Highlight on DPYD gene polymorphisms and treatment by capecitabine (.).

Scand J Clin Lab Invest Suppl. 2016;245:S30-3

Authors: Milano G

Abstract
BACKGROUND: Sequencing of DPYD exome was conducted in a prospective cohort of advanced breast cancer patients receiving capecitabine.
METHODS: A total of 243 patients were analyzed. Digestive, neurologic and hematotoxicity over cycles 1-2 showed 10.3% G3 and 2.1% G4, including one toxic death. DPYD exome, flanking intronic regions (20 bp), 3'UTR and part of 5'UTR (500 bp) were sequenced on MiSeq Illumina (Integragen, 97% coverage, HWE checked).
RESULTS: In total, 48 SNPs were identified: three in 3'UTR, 19 in coding regions (four synonymous including E412E; 15 missenses including D949V, V732I, R592W, I560S, I543V, S534N, S492L, M406I, D342G, M166V, T65M, C29R), 19 in flanking intronic regions (including *2A) and seven in 5'UTR. In total, 11 SNPs have not been previously described, including three missense variations each heterozygous in three separate patients: R696H, F100L and A26T. The patient with a toxic death carried one D949V allele. The three consensual variants *2A, D949V and I560S were carried by seven patients (heterozygous). Analysis of consensual variants showed that they were associated with G3-4 toxicity (OR = 21.0, sensitivity 16.7%) but not with G4 toxicity. Adding the variants previously associated with DPD deficiency in vitro, i.e. R592W, S492L and D342N/G, increased sensitivity on G3-4 (23.3%, OR = 21.1) and was predictive of G4 toxicity (sensitivity 40%, OR = 19.0). Of note, adding the new F100L variant further improved predictivity of genotyping on G4 toxicity (sensitivity 60%, OR = 42.8).
CONCLUSIONS: Present data establish the impact of consensual variants on capecitabine toxicity and reveal the existence of a novel DPYD variant, F100L, associated with G4 toxicity.

PMID: 27454530 [PubMed - indexed for MEDLINE]

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome.

Am J Hum Genet. 2017 Mar 11;:

Authors: Ta-Shma A, Khan TN, Vivante A, Willer JR, Matak P, Jalas C, Pode-Shakked B, Salem Y, Anikster Y, Hildebrandt F, Katsanis N, Elpeleg O, Davis EE

Abstract
Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.

PMID: 28318500 [PubMed - as supplied by publisher]

Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita.

Am J Hum Genet. 2017 Mar 08;:

Authors: Xue S, Maluenda J, Marguet F, Shboul M, Quevarec L, Bonnard C, Ng AY, Tohari S, Tan TT, Kong MK, Monaghan KG, Cho MT, Siskind CE, Sampson JB, Rocha CT, Alkazaleh F, Gonzales M, Rigonnot L, Whalen S, Gut M, Gut I, Bucourt M, Venkatesh B, Laquerrière A, Reversade B, Melki J

Abstract
Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.

PMID: 28318499 [PubMed - as supplied by publisher]

Reasons for Declining Preconception Expanded Carrier Screening Using Genome Sequencing.

J Genet Couns. 2017 Mar 17;:

Authors: Gilmore MJ, Schneider J, Davis JV, Kauffman TL, Leo MC, Bergen K, Reiss JA, Himes P, Morris E, Young C, McMullen C, Wilfond BS, Goddard KA

Abstract
Genomic carrier screening can identify more disease-associated variants than existing carrier screening methodologies, but its utility from patients' perspective is not yet established. A randomized controlled trial for preconception genomic carrier screening provided an opportunity to understand patients' decisions about whether to accept or decline testing. We administered a survey to potential genomic carrier screening recipients who declined participation (N = 240) to evaluate their reasons for doing so. Two thirds of women declined participation. We identified major themes describing reasons these individuals declined to participate; the most common were time limitation, lack of interest, not wanting to know the information, and potential cause of worry or anxiety. Most women eligible for genomic carrier screening indicated that their reasons for opting out were due to logistical issues rather than opposing the rationale for testing. As expanded carrier screening and genomic sequencing become a more routine part of clinical care, it is anticipated there will be variable uptake from individuals for this testing. Thus, the advancement of clinical carrier screening from single genes, to expanded screening panels, to an exome- or genome-wide platform, will require approaches that respect individual choice to receive genetic testing for reproductive risk assessment.

PMID: 28315134 [PubMed - as supplied by publisher]

Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB.

J Pediatr Endocrinol Metab. 2017 Mar 17;:

Authors: Zeng Q, Fan Y, Wang L, Huang Z, Gu X, Yu Y

Abstract
BACKGROUND: Mucopolysaccharidosis IIIB (MPS IIIB) is a genetic disease characterized by mutations in the NAGLU gene, deficiency of α-N-acetylglucosaminidase, multiple congenital malformations and an increased susceptibility to malignancy. Because of the slow progressive nature of this disease and its atypical symptoms, the misdiagnosis of MPS IIIB is not rare in clinical practice. This misdiagnosis could be avoided by using next-generation sequencing (NGS) techniques, which have been shown to have superior performance for detecting mutations underlying rare inherited disorders in previous studies.
CASE PRESENTATION: Whole exome sequencing (WES) was conducted and the putative pathogenic variants were validated by Sanger sequencing. The activity of MPS IIIB related enzyme in the patient's blood serum was assayed. A heterozygous, non-synonymous mutation (c.1562C>T, p.P521L) as well as a novel mutation (c.1705C>A, p.Q569K) were found in the NAGLU gene of the patient. The two mutations were validated by Sanger sequencing. Our data showed that this patient's c.1562C>T, p.P521L mutation in the NAGLU gene was inherited from his father and c.1705C>A, p.Q569K was from his mother. The diagnosis was further confirmed by an enzymatic activity assay after patient recall and follow-up.
CONCLUSIONS: Our results describe an atypical form of MPS IIIB and illustrate the diagnostic potential of targeted WES in Mendelian disease with unknown etiology. WES could become a powerful tool for molecular diagnosis of MPS IIIB in clinical setting.

PMID: 28306536 [PubMed - as supplied by publisher]

The genetics of gastroesophageal adenocarcinoma and the use of circulating cell free DNA for disease detection and monitoring.

Expert Rev Mol Diagn. 2017 Mar 17;:

Authors: Openshaw MR, Richards CJ, Guttery DS, Shaw JA, Thomas AL

Abstract
INTRODUCTION: Gastroesophageal adenocarcinoma (GOA) is a frequently occurring cancer worldwide with a poor clinical outcome. Adenocarcinomas of the oesophagus and gastroesophageal junction have shown a recent increase in frequency, therefore there is need to increase our understanding of GOA in order to improve our ability to detect, monitor and treat the disease. Areas covered: The authors discuss the current classification of GOA in the context of recent changes in incidence. The authors also discuss developments in the understanding of disease biology and recent discoveries from whole genome and whole exome sequencing, and studies in immunotherapy. Finally, the authors discuss the recent developments in the use of circulating tumour DNA (ctDNA). PubMed search terms were in English including "oesophageal/gastric adenocarcinoma", "gastroesophageal junctional tumour", "whole genome/exome sequencing", "immunotherapy" and "circulating tumour DNA". Expert commentary: Shared biological and genetic changes in GOA suggest it can be investigated as a single disease entity with different molecular subtypes. A number of genes are recurrently mutated including TP53, SMAD4, PIK3CA and there are frequent somatic copy number alterations and high levels of chromosomal instability. A subset of these genetic alterations have been detected in ctDNA and may provide an important avenue of research for detecting minimal residual disease and response to chemo- and immunotherapies.

PMID: 28306358 [PubMed - as supplied by publisher]

Changing the Therapeutic Landscape in Non-small Cell Lung Cancers: the Evolution of Comprehensive Molecular Profiling Improves Access to Therapy.

Curr Oncol Rep. 2017 Apr;19(4):24

Authors: Sabari JK, Santini F, Bergagnini I, Lai WV, Arbour KC, Drilon A

Abstract
Targeting genomic alterations has led to a paradigm shift in the treatment of patients with lung cancer. In an effort to better identify potentially actionable alterations that may predict response to FDA-approved and or investigational therapies, many centers have migrated towards performing targeted exome sequencing in patients with stage IV disease. The implementation of next-generation sequencing (NGS) in the evaluation of tumor tissue from patients with NSCLC has led to the discovery of targetable alterations in tumors that previously had no known actionable targets by less comprehensive profiling. An improved understanding of the molecular pathways that drive oncogenesis in NSCLC and a revolution in the technological advances in NGS have led to the development of new therapies through biomarker-driven clinical trials. This review will focus on the advances in molecular profiling that continue to fuel the revolution of precision medicine, identifying targets such as MET exon 14 skipping alterations and select recurrent gene alterations with increasing frequency.

PMID: 28303491 [PubMed - in process]

Ankyrin Repeat and Zinc Finger Domain containing 1 Mutations are associated with Infantile-Onset Inflammatory Bowel Disease.

J Biol Chem. 2017 Mar 16;:

Authors: van Haaften-Visser DY, Harakalova M, Mocholi E, van Montfrans JM, Elkadