical subgroup of CLL. NOTCH1 and FBXW7 mutations (present in independent samples) were associated with trisomy 12 (p=0.009 and 0.05), suggesting that aberrant Notch signaling plays an important role in this clinical subgroup. Finally, all detected mutations in MYD88 (known to be activating for the NFkB pathway) were present in samples harboring heterozygous del(13q) (p=0.009) with mutated IGHV status (p=0.002). These findings suggest that NFkB activation plays a driving role in this low risk clinical subgroup. To define the impact of the mutated cancer genes on disease outcome, we constructed a Cox multivariable regression model for factors contributing to earlier time to first therapy (TTFT) in the 91 CLLs. SF3B1 mutation was predictive of poor prognosis (HR 3.17, p=0.004), independent of other established markers (i.e. IGVH mutation; del(17p); ATM mutation). Consistent with this analysis, patients harboring the SF3B1 mutation alone had short TTFT, as did patients with del(11q) or del(11q)+SF3B1 mutation. All 3 groups demonstrated significantly shorter TTFT than patients without either SF3B1 mutation or del(11q). Because SF3B1 encodes a splicing factor, we looked for functional evidence of splicing alterations associated with SF3B1 mutation. Indeed, mRNA targets of the spliceosome exhibited greater intron retention in CLLs with mutated vs nonmutated SF3B1, confirming alteration in normal SF3B1 function. Understanding the mutational landscape of CLL provides a starting point for systematic analyses to address fundamental questions in CLL, including how mutated genes alter cellular networks and phenotypes, and thereby contribute to disease heterogeneity. Our discovery of striking associations between driver mutations and standard CLL prognostic markers (cytogenetic aberrations, IGVH mutational status) suggest synergistic interactions. In particular, our studies highlight pre-mRNA splicing as a critical but thus far unexplored cellular process contributing to CLL. Disclosures: No relevant conflicts of interest to declare.

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Ding, Fadian, Xiaoping Hong, Xiangqun Fan, Shirong Huang, Wei Lian, Xingting Chen, Qicai Liu, Youting Chen et Feng Gao. « DDIT4 Novel Mutations in Pancreatic Cancer ». Gastroenterology Research and Practice 2021 (30 avril 2021) : 1–10. http://dx.doi.org/10.1155/2021/6674404.

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Pancreatic cancer is one of the most common malignancies worldwide. This study is aimed at searching the possible genetic mutations and the value of novel gene mutation in the DNA damage-inducible transcript 4 (DDIT4) and signaling pathway in pancreatic cancer. Polymerase chain reaction (PCR) was performed to amplify the DNA sequences of DDIT4 from patients with pancreatic ductal adenocarcinoma. In addition, we used IHC to detect the expression level of DDIT4 in patients with pancreatic cancer in different types of gene mutation. Double-labeled immunofluorescence was employed to explore the expression levels of DDIT4/LC3 and their potential correlation. Our work indicated the two novel stable gene mutations in DDIT4 mRNA 3 ′ -untranslated region (m.990 U>A and m.1246 C>U). Thirteen samples were found to have mutation in the DDIT4 3 ′ -untranslated regions (UTR). To further verify the influence of gene mutation on protein expression, we performed immunohistochemistry on different gene mutation types, and we found a correlation between DDIT4 expression and gene mutation, which is accompanied by nuclear staining deepening. In order to further discuss the clinical value of DDIT4 gene mutation, immunofluorescence suggested that the expression of DDIT4 colocated with LC3; thus, we speculated that DDIT4 mutation may be involved in autophagy in pancreatic cancer cell. In this study, we found mutation in the 3 ′ -UTR region of DDIT4, which may be associated with DDIT4 expression and tumor autophagy in pancreatic cancer tissues.

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Johnson, Benny, Laurence Cooke et Daruka Mahadevan. « Novel mutational and pathway signatures in relapsed/refractory colorectal cancer patients. » Journal of Clinical Oncology 34, n^o 4_suppl (1 février 2016) : 591. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.591.

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591 Background: In the management of metastatic colorectal cancer (mCRC), all RAS (KRAS, NRAS) and BRAF V600E mutation status guides therapeutic options and identify a unique cohort of patients (pts) with a more aggressive clinical course. We hypothesized that relapsed/refractory CRC pts develop unique mutational signatures that guide standard and targeted therapy but also predict for therapeutic response, identify novel driver mutations and highlight key signaling pathways for clinical decision making. Methods: Relapsed/refractory mCRC pts (N=31) were molecularly profiled by NGS Caris Molecular Intelligence (IHC, FISH/CISH, NGS) and/or Foundation One (NGS, copy number). Samples were annotated by histology, primary and/or metastatic site, biopsy location, gene mutation, domain, topology, and mutation count. Web-based bioinformatics tools (Enrichr/IntAct) were utilized to analyze mutational profiles, identifying pathway-networks. Results: Pts included progressed on fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab. Most common histology was adenocarcinoma followed by squamous cell carcinoma (colon N=28; rectal N=3). TP53 was the most common mutation followed by APC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1, FAT1, PDGFRA, ATM, ROS1, ALK, CDKN2A, FBXW7, TGFBR2, NOTCH1 and HER3. Pts had on average >5 unique gene mutations. High mutational burden was not predictive for PD-1 (5 pts) or PD-L1 (1 pt) positivity. The most common activated signaling pathways were: ERRB2/HER2, FGFR, p38 activation through BRAF-MEK cascade via RIT and RIN, ARMS-mediated activation of MAPK cascade, and VEGFR2. Conclusions: Dominant oncogene mutations do not always equate with oncogenic dependence, therefore understanding the pathologic interactome in each patient is important to both identification of clinically relevant targets and choosing the next best therapy. Mutational signatures derived from corresponding ‘pathway-networks’ represent a meaningful tool to 1). Evaluate functional investigation in the laboratory, 2). Predict response to drug therapy, and 3). Guide rational drug combinations in relapsed/refractory mCRC pts entering targeted and immune checkpoint trials.

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Windpessl, Martin, Marco Ritelli, Manfred Wallner et Marina Colombi. « A Novel Homozygous SLC2A9 Mutation Associated with Renal-Induced Hypouricemia ». American Journal of Nephrology 43, n^o 4 (2016) : 245–50. http://dx.doi.org/10.1159/000445845.

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Background: Hereditary renal hypouricemia (RHUC) is a genetically heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA; acute kidney injury (AKI) and nephrolithiasis are recognized complications. Type 1 (RHUC1) is caused by mutations in the SLC22A12 gene, whereas RHUC2 is caused by mutations in the SLC2A9 gene. Patient ethnicity is diverse but only few Caucasian families with an SLC2A9 mutation have been reported. Methods: The current report describes the clinical history, biochemical and molecular genetics findings of a native Austrian family with RHUC2. The propositus presented with 2 episodes of exercise-induced AKI and exhibited profound hypouricemia. Mutational screening of the SLC22A12 and SLC2A9 genes was performed. Results: The molecular analyses revealed the homozygous c.512G>A transition that leads to the p.Arg171His missense substitution in SLC2A9, confirming the diagnosis of RHUC2. Segregation study of the causal mutation revealed that the mother and elder sister were heterozygous carriers, whereas the younger sister was found to be homozygous. Conclusion: We report the identification of a novel mutation in SLC2A9 as the cause of RHUC2 in a native Austrian family. We show that glucose transporter 9 mutations cause severe hypouricemia in homozygous individuals and confirm the high risk of AKI in male individuals harbouring these mutations. In our literature review, we provide an overview of the putative underlying pathophysiology, potential renal complications, findings on kidney biopsy as well as potential long-time renal sequelae.

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Åkerström, Tobias, Holger Sven Willenberg, Kenko Cupisti, Julian Ip, Samuel Backman, Ana Moser, Rajani Maharjan et al. « Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas ». Endocrine-Related Cancer 22, n^o 5 (octobre 2015) : 735–44. http://dx.doi.org/10.1530/erc-15-0321.

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Aldosterone-producing adenomas (APAs) are found in 1.5–3.0% of hypertensive patients in primary care and can be cured by surgery. Elucidation of genetic events may improve our understanding of these tumors and ultimately improve patient care. Approximately 40% of APAs harbor a missense mutation in the KCNJ5 gene. More recently, somatic mutations in CACNA1D, ATP1A1 and ATP2B3, also important for membrane potential/intracellular Ca2+ regulation, were observed in APAs. In this study, we analyzed 165 APAs for mutations in selected regions of these genes. We then correlated mutational findings with clinical and molecular phenotype using transcriptome analysis, immunohistochemistry and semiquantitative PCR. Somatic mutations in CACNA1D in 3.0% (one novel mutation), ATP1A1 in 6.1% (six novel mutations) and ATP2B3 in 3.0% (two novel mutations) were detected. All observed mutations were located in previously described hotspot regions. Patients with tumors harboring mutations in CACNA1D, ATP1A1 and ATP2B3 were operated at an older age, were more often male and had tumors that were smaller than those in patients with KCNJ5 mutated tumors. Microarray transcriptome analysis segregated KCNJ5 mutated tumors from ATP1A1/ATP2B3 mutated tumors and those without mutation. We observed significant transcription upregulation of CYP11B2, as well as the previously described glomerulosa-specific gene NPNT, in ATP1A1/ATP2B3 mutated tumors compared to KCNJ5 mutated tumors. In summary, we describe novel somatic mutations in proteins regulating the membrane potential/intracellular Ca2+ levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.

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Turton, James P. G., Rachel Reynaud, Ameeta Mehta, John Torpiano, Alexandru Saveanu, Kathryn S. Woods, Anatoly Tiulpakov et al. « Novel Mutations within the POU1F1 Gene Associated with Variable Combined Pituitary Hormone Deficiency ». Journal of Clinical Endocrinology & ; Metabolism 90, n^o 8 (1 août 2005) : 4762–70. http://dx.doi.org/10.1210/jc.2005-0570.

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Context: Mutations within the gene encoding the pituitary-specific transcription factor POU1F1 are associated with combined pituitary hormone deficiency (CPHD). Most of the affected individuals manifest GH, prolactin, and TSH deficiency. Objective: We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1. Results: Causative mutations were identified in 10 of 129 individuals (7.8%). Of these, five patients harbored the dominant negative R271W mutation, which is a well-recognized mutational hot spot. We have also identified a second frequently occurring mutation, E230K, which appears to be common in Maltese patients. Additionally, we describe two novel mutations within POU1F1, an insertion of a single base pair (ins778A) and a missense mutation (R172Q). Functional studies have revealed that POU1F1 (E230K) is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wild-type protein. On the other hand, POU1F1 (R172Q) is associated with a reduction in DNA binding and transactivation, whereas POU1F1 (ins778A) is associated with loss of DNA binding and a reduction in transactivation. Conclusions: Our data suggest that the phenotype associated with POU1F1 mutations may be more variable, with the occasional preservation of TSH secretion. Additionally, our data revealed POU1F1 mutations in three patients who were diagnosed as having ACTH deficiency but who, on further evaluation, were found to have normal cortisol secretion. Hence, elucidation of the genotype led to further evaluation of the phenotype, with the cessation of cortisol replacement that had been commenced unnecessarily. These data reflect the importance of mutational analysis in patients with CPHD.

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Zhang, Edward D., Meixia Zhang, Gen Li, Charlotte L. Zhang, Zhihuan Li, Guangxi Zang, Zhiguang Su et al. « Mutation spectrum in GNAQ and GNA11 in Chinese uveal melanoma ». Precision Clinical Medicine 2, n^o 4 (13 novembre 2019) : 213–20. http://dx.doi.org/10.1093/pcmedi/pbz021.

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Abstract Uveal melanoma is the most common intraocular cancer in the adult eye. R183 and Q209 were found to be mutational hotspots in exon 4 and exon 5 of GNAQ and GNA11 in Caucasians. However, only a few studies have reported somatic mutations in GNAQ or GNA11 in uveal melanoma in Chinese. We extracted somatic DNA from paraffin-embedded biopsies of 63 Chinese uveal melanoma samples and sequenced the entire coding regions of exons 4 and 5 in GNAQ and GNA11. The results showed that 33% of Chinese uveal melanoma samples carried Q209 mutations while none had R183 mutation in GNAQ or GNA11. In addition, seven novel missense somatic mutations in GNAQ (Y192C, F194L, P170S, D236N, L232F, V230A, and M227I) and four novel missense somatic mutations in GNA11 (R166C, I200T, S225F, and V206M) were found in our study. The high mutation frequency of Q209 and the novel missense mutations detected in this study suggest that GNAQ and GNA11 are common targets for somatic mutations in Chinese uveal melanoma.

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Schubert, Victoria, Eva Auffenberg, Saskia Biskup, Karin Jurkat-Rott et Tobias Freilinger. « Two novel families with hemiplegic migraine caused by recurrent SCN1A mutation p.F1499L ». Cephalalgia 38, n^o 8 (16 novembre 2017) : 1503–8. http://dx.doi.org/10.1177/0333102417742365.

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Background Familial hemiplegic migraine type 3 is a monogenic subtype of migraine caused by missense mutations in the neuronal voltage-gated sodium channel gene SCN1A, with 10 different mutations reported so far. In two familial hemiplegic migraine type 3 families, partial cosegregation with a rare eye phenotype (elicited repetitive daily blindness) was previously reported. Methods Two novel familial hemiplegic migraine pedigrees were subjected to genetic analysis and detailed work-up of associated clinical features. Results In both pedigrees, we identified SCN1A mutation p.F1499L, which has been previously associated with familial hemiplegic migraine type 3 and elicited repetitive daily blindness. Both families displayed a pure familial hemiplegic migraine phenotype without evidence of an episodic eye phenotype. Conclusion Like a substantial proportion of other familial hemiplegic migraine type 3 mutations, p.F1499L affects the intracellular linker between domains III and IV of SCN1A, which seems to be a mutational hot-spot. Our new data establish p.F1499L as a recurrent familial hemiplegic migraine type 3 mutation. Elicited repetitive daily blindness seems to be a rare phenomenon in familial hemiplegic migraine type 3, even in carriers of the same mutation.

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Seymen, Figen, Hong Zhang, Yelda Kasimoglu, Mine Koruyucu, James P. Simmer, Jan C. C. Hu et Jung-Wook Kim. « Novel Mutations in GPR68 and SLC24A4 Cause Hypomaturation Amelogenesis Imperfecta ». Journal of Personalized Medicine 12, n^o 1 (28 décembre 2021) : 13. http://dx.doi.org/10.3390/jpm12010013.

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Amelogenesis imperfecta (AI) is a rare genetic condition affecting the quantity and/or quality of tooth enamel. Hypomaturation AI is characterized by brownish-yellow discoloration with increased opacity and poorly mineralized enamel prone to fracture and attrition. We recruited three families affected by hypomaturation AI and performed whole exome sequencing with selected individuals in each family. Bioinformatic analysis and Sanger sequencing identified and confirmed mutations and segregation in the families. Family 1 had a novel homozygous frameshift mutation in GPR68 gene (NM_003485.3:c.78_83delinsC, p.(Val27Cysfs*146)). Family 2 had a novel homozygous nonsense mutation in SLC24A4 gene (NM_153646.4:c.613C>T, NP_705932.2:p.(Arg205*)). Family 3 also had a homozygous missense mutation in SLC24A4 gene which was reported previously (c.437C>T, p.(Ala146Val)). This report not only expands the mutational spectrum of the AI-causing genes but also improves our understanding of normal and pathologic amelogenesis.

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Torpy, D. J., B. Ardesjö Lundgren, J. T. Ho, J. G. Lewis, H. S. Scott et V. Mericq. « CBG Santiago : A Novel CBG Mutation ». Journal of Clinical Endocrinology & ; Metabolism 97, n^o 1 (1 janvier 2012) : E151—E155. http://dx.doi.org/10.1210/jc.2011-2022.

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Context: Corticosteroid-binding globulin (CBG; SERPIN A6) gene mutations are rare; only four mutations have been described, often in association with fatigue and chronic pain, albeit with incomplete penetrance. Patient: We report a kindred with a novel SERPINA6 mutation. The proband, a 9-yr-old male, had excessive postexertional fatigue, weakness, and migraine. Main Outcome Measures and Results: Investigations revealed low morning and ACTH-stimulated peak cortisol levels. SERPIN A6 sequencing detected a novel exon 2 single base deletion (c.13delC) leading to a frameshift generating a stop codon within the signal peptide coding region (p.Leu5CysfsX26) and 50% reduced CBG levels in heterozygotes. The patient's father and two sisters share the mutation. Symptom expression within the family may have been modified by a polymorphic CBG allele (c.735G>T). Exogenous hydrocortisone had no effect on the fatigue. Conclusion: This report documents the fifth CBG gene mutation in humans and the second causing major effects on CBG levels. Individuals with low CBG levels may be misdiagnosed as having secondary hypocortisolism. The association with fatigue and idiopathic pain is again noted and may relate to altered stress system function. Variability of the phenotype may relate to other genetic variations of the CBG gene or environmental factors.

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Liu, Chengling, Xingchen Liu, Rui Wang, Lang Chen, Hua Zhao et Yong Zhou. « A Novel NCSTN Mutation in a Three-Generation Chinese Family with Hidradenitis Suppurative ». Journal of Healthcare Engineering 2022 (24 mars 2022) : 1–8. http://dx.doi.org/10.1155/2022/1540774.

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Objective. Hidradenitis suppurativa (HS) is a rare autosomal dominant condition characterized by inflamed nodules, cysts, deep abscesses, draining sinuses in the axillae, inguinal, and anogenital regions. Mutations in the NCSTN gene have been perceived to be responsible for the major underlying changes in the disorder. The purpose of this study is to identify a novel gene mutation in a Chinese family with HS. Methods. A Chinese family with HS present was investigated. The proband had manifested with multiple draining sinuses on the posterior neck, chest, bilateral axillae, and perineal regions. DNA was isolated from the peripheral blood of the family members. The encoding exons with introns of the NCSTN gene were analyzed by polymerase chain reactions (PCR) and direct DNA sequencing. Sanger sequencing was performed to confirm the next-generation sequencing results and to analyze each mutation’s familial segregation. Furthermore, the identified mutation was localized onto a 3D structure model using the DeepView Swiss-PdbViewer 4.1 software. Results. In this family comprising 10 HS patients, one novel mutation of the NCSTN gene was identified, involving a deletion mutation (c.447delC(p.N150Ifs ∗ 52)) in the NCSTN gene resulting in a frameshift and the new formation of a hydrogen bond. Conclusion. Our study reports the identification of a novel mutation that causes familial HS and could expand the spectrum of mutations in the γ-secretase genes underlying HS.

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Veríssimo, Rita, Luís Leite de Sousa, Tiago J. Carvalho et Pedro Fidalgo. « Novel SLC12A3 mutation in Gitelman syndrome ». BMJ Case Reports 14, n^o 1 (janvier 2021) : e238097. http://dx.doi.org/10.1136/bcr-2020-238097.

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Gitelman syndrome (GS) is an autosomal recessive disease characterised by the presence of hypokalaemic metabolic alkalosis with hypomagnesaemia and hypocalciuria. The prevalence of this disease is 1–10/40 000. GS is usually associated with mild and non-specific symptoms and many patients are only diagnosed in adulthood. The disease is caused by mutations in the SLC12A3 gene. We present the case of a 49-year-old man referred to a nephrology appointment due to persistent hypokalaemia and hypomagnesaemia. Complementary evaluation revealed hypokalaemia, hypomagnesaemia, metabolic alkalosis, hyperreninaemia, increased chloride and sodium urinary excretion, and reduced urinary calcium excretion. Renal function, remainder serum and urinary ionogram, and renal ultrasound were normal. A diagnosis of GS was established and confirmed with genetic testing which revealed a novel mutation in SLC12A3 (c.1072del, p.(Ala358Profs*12)). This novel mutation extends the spectrum of known SLC12A3 gene mutations and further supports the allelic heterogeneity of GS.

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Lyons, Daniel, et Adam Lauring. « Mutation and Epistasis in Influenza Virus Evolution ». Viruses 10, n^o 8 (3 août 2018) : 407. http://dx.doi.org/10.3390/v10080407.

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Influenza remains a persistent public health challenge, because the rapid evolution of influenza viruses has led to marginal vaccine efficacy, antiviral resistance, and the annual emergence of novel strains. This evolvability is driven, in part, by the virus’s capacity to generate diversity through mutation and reassortment. Because many new traits require multiple mutations and mutations are frequently combined by reassortment, epistatic interactions between mutations play an important role in influenza virus evolution. While mutation and epistasis are fundamental to the adaptability of influenza viruses, they also constrain the evolutionary process in important ways. Here, we review recent work on mutational effects and epistasis in influenza viruses.

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Solmaz, Aslı Ece, Hüseyin Onay, Levent Yeniay, Erhan Gökmen, Necmettin Özdemir, Senem Alanyalı, Ayşenur Oktay, Zeynep Özsaran, Murat Kapkaç et Ferda Özkınay. « BRCA1-BRCA2 mutation analysis results in 910 individuals : Mutation distribution and 8 novel mutations ». Cancer Genetics 241 (février 2020) : 20–24. http://dx.doi.org/10.1016/j.cancergen.2019.12.008.

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Zhang, Xuefei, Mo Li, Desheng Lv, Ge Sun, Yu Bai, Hui Tian et Changhong Liu. « Identification of a novel BRAF Thr599dup mutation in lung adenocarcinoma ». Open Medicine 13, n^o 1 (10 juillet 2018) : 278–80. http://dx.doi.org/10.1515/med-2018-0042.

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AbstractBRAF mutations are known as oncogenic drivers of non-small cell lung cancer (NSCLC). BRAF inhibition has demonstrated anti-tumor activity in patients with BRAF V600E mutant NSCLC. Further molecular screening for novel BRAF thr599dup mutation is warranted. The novel BRAF Thr599dup gene mutation, for which the repeat amino acid-tyrosine is inserted between the 599th amino acid and the 600th amino acid in exon 15 of BRAF, was identified by next-generation sequencing (NGS) during routine clinical care in a lung carcinoma sample from an Asian never-smoker. Other putative driver alterations including EGFR, ALK were not found in that patient. BRAF Thr599dup gene mutation analysis was consistent with BRAF v600E gene mutation. Here we report a novel BRAF gene mutation with molecular characteristics consistent with those in BRAF-driven NSCLC. Our case expands the scope of BRAF gene mutations and provides broader molecular profiling for optimizing therapeutic options for patients with NSCLC. The new BRAF gene mutation has important clinical meaning for cancer patients.

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Muhammad, Noor, Muhammad Tahir Khan, Sajid Ali, Taj Ali Khan, Anwar Sheed Khan, Nadeem Ullah, Hassan Higazi, Sara Ali, Salma Mohamed et Muhammad Qasim. « Novel Mutations in MPT64 Secretory Protein of Mycobacterium tuberculosis Complex ». International Journal of Environmental Research and Public Health 20, n^o 3 (31 janvier 2023) : 2530. http://dx.doi.org/10.3390/ijerph20032530.

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Tuberculosis (TB) is a global health problem caused by the Mycobacterium tuberculosis complex (MTBC). These bacteria secrete various proteins involved in the pathogenesis and persistence of MTBC. Among the secretory proteins, MPT64 (Rv1980C) is highly conserved and is also known as a major culture filtrate that is used in rapid diagnosis of MTBC. In the current study, we aimed to find the mutation in this highly conserved protein in isolates from the Pashtun-dominant province of Pakistan. We analyzed 470 M. tuberculosis whole-genome sequences of Khyber Pakhtunkhwa Province. Mutations in the MPT64 gene were screened through TB-Profiler and BioEdit software tools. The DynaMut web server was used to analyze the impact of the mutation on protein dynamics and stability. Among 470 MTB genomes, three non-synonymous mutations were detected in nine isolates, and one synonymous mutation (G208A) was found in four isolates. Mutation G211T (F159L), which was detected at the C-terminal domain of the protein in six isolates, was the most prominent. The second novel mutation, T480C (I70V), was detected in two isolates at the C-terminal side of the protein structure. The third novel mutation, A491C (L66R), was detected in a single isolate at the N-terminal side of the MPT64 protein. The effect of these three mutations was destabilizing on the protein structure. The molecular flexibility of the first two mutations increased, and the last one decreased. MPT64 is a highly conserved secretory protein, harboring only a few mutations. This study provides useful information for better managing the diagnosis of MTB isolates in high TB-burden countries.

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Peña-Quintana, L., G. Scherer, M. L. Curbelo-Estévez, F. Jiménez-Acosta, B. Hartmann, F. La Roche, S. Meavilla-Olivas et al. « Tyrosinemia type II : Mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation ». Clinical Genetics 92, n^o 3 (18 mai 2017) : 306–17. http://dx.doi.org/10.1111/cge.13003.

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Lee, Yejin, Wonseon Chae, Youn Jung Kim et Jung-Wook Kim. « Novel LRP6 Mutations Causing Non-Syndromic Oligodontia ». Journal of Personalized Medicine 12, n^o 9 (29 août 2022) : 1401. http://dx.doi.org/10.3390/jpm12091401.

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The process of tooth formation is a series of reciprocal interactions between the ectoderm and mesoderm, and it is believed that many genetic factors are involved in this complex process. More than a dozen genes have been identified in non-syndromic tooth agenesis; however, the genetic etiology underlying tooth agenesis is not fully understood yet. In this study, we identified two novel LRP6 mutations in two non-syndromic oligodontia families. Both probands had 16 and 17 missing teeth in their permanent dentition. Mutational analysis identified a de novo frameshift mutation by a 1-bp insertion in exon 9 (NM_002336.2: c.1870dupA, p.(Met624Asnfs*29)) and a splicing donor site mutation in intron 8 (c.1762+2T>C). An in vitro splicing assay confirmed the deletion of exon 8, and the deletion would result in a frameshift. Due to the premature termination codons introduced by the frameshift, both mutant transcripts would be degraded by nonsense-mediated mRNA decay, resulting in haploinsufficiency.

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Goos, Jacqueline A. C., Ans M. W. van den Ouweland, Sigrid M. A. Swagemakers, Annemieke J. M. H. Verkerk, A. Jeannette M. Hoogeboom, Marie-Lise C. van Veelen, Irene M. J. Mathijssen et Peter J. van der Spek. « A novel mutation inFGFR2 ». American Journal of Medical Genetics Part A 167, n^o 1 (25 novembre 2014) : 123–27. http://dx.doi.org/10.1002/ajmg.a.36827.

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Nguyen, Thi Kim Lien, Van Dem Pham, Thu Huong Nguyen, Trung Kien Pham, Thi Quynh Huong Nguyen et Huy Hoang Nguyen. « Three Novel Mutations in the NPHS1 Gene in Vietnamese Patients with Congenital Nephrotic Syndrome ». Case Reports in Genetics 2017 (2017) : 1–7. http://dx.doi.org/10.1155/2017/2357282.

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Congenital nephrotic syndrome, a rare and severe disease, is inherited as an autosomal recessive trait. The disease manifests shortly after birth and occurs predominantly in families of Finnish origin but has now been observed in all countries and races. Mutations in the NPHS1 gene, which encodes nephrin, are the main causes of congenital nephrotic syndrome in patients. In this study, we report the first mutational analysis of the NPHS1 gene in three unrelated children from three different Vietnamese families. These patients were examined and determined to be suffering from congenital nephrotic syndrome in the Department of Pediatrics, Vietnam National Hospital of Pediatrics. All 29 exons and exon-intron boundaries of NPHS1 were analyzed by PCR and DNA sequencing. Genetic analysis of the NPHS1 gene revealed one compound heterozygous variant p.Glu117Lys, one heterozygous missense mutation p.Asp310Asn, and one heterozygous frame-shifting mutation (c.3250_3251insG causing p.Val1084Glyfs⁎12) in patient 1. In patient 2, one heterozygous variant p.Glu117Lys and one novel heterozygous missense mutation p.Ser324Ala were identified. Finally, a novel missense mutation p.Arg802Leu and a novel nonsense mutation (c.2442C>G causing p.K792⁎) were identified in patient 3.

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Doherty, Elaine, Pirjo Pakarinen, Aila Tiitinen, Anna Kiilavuori, Ilpo Huhtaniemi, Susan Forrest et Kristiina Aittomäki. « A Novel Mutation in the FSH Receptor Inhibiting Signal Transduction and Causing Primary Ovarian Failure ». Journal of Clinical Endocrinology & ; Metabolism 87, n^o 3 (1 mars 2002) : 1151–55. http://dx.doi.org/10.1210/jcem.87.3.8319.

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Inactivating mutations of the FSH receptor (FSHR) are known to cause ovarian failure with amenorrhea and infertility in women. The first mutation identified in the FSHR gene was a missense mutation (566C→T, predicting Ala189Val transition) found in several Finnish patients with primary amenorrhea due to ovarian failure. Only five additional, partially or totally inactivating, mutations of the FSHR have been reported. Here, we report a novel FSHR mutation, 1255G→A, in a Finnish female with primary amenorrhea. The patient was a compound heterozygote for two mutations in the FSHR gene: 566C→T, the Finnish founder mutation, and 1255G→A, a previously unidentified mutation. The new mutation is located in exon 10 in the second transmembrane stretch of the FSHR, and it predicts an Ala419Thr change in the protein structure. In functional testing, the mutation was shown to have minimal effect on ligand binding capacity and affinity, but it almost totally abolished the cAMP second messenger response. Neither of the two FSHR mutations (566C→T or1255G→A) was identified in 40 other Finnish patients with premature ovarian failure. Based on this and previous studies, FSHR mutations remain a rare cause of ovarian failure.

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Park, Sang-Kyu, Louella Amos, Aparna Rao, Michael W. Quasney, Yoshihiro Matsumura, Nobuya Inagaki et Mary K. Dahmer. « Identification and characterization of a novel ABCA3 mutation ». Physiological Genomics 40, n^o 2 (janvier 2010) : 94–99. http://dx.doi.org/10.1152/physiolgenomics.00123.2009.

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Mutations in the gene coding for ATP-binding cassette protein A3 (ABCA3) are recognized as a genetic cause of lung disease of varying severity. Characterization of a number of mutant ABCA3 proteins has demonstrated that the mutations generally affect intracellular localization or the ability of the protein to hydrolyze ATP. A novel heterozygous mutation that results in the substitution of cysteine for arginine at amino acid 295 in ABCA3 was identified in a premature infant with chronic respiratory insufficiency and abnormal lamellar bodies. Sequencing of DNA performed in study participants demonstrated that this was a mutation and not a common variant. Plasmid vectors containing ABCA3 with the identified novel mutation tagged with green fluorescent protein on the carboxy terminus were generated. The effect of the mutation on protein function was characterized by examining the glycosylation state of the mutant protein in transiently transfected HEK293 cells and by examining ATP hydrolysis activity of the mutant protein with a vanadate-induced nucleotide trapping assay in stably transfected HEK293 cells. The ABCA3 protein containing the R295C mutation undergoes normal glycosylation and intracellular localization but has dramatically reduced ATP hydrolysis activity (12% of wild type). The identification of one copy of this novel mutation in a premature infant with chronic respiratory insufficiency suggests that ABCA3 haploinsufficiency together with lung prematurity may result in more severe, or more prolonged, respiratory failure.

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Stuart, Shani, Bishakha Roy, Gail Davies, Nevene Maksemous, Robert Smith et Lyn R. Griffiths. « Detection of a Novel Mutation in the CACNA1A gene ». Twin Research and Human Genetics 15, n^o 1 (février 2012) : 120–25. http://dx.doi.org/10.1375/twin.15.1.120.

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Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. It is divided into three subtypes FHM1, FHM2 and FHM3, which are caused by mutations in the CACNA1A, ATP1A2 and SCN1A genes respectively. As part of a regular diagnostic service, we investigated 168 patients with FHM symptoms. Samples were tested for mutations contained within the CACNA1A gene. Some tested samples (4.43%) showed an FHM1 mutation, with five of the mutations found in exon 5, one mutation in exon 16 and one in exon 17. Four polymorphisms were also detected, one of which occurred in a large percentage of samples (14.88%). The exon 16 2094G>A polymorphism, however, has been found to occur in healthy Caucasian control populations up to a frequency of 16% and is not considered to be significantly associated with FHM. A finding of significance, found in a single patient, was the detection of a novel mutation in exon 5 that results in a P225H change. The affected individual was an 8-year-old female. The exact phenotypic effect of this mutation is unknown, and further studies are needed to understand the pathophysiology of this mutation in FHM1. New information will allow for diagnostic procedures to be constantly updated, thus improving accuracy of diagnosis. It is possible that new information will also aid the development of new therapeutic agents for the treatment of FHM.

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Yuan, Lijuan, Xihui Chen, Ziyu Liu, Dan Wu, Jianguo Lu, Guoqiang Bao, Sijia Zhang, Lifeng Wang et Yuanming Wu. « Novel SLCO2A1 mutations cause gender-differentiated pachydermoperiostosis ». Endocrine Connections 7, n^o 11 (novembre 2018) : 1116–28. http://dx.doi.org/10.1530/ec-18-0326.

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Primary hypertrophic osteoarthropathy (PHO) is a rare familial disorder with reduced penetrance for females. The genetic mutations associated with PHO have been identified in HPGD and SLCO2A1, which involved in prostaglandin E2 metabolism. Here, we report 5 PHO patients from four non-consanguineous families. Two heterozygous mutations in solute carrier organic anion transporter family member 2A1 (SLCO2A1) were identified in two brothers by whole-exome sequencing. Three heterozygous mutations and one homozygous mutation were identified in other three PHO families by Sanger sequencing. However, there was no mutation in HPGD. These findings confirmed that homozygous or compound heterozygous mutations of SLCO2A1 were the pathogenic cause of PHO. A female individual shared the same mutations in SLCO2A1 with her PHO brother but did not have any typical PHO symptoms. The influence of sex hormones on the pathogenesis of PHO and its implication were discussed.

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Fitzgibbon, Jude, Matthew Smith, Rachael Arch, Lan-Lan Smith, Nigel Bainton, Michael Neat, Dominique Bonnet, Jamie Cavenagh et T. Andrew Lister. « Development of a Human Acute Myeloid Leukaemia Screening Panel and Identification of Novel Gene Mutations. » Blood 104, n^o 11 (16 novembre 2004) : 2991. http://dx.doi.org/10.1182/blood.v104.11.2991.2991.

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Abstract Mutation studies in Acute Myeloid Leukaemia (AML) are complicated by the existence of distinct morphological and cytogenetic subtypes; consequently although mutations in any one gene may occur in only 5% of AML, the frequency of mutation may differ both between the different FAB-types and cytogenetic risk groups studied. It is important therefore not only to validate the screening methodology used but also the suitability of the patient panel tested. A screening panel was developed allowing detection of novel recurring gene mutations within samples derived from patients with AML. Mutation analysis of 6 previously described genes (RUNX1, FLT3, KIT, CEBPA, PTPN11, NRAS) and 2 candidate genes (CCND3, FES) were carried out in a cohort of 175 AML samples representing all FAB types (except M3) and cytogenetic risk groups using a combination of SSCP, DHPLC and sequence analysis. One hundred and fifteen mutations were identified in 97 (55%) patients comprising 81 patients (46%) with one mutation, 14 patients (8%) with 2 mutations, and 2 patients (1%) with 3 mutations. Fifty-five out of 88 (63%) patients with normal karyotype AML had at least one mutation. There was was a weak negative association between FLT3 ITD and loop mutation (p = 0.095), a positive association between KIT mutation and favourable risk cytogenetics (p = 0.001), CEBPA mutation and intermediate risk/normal cytogenetics (p = 0.045) and PTPN11 mutation and poor risk disease (p = 0.001). The frequency of individual gene mutation was in accordance with previously published studies. Three novel mutations of FLT3 (Y589D, D839G, Y842H) were detected in 4 patients that would have been overlooked by conventional gel electrophoresis techniques. A single in frame 51bp deletion of nucleotide 939 – 990, resulting in a deletion of 17 amino acids at the carboxyl-terminus of the cyclin D3 protein was identified in a single patient. Overall, both the pattern and mutation frequencies reported in this cohort are similar to those in the literature supporting its further use as an investigational tool in the evaluation of candidate genes in the genesis of myeloid malignancy.

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Cheasley, Dane Anthony. « Comprehensive genomic analysis of mucinous ovarian cancer reveals unique therapeutic vulnerabilities. » Journal of Clinical Oncology 37, n^o 15_suppl (20 mai 2019) : 5571. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5571.

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5571 Background: Mucinous ovarian carcinoma (MOC) is a rare subtype of epithelial ovarian cancer that responds poorly to ovarian chemotherapies and has an unknown etiology. It is diagnostically challenging and can be confused with metastases from gastro-intestinal tract primaries. The GAMuT study is a multi-national effort to understand molecular drivers and cell of origin of this rare tumour, including identification of a genetic progression model and novel therapeutic options. Methods: We performed RNAseq (n = 67), exome sequencing (n = 61), SNP arrays (n = 67) and whole genome sequencing (n = 5) on MOC and precursor lesions. A subset of ~500 genes was further evaluated by targeted sequencing, including 129 MOC, 23 borderline mucinous tumours (non-invasive) and 23 extra-ovarian mucinous metastases. Immunohistochemistry data was collected for CK7, CK20, ER, PAX8, p53 and HER2 (n = 162-256). Extensive pathology review was performed and associated clinical data obtained. Results: Comparison with TCGA and other data sets showed that MOC are distinct from mucinous tumours from other organs, including colorectal, appendiceal and gastric cancers. Our data supports a clear genetic progression model from benign and borderline precursors to both low- and high-grade MOC. TP53 mutation, ERBB2 amplification and increasing copy number changes were key events associated with progression to invasive disease, including a novel amplicon on 9p13. Copy number aberration burden was significantly associated with poor survival. We identified several recurrent mutational events suggesting utility of an existing targeted therapy, including ERBB2 amplification (26%), ERBB3 mutation (4%) and BRAF mutation (9%). MOC could be included in clinical trials for novel agents targeting TP53 missense mutation (46%), RNF43 mutation (12%), PIK3CA mutation (8%) and KRAS/ NRAS mutations (66%). Other frequent events included CDKN2A inactivation (57%), ARID1A mutation (9%) and TP53 inactivating mutations (15%). Conclusions: MOC of any grade can derive from a primary ovarian tumour precursor, and is distinct from extra-ovarian metastases. MOC is genetically diverse and advanced disease should be assessed for targetable mutations which may provide novel therapeutic options.

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Wang, Yuanli, Kah Yong Goh, Zhencheng Chen, Wen Xing Lee, Sze Mun Choy, Jia Xin Fong, Yun Ka Wong, Dongxia Li, Fangrong Hu et Hong-Wen Tang. « A Novel TP53 Gene Mutation Sustains Non-Small Cell Lung Cancer through Mitophagy ». Cells 11, n^o 22 (13 novembre 2022) : 3587. http://dx.doi.org/10.3390/cells11223587.

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Lung cancer is the leading cause of cancer death in the world. In particular, non-small-cell lung cancer (NSCLC) represents the majority of the lung cancer population. Advances in DNA sequencing technologies have significantly contributed to revealing the roles, functions and mechanisms of gene mutations. However, the driver mutations that cause cancers and their pathologies remain to be explored. Here, we performed next-generation sequencing (NGS) on tumor tissues isolated from 314 Chinese NSCLC patients and established the mutational landscape in NSCLC. Among 656 mutations, we identified TP53-p.Glu358Val as a driver mutation in lung cancer and found that it activates mitophagy to sustain cancer cell growth. In support of this finding, mice subcutaneously implanted with NSCLC cells expressing TP53-p.Glu358Val developed larger tumors compared to wild-type cells. The pharmaceutical inhibition of autophagy/mitophagy selectively suppresses the cell proliferation of TP53-null or TP53-p.Glu358Val-expressing lung cancer cells. Together, our study characterizes a new TP53 mutation identified from Chinese lung cancer patients and uncovers its roles in regulating mitophagy, providing a new insight into NSCLC treatment.

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Liu, Ji-Shi, Liang-Liang Fan, Hao Zhang, Xiaoxian Liu, Hao Huang, Li-Jian Tao, Kun Xia et Rong Xiang. « Whole-Exome Sequencing Identifies Two Novel TTN Mutations in Chinese Families with Dilated Cardiomyopathy ». Cardiology 136, n^o 1 (20 août 2016) : 10–14. http://dx.doi.org/10.1159/000447422.

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Objectives: Dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death. So far, only 127 mutations of Titin(TTN) have been reported in patients with different phenotypes such as isolated cardiomyopathies, purely skeletal muscle phenotypes or complex overlapping disorders of muscles. Methods: We applied whole-exome sequencing (WES) to investigate cardiomyopathy patients and a cardiomyopathy-related gene-filtering strategy was used to analyze the disease-causing mutations. Sanger sequencing was applied to confirm the mutation cosegregation in the affected families. Results: A nonsense mutation (c.12325C>T/p.R4109X) and a missense mutation (c.17755G>C/p.G5919R) of TTN were identified in 2 Chinese DCM families, respectively. Both mutations were cosegregated in all affected members of both families. The nonsense mutation is predicted to result in a truncated TTN protein and the missense mutation leads to a substitution of glycine by arginine. Both variants may cause the structure changes of titin protein. Conclusions: We employed WES to detect the mutations of DCM patients and identified 2 novel mutations. Our study expands the spectrum of TTN mutations and offers accurate genetic testing information for DCM patients who are still clinically negative.

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Ding, Lan, Sizhong Zhang, Weimin Qiu, Cuiying Xiao, Shaoqing Wu, Ge Zhang, Lu Cheng et Sixiao Zhang. « Novel mutations of PKD1 gene in Chinese patients with autosomal dominant polycystic kidney disease ». Nephrology Dialysis Transplantation 17, n^o 1 (1 janvier 2002) : 75–80. http://dx.doi.org/10.1093/ndt/17.1.75.

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Abstract Background. Autosomal dominant polycystic kidney disease (ADPKD) is a common disease in China. The major gene responsible for ADPKD, PKD1, has been fully characterized and shown to encode an integral membrane protein, polycystin 1, which is thought to be involved in cell–cell and cell–matrix interaction. Until now, 82 mutations of PKD1 gene have been reported in European, American, and Asian populations. However, there has been no report on mutations of the PKD1 gene in a Chinese population. Methods. Eighty Chinese patients in 60 families with ADPKD were screened for mutations in the 3′ region of the PKD1 gene using polymerase chain reaction–single-strand conformation polymorphism (PCR–SSCP) and DNA-sequencing techniques. Results. Three mutations were found. The first mutation is a 12593delA frameshift mutation in exon 45, and the polycystin change is 4129WfsX4197, 107 amino acids shorter than the normal polycystin (4302aa). The second mutation is a 12470InsA frameshift mutation in exon 45, producing 4088DfsX4156, and the predicted protein is 148 amino acids shorter than the normal. The third one is a 11151C→T transition in exon 37 converting Pro3648 to Leu. In addition, nine DNA variants, including IVS44delG, were identified. Conclusions. Three mutations in Chinese ADPKD patients are described and all of them are de novo mutations. Data obtained from mutation analysis also suggests that the mutation rate of the 3′ single-copy region of PKD1 in Chinese ADPKD patients is very low, and there are no mutation hot spots in the PKD1 gene. Mutations found in Chinese ADPKD patients, including nucleotide substitution and minor frameshift, are similar to the findings reported by other researchers. Many mutations of the PKD1 gene probably exist in the duplicated region, promoter region, and the introns of PKD1.

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Robinson, Mayra C., Majd T. Ghanim et Shayla Bergmann. « A Family with a Novel Mutation and Polycythemia Vera ». Blood 132, Supplement 1 (29 novembre 2018) : 4875. http://dx.doi.org/10.1182/blood-2018-99-119234.

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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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Pestana, Maria Nicole, Francisca Gomes da Silva, José Durães et Gil Silva. « Novel GLA T194A variant causes Fabry disease ». BMJ Case Reports 14, n^o 3 (mars 2021) : e239204. http://dx.doi.org/10.1136/bcr-2020-239204.

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Fabry disease (FD) is an X-linked, systemic lysosomal deposition disease caused by alpha-galactosidase A (AGAL) enzyme deficiency deriving out of changes on the GLA gene. Though several mutations have been described, one must consider that even a specific mutation may present with variable clinical expression within the same family. Typically described as a disease that affects hemizygous men with no residual AGAL activity, we describe a novel FD mutation (first case of GLA T194A variant worldwide) in a 49-year-old woman presenting with a classic phenotype of FD. The patient investigation highlighted a previously not described mutation in exon 4 of the GLA gene, as for the substitution of threonine for alanine. The same mutation was identified in her children, one of them presenting with end-stage kidney disease (ESKD) in early adulthood.

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Guerra-Shinohara, Elvira Maria, Paulo Caleb Santos, Rodolfo Cancado, Alexandre Pereira, Isolmar Schettert, Renata Soares, Rosario D. C. Hirata et al. « Global Sequencing for the Molecular Background of Hereditary Hemochomatosis In Brazilian Patients ». Blood 116, n^o 21 (19 novembre 2010) : 5146. http://dx.doi.org/10.1182/blood.v116.21.5146.5146.

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Abstract Abstract 5146 INTRODUTION: Most hereditary hemochromatosis (HH) patients are homozygous for the p.C282Y mutation in the HFE gene. But rare HFE variants have been shown to be associated with HH. In addition, four main types of non-HFE HH are caused by mutations in the hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1) genes. The main aim of this study was to screen for HFE, HJV, HAMP, TFR2 and SLC40A1 mutations and to investigate their relationship with HH. MATERIAL E METHODS: Fifty-one Brazilian patients with primary iron overload (transferrin saturation > 50% in females and 60% in males) were eligible. Subsequent bidirectional sequencing for each exon of HFE, HJV, HAMP, TFR2 and SLC40A1 genes was performed. The effect of HFE p.V256I novel mutations on protein structure was analyzed by in silico molecular dynamic and free energy calculations. RESULTS: Thirty-seven (72.5%) out of the 51 patients presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n = 11, 21.6%). In addition, the p.S65C mutation was found in heterozygosis with p.H63D in two patients and the homozygous genotype for the p.H63D was found in two patients. One novel mutation (p.V256I) was indentified in heterozygosis with the p.H63D mutation. In silico modeling analysis of protein behavior suggested that the p.V256I mutation does not reduce the binding affinity between HFE and β2-microglobulin (β2M) in the same way the p.C282Y mutation does compared with the native HFE protein. Sequencing HJV revealed one patient presenting Juvenile hemochromatosis (JH) (homozygous genotype for the HJV p.G320V mutation); two patients carrying heterozygous genotype for the p.E302K mutation; and one patient with heterozygosis p.A310G polymorphism. Sequencing HAMP revealed one patient carrying p.P48G novel mutation in the heterozygous form. Three and five non-pathogenic polymorphisms were observed in the TFR2 and SLC40A1 genes, respectively. Sequencing SLC40A1 also identified one patient with homozygous genotype for the p.R561G described mutation; and one patient with homozygous genotype for the p.G204S novel mutation. CONCLUSION: The HFE p.C282Y in homozygosis or in heterozygosis with p.H63D was the most frequent mutation associated with HH in our sample population. The novel HFE p.V256I mutation could not be implicated in the molecular basis of the HH phenotype. Two described mutations, HJV p.E302K and SLC40A1 p.R561G, could have functional consequences according to previously studies contributing to HH phenotype. Two novel mutations, HAMP p.R48G and SLC40A1 p.G204S, may be implicated with iron overload in these patients, but further studies are need to explain their impact on proteins. Disclosures: No relevant conflicts of interest to declare.

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Tang, E., A. Kwong, C. Wong, F. Law, C. Wong, E. Ng, E. Ma et J. M. Ford. « Novel de novo BRCA1 mutation in a woman with early onset breast cancer ». Journal of Clinical Oncology 27, n^o 15_suppl (20 mai 2009) : e22143-e22143. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22143.

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e22143 Background: Germline mutations in BRCA1/2 account for a significant portion of hereditary breast/ovarian cancer. Mutation carriers usually have a family history of breast/ovarian cancer or early onset disease. Rarely, germline mutations are found only in the probands but not in any family members. Such de novo mutations have been reported in diseases such as hemophilia A, thalassaemia and familial adenomatous polyposis. De novo mutations in the BRCA1 or BRCA2 genes are rare and the few reported have been in BRCA2. Here, we describe de novo as well as novel mutation of the BRCA1 gene in a breast cancer patient. Methods: Blood DNA samples from a 30 year old Chinese woman with breast cancer and no family history of cancer was tested for a BRCA1/2 mutation by full gene sequencing and Multiple Ligation-dependent Probe Amplification (MLPA). Family members were analyzed for the same mutation. Paternity was determined by a set of highly polymorphic short tandem repeat (STR) markers. Results: Full gene sequencing found no deleterious mutation. MLPA revealed a large deletion of exons 1 to 12 of BRCA1 in the proband. MLPA performed on 5 family members: proband's mother and father (who were 1st degree relative- cousins), stepmother (mother's biological sister), 2 sisters (1, same parents; 1, same father and stepmother) found no similar deletion. By using a set of highly polymorphic STR markers, the proband's father and mother were confirmed to be her biological parents. Conclusions: We report a novel de novo BRCA1 deletion mutation encompassing exons 1 - 12 in a Chinese breast cancer patient of early onset with no family history. Identification of this large deletion confirms the importance of pursuing rearrangement testing if full gene sequencing fails to detect a point mutation or short insertion deletion. The mutation found in this study is de novo. This may simply be a random mutation event which occurred in the parents' germ cells during their lifetime which passed onto one of their offspring or maybe a result of gene inversion or splicing deficiency. The relations of such mutations with consanguineous marriage cannot be ruled out. Mutation screening is important in early onset breast cancer patients even if there is no family history. No significant financial relationships to disclose.

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Nadeu, Ferran, Shimin Shuai, Ander Diaz-Navarro, Irene López, Silvia Martín, Hiromichi Suzuki, Romina Royo et al. « The U1 Spliceosomal RNA : A Novel Non-Coding Hotspot Driver Mutation Independently Associated with Clinical Outcome in Chronic Lymphocytic Leukemia ». Blood 134, Supplement_1 (13 novembre 2019) : 847. http://dx.doi.org/10.1182/blood-2019-130052.

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Introduction: Genomic studies of chronic lymphocytic leukemia (CLL) have uncovered >80 potential driver mutations. The vast majority of these mutations affect coding regions, and just two potential drivers have been identified in non-coding elements. Aim: To describe the biological and clinical impact of a recurrent A>C mutation at the third base of the small nuclear RNA U1, the non-coding component of the spliceosome involved in the recognition of the 5' splice site (5'SS). Methods: Whole-genome sequencing (WGS) and RNA-seq from 318 CLL patients were used to identify and characterize a highly recurrent A>C point mutation occurring at position 3 of the U1 snRNA gene (g.3A>C mutation). The U1 wild-type and mutant forms were introduced into three CLL cell lines (JVM3, HG3, MEC1) to validate in vitro the predicted effect of this alteration. We screened two independent cohorts including a total of 1,314 CLL patients for the presence of the mutation using the rhAmp SNP genotyping assay, and integrated the U1 mutational status with well-known driver alterations, IGHV and epigenetic subgroups, and clinical parameters. Results: The U1 mutation was found in 8/78 (10.3%) CLL cases analyzed by WGS. Given its role in 5'SS recognition by base-pairing, we reasoned that this mutation was likely to alter the splicing and expression patterns of CLL. We were able to confirm widespread specific alterations in the transcriptome by comparing RNA-seq data between wild-type and g.3A>C mutated samples. Applying this knowledge to an algorithm aimed to infer the U1 mutational status from expression data, we were able to identify 4 mutated cases among 240 additional cases that had RNA-seq but no WGS. In total, 12/318 (3.8%) CLL patients analyzed by WGS and/or RNA-seq harbored this mutation. This g.3A>C U1 mutation changes the preferential A-U base-pairing between U1 and 5'SS to C-G base-pairing, creating novel splice junctions and altering the splicing pattern of 3,193 introns in 1,519 genes. In addition to altered splicing, 869 genes were differentially expressed between mutated and wild-type cases. We identified specific cancer genes (e.g. MSI2, POLD1, or CD44) and pathways (B-cell receptor signaling, promotion of apoptosis, telomere maintenance, among others) altered by the U1 mutation. To confirm a causal link between this mutation and splicing changes, we introduced exogenous U1 genes with or without the mutation into three cell lines. Subsequent RNA-seq of these cell lines recapitulated the altered splicing and expression patterns observed in CLL patients. We next screened for the presence of the U1 mutation 1,057 patients (cohort 1) using the rhAmp assay and it was found in 30 (2.8%) cases. The distribution of the mutation was similar in Binet stages and CLL vs monoclonal B-cell lymphocytosis. However, the U1 mutation was almost always found in IGHV unmutated CLL (29/30, p=9.0e-11) and within the naïve-like CLL epigenetic subgroup (p=3.7e-7). None of the U1 mutated cases had mutations in the SF3B1 splicing factor. Considering only pre-treatment CLL samples, U1 mutation was associated with a shorter time to first treatment independently of the Binet stage, IGHV mutational status, epigenetic subgroups, and mutations in the well-known CLL drivers SF3B1, NOTCH1, ATMor TP53. In cohort 2 (n=257), this mutation was found in 13 (5.1%) patients, confirming its enrichment in IGHV unmutated cases, naïve-like epigenetic subgroup, and splicing modulation. Despite the relatively small number of pre-treatment samples carrying the U1 mutation (7/178) and short follow-up of the patients (median 2.6 years), the effect of this mutation on time to first treatment in cohort 2 was compatible with the one observed in cohort 1. Finally, we screened for the U1 mutation a cohort of diffuse large B-cell lymphoma (n=108), mantle cell lymphoma (n=101), follicular lymphoma (n=87), splenic marginal zone lymphoma (n=12), acute myeloid leukemia (n=52), and myelodysplastic syndrome (n=67). The mutation was not present in any of the samples analyzed. Conclusions: Here we have reported that the third base of the small nuclear RNA U1 is recurrently mutated in CLL, proved its effect in splicing and gene expression, and shown that this mutation is independently associated with faster disease progression. The g.3A>C U1 mutation represents a novel non-coding driver alteration in CLL with potential clinical and therapeutic implications. Disclosures Ramirez Payer: GILEAD SCIENCES: Research Funding. Terol:Astra Zeneca: Consultancy; Gilead: Research Funding; Abbvie: Consultancy; Janssen: Consultancy, Research Funding; Roche: Consultancy. Lopez-Guillermo:Celgene: Consultancy, Research Funding; Janssen: Research Funding; Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding.

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Zhu, Zhi-Hong, Yi-Xin Zhang, Rui Wang, Tong Wu, Wei Liu, Ze-Hua Chen, Hai-Nan Xie, Lan-Lan Chen, Zi-Hao Liu et Hou-Bin Huang. « Novel mutations in the BEST1 gene cause distinct retinopathies in two Chinese families ». International Journal of Ophthalmology 15, n^o 2 (18 février 2022) : 205–12. http://dx.doi.org/10.18240/ijo.2022.02.03.

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AIM: To describe the clinical heterogeneity of patients with novel mutations in BEST1. METHODS: All the members in the two Chinese families underwent detailed clinical evaluations including best-corrected visual acuity, slit-lamp examination, applanation tonometry, and dilated fundus examination. Fundus autofluorescence, fundus fluorescein angiography, spectral-domain optical coherence tomography, electrooculography, and electroretinogram were also performed. Genomic DNA was extracted from venous blood for all the participants. The targeted next-generation sequencing of inherited retinal disease-associated genes was conducted to identify the causative mutation. RESULTS: A novel BEST1 missense mutation c.41T&#x003E;C (p.Leu14Ser) was identified in Family 1. It was co-segregated with the phenotype of best vitelliform macular dystrophy (BVMD) and bioinformatics analysis confirmed it was harmful. Another novel BEST1 frameshift mutation c.345_346insGGCAAGGACG (p.Glu119Glyfs*116) and a novel USH2A missense mutation c.12560G&#x003E;A, p.Arg4187His were identified in family 2 with retinitis pigmentosa (RP), which might interact and lead to the phenotype of RP. CONCLUSION: Two novel mutations in the BEST1 gene in two unrelated families with distinct phenotypes and BEST1 mutation accompanied with USH2A mutation would result in RP, which could be enormously helpful in understanding the pathogenesis of the inherited retinal disease caused by a BEST1 mutation.

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Barzon, Luisa, Giulia Masi, Isabella Merante Boschin, Enrico Lavezzo, Monia Pacenti, Eric Casal Ide, Antonio Toniato, Stefano Toppo, Giorgio Palù et Maria Rosa Pelizzo. « Characterization of a novel complex BRAF mutation in a follicular variant papillary thyroid carcinoma. » European Journal of Endocrinology 159, n^o 1 (juillet 2008) : 77–80. http://dx.doi.org/10.1530/eje-08-0239.

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IntroductionActivating mutations of the BRAF oncogene are frequently detected in papillary thyroid carcinoma (PTC) and have been associated with a worse prognosis. The amino acid substitution V600E accounts for 90% of all oncogenic BRAF mutations and is typically detected in classic PTCs, whereas other less frequent BRAF mutations seem to be associated with other PTC histotypes.CaseScreening for activating BRAF mutations in a series of 83 PTCs identified the most common V600E mutation in 39 cases (histologically, 38 classic PTCs and 1 sclerosing variant PTC) and a complex in-frame mutation involving amino acids V600–S605 in a stage III multicentric follicular variant PTC, occurring in a 50-year-old female patient, who was affected by hypothyroidism in autoimmune thyroiditis and had a family history of PTC and autoimmune thyroiditis. Since the identified BRAF mutation was novel in the literature, bioinformatic modeling was performed to predict its impact on BRAF activity. Although the mutation resulted in loss of a phosphorylation site in the activation loop of BRAF, it was predicted to increase BRAF kinase activity by mimicking an activating phosphorylation.ConclusionsThis study, which reports a new BRAF mutation, highlights the usefulness of bioinformatic modeling in the prediction of functional effects of new mutations and indicates that mutation-specific screening tests might miss some rare BRAF mutations. These facts should be taken into consideration in the molecular diagnosis of thyroid cancer and in the design of therapeutic protocols based on inhibitors of the BRAF pathway.

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Liu, Xin, Ke-Liang Chen, Yi Wang, Yu-Yuan Huang, Shi-Dong Chen, Qiang Dong, Mei Cui et Jin-Tai Yu. « A Novel ITM2B Mutation Associated with Familial Chinese Dementia ». Journal of Alzheimer's Disease 81, n^o 2 (18 mai 2021) : 499–505. http://dx.doi.org/10.3233/jad-210176.

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Mutations in ITM2B have been found to be associated with familial Danish dementia (FDD) and familial British dementia (FBD). Here, we describe a patient with dementia caused by a novel ITM2B p.*267Leuext*11 mutation. The patient presented with dementia, ataxia, deafness, and paraplegia. Amyloid PET and Tau PET showed abnormal deposition of amyloid and tau protein in brain. Summarized from previous 26 FBD and FDD cases, the clinical phenotype of ITM2B; p.*267Leuext*11 mutation in ITM2B is different from the features of FBD and FDD. Our findings increased genetic knowledge of familial dementia and extend the ethnic distribution of ITM2B mutations.

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Griesmacher, A., V. Ivaskevicius, A. Biswas, S. Zehetbauer, J. Oldenburg, K. Hohenstein, G. Weigel et P. Würtinger. « Novel point mutation in fibrinogen (Innsbruck ; BβArg44Gly) ». Hämostaseologie 35, S 01 (2015) : S22—S26. http://dx.doi.org/10.1055/s-0037-1619825.

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SummaryThis is a report of a novel fibrinogen point mutation (fibrinogen Innsbruck), a C/G point mutation at position 220 of exon two of the fibrinogen B|-chain leading to B|3Arg44Gly. The heterozygous mutation was found in a 16-year-old adolescent, hospitalized for the management of juvenile depression, who suffered from multiple epistaxis episodes during his stay at the university hospital in Innsbruck, Austria. Fibrinogen (based on the Clauss method) and fibrinogen antigen levels were highly discrepant (86 vs. 223 mg/dl) with thrombin time and reptilase time being in the respective upper reference ranges. Densitometric analysis of electrophoretic band pattern showed a reduction of a-polymers, indicating an impaired fibrin polymerization. This is in agreement with structural analysis, which showed a disturbance of the flexibility and structure of the region surrounding the fibrinoeptide B cleavage site. Fibrinogen Nijmegen, a mutation at the same position, is causative for thrombosis, whereas fibrinogen Innsbruck appears to lead to a bleeding tendency, illustrating that even mutations at the same position can cause contrary symptoms.

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Santoro, Alessandra, Sonia Cannella, Antonino Trizzino, Cesare Danesino, Daniela Pende, Carmen De Fusco, Concetta Micalizzi et al. « Novel Munc13-4 Mutations in Patients with Hemophagocytic Lymphohistiocytosis. » Blood 106, n^o 11 (16 novembre 2005) : 2807. http://dx.doi.org/10.1182/blood.v106.11.2807.2807.

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Abstract Familial hemophagocytic Lymphohistiocytosis (FLH) is a rare disorder characterized by fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia and reduced natural killer (NK) cell activity. Several genetic defects have been recognized as associated with FHL. After identification of perforin gene (PRF1) mutation as the cause of about one third of cases of FHL (Stepp,1999), in 2003 the same group reported that another gene involved in cellular cytotoxicity, Munc13-4, encoding for a protein involved in granule release in cytotoxic lymphocyte, is associated with a subset of patients with FHL. We have analyzed for Munc13-4 mutations 16 families of patients diagnosed with FHL according to current criteria, in whom PRF1 mutations had been excluded; 14 were Italian, 1 from USA, one from UK. The 32 exons and their proximal flanking regions of Munc13-4 gene were amplified from genomic DNA and amplification products were directly sequenced by cycle sequencing approach (BigDye Terminator Applied Biosystems). Sequences of primers utilized for the amplification reactions were designed with dedicated software (Primer Express) according to the gene sequence retrived from Genebank. A total of 13 mutations were identified in 12 families; 3 had homozygous mutations, 5 had combined heterozygous mutations, and 4 had only one detectable mutated allele. Mutation 753+IG in exon 9 (splice donor site) had been already reported (Feldman 2003, zurStadt 2005); The following novel mutations were found: G175A in exon 3 (A59T), delC532 in exon 6 (178 fs), A610G in exon 7 (M204V), G1241T in exon 14 (R414L), A1847G in exon 20 (E616G), del GGAG 2346 (782 fs) in exon 24, A2599G (K867E) in exon 27, C2650T in exon 28 (Q884stop), C2782T in exon 29 (R928C), C2896T in exon 30 (R966W), 3082delC in exon 31 (1028fs), insG3226 in exon 32 (1076fs). Mutation A2599 was observed in 6 families; mutation A1847G in 3 families; C2782T and G1241T in 2 families. We have also identified the polymorphisms C279T, and A3198G. Mutations were scattered over different exons and almost entirely different from those reported so far. A2599G mutation was frequently observed and its role deserves further investigation. Screening of Munc13-4 mutations is a powerful tool to confirm the diagnosis, to refine the therapeutic choice including indication to HSCT, selection of familiar donor, and identification of carriers and prenatal diagnosis in most of the families with FHL not associated with PRF1 mutations. Due to lack of immunologic or flow-cytometric tools for rapid screening of Munc13-4 defective patients, the high number of coding exons and lack of mutation clustering, screening of Munc13-4 mutations, although expensive and time consuming, remains necessary and allowed us to identify the genetic defect in the majority of our patients with FHL not associated with PRF1 mutations.

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Kazlow, Esther, Robert Ferguson, Danny Simpson, Carlos N. Martinez, Matjaz Vogelsang, Una Moran, Yesung Lee, Iman Osman, David Polsky et Tomas Kirchhoff. « Novel germline risk loci in familial melanoma (FM). » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : 1535. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1535.

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1535 Background: While about 10% of cutaneous melanoma (CM) clusters in families, known high-risk loci explain not more than 40% of expected inherited risk. Besides the most frequently mutated genes in FM (e.g. CDKN2A), it is estimated that the remaining 60% of FM susceptibility is due to the interaction of environment with specific pools of rare known loci and yet unknown high-risk genes. In our study, we report the discoveries of novel germline genetic risk factors in FM in a recently developed FM cohort at New York University Langone Medical Center (NYULMC) consisting of CM and multiple primary melanomas (MPM) of Ashkenazi Jewish (AJ) and non-AJ European ancestries. Methods: As part of an ongoing ascertainment of FM at NYULMC, we assessed the status of CDKN2A mutations using Sanger sequencing, examining the coding regions of 47 AJ FM families and 81 non-AJ FM kindreds. In high-risk mutation-negative families, we applied whole-exome sequencing (WXS) and an innovative hot-spot mutational analysis of non-coding regions to identify novel high-risk loci associated with FM susceptibility. Results: We found that frequencies of CDKN2A deleterious mutations in our FM cohort (13%) are comparable with observations from previous studies. We have also identified a specific CDKN2A coding mutation in FM kindreds of AJ ancestry, which is particularly interesting as CDKN2A mutations in AJ cohorts have been sparsely reported in prior studies. The WXS/targeted non-coding sequencing of mutation-negative families identified putatively deleterious mutations in regulatory regions in the vicinity of several novel loci, including SMAD4 and PAX8, co-segregating in FM kindreds. Conclusions: Our unique FM ascertainment, including > 50% AJ kindreds, provides an excellent platform for mapping high-risk genetic susceptibility in FM. Novel deleterious mutations identified in non-coding regulatory regions of SMAD4 and PAX8 genes, some with increased frequency in AJ families, suggest a need for a more thorough investigation of the non-coding genome using a founder FM population, as we propose here. As our ongoing ascertainment expands, we are pursuing validation of our observations through comprehensive sequencing efforts.

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Yamazaki, Tomio, Akira Katsumi, Yoshihiro Okamoto, Toshio Takafuta, Shinobu Tsuzuki, Kazuo Kagami, Isamu Sugiura, Tetsuhito Kojima, Kingo Fujimura et Hidehiko Saito. « Two Distinct Novel Splice Site Mutations in a Compound Heterozygous Patient with Protein S Deficiency ». Thrombosis and Haemostasis 77, n^o 01 (1997) : 014–20. http://dx.doi.org/10.1055/s-0038-1655729.

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SummaryGenetic analysis revealed two distinct novel splice site mutations in a compound heterozygous patient with protein S deficiency. The paternal mutation was a G-to-T transition at position -1 of the acceptor splice site of intron N (Mutation I), and the maternal mutation was a G-to-C transversion at position -1 of the donor splice site of intron C (Mutation II). Both splice site mutations decreased the mutated mRNA accumulation to the same extent, approximately 40% of the normal mRNA. However, the mutations were associated with different phenotypical expressions: the paternal mutant protein S was not detected in vivo, while the maternal mutant protein S was present in the plasma in reduced quantity. Because Mutation I caused a cryptic splicing in the mutated mRNA, resulting in a reading frameshift and premature termination, the predicted mutant protein S might be highly unstable. In contrast, Mutation II led to the substitution of Val46 by Leu, which might be much less deleterious for the synthesis, secretion and stability of the predicted mutant protein S. It was supposed that the different post-translational metabolisms produced the distinct phenotypical expressions of the mutations.

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Onay, Hüseyin, Hilmi Bolat, Gonca Kılıç Yıldırım, Engin Kose, Sema Kalkan Uçar, Semih Aşıkovalı, Ferda Özkınay et Mahmut Çoker. « Analysis of the alpha galactosidase gene : mutation profile and description of two novel mutations with extensive literature review in Turkish population ». Journal of Pediatric Endocrinology and Metabolism 33, n^o 10 (19 août 2020) : 1245–50. http://dx.doi.org/10.1515/jpem-2020-0056.

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AbstractObjectivesFabry disease (FD, OMIM #301500) is a rare and progressive X-linked lysosomal storage disorder. FD is caused by mutations in the GLA gene on chromosome Xq22.MethodsIn this article, we aimed to present the largest sample of GLA mutation spectrum including common and novel variants in Turkish population. GLA gene sequence analysis was performed on the subjects who applied to the department of medical genetics with the preliminary diagnosis of FD between 2013 and 2018.ResultsWe detected 22 different mutations as two novel [(p.F69S(c.206T>C), p.P205A (c.613C>G)] and 20 previously reported GLA mutations in 47 individuals from 22 unrelated families. These mutations included 14 missense mutations, four nonsense mutations, two small deletions, one small deletion/insertion and one small insertion. Major clinical findings of the female case with p.F69S(c.206T>C) mutation were cornea verticillata, acroparesthesia, angiokeratoma, psychiatric and gastrointestinal symptoms. Other novel mutation (p.P205A [c.613C>G]) was carried by a male case presenting gastrointestinal symptoms.ConclusionsWe described clinical findings of two cases that had novel mutations to provide more insight in genotype-phenotype correlation. We presented the largest mutation spectrum in Turkish population and reviewed previous mutations in this article.

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Prigoda, N. L. « Hereditary haemorrhagic telangiectasia : mutation detection, test sensitivity and novel mutations ». Journal of Medical Genetics 43, n^o 9 (5 avril 2006) : 722–28. http://dx.doi.org/10.1136/jmg.2006.042606.

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Aung-Htut, May T., Kristin A. Ham, Michel C. Tchan, Sue Fletcher et Steve D. Wilton. « Novel Mutations Found in Individuals with Adult-Onset Pompe Disease ». Genes 11, n^o 2 (28 janvier 2020) : 135. http://dx.doi.org/10.3390/genes11020135.

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Pompe disease, or glycogen storage disease II is a rare, progressive disease leading to skeletal muscle weakness due to deficiency of the acid α-1,4-glucosidase enzyme (GAA). The severity of disease and observed time of onset is subject to the various combinations of heterozygous GAA alleles. Here we have characterized two novel mutations: c.2074C>T and c.1910_1918del, and a previously reported c.1082C>G mutation of uncertain clinical significance. These mutations were found in three unrelated patients with adult-onset Pompe disease carrying the common c.-32-13T>G mutation. The c.2074 C>T nonsense mutation has obvious consequences on GAA expression but the c.1910_1918del (deletion of 3 amino acids) and c.1082C>G missense variants are more subtle DNA changes with catastrophic consequences on GAA activity. Molecular and clinical analyses from the three patients corresponded with the anticipated pathogenicity of each mutation.

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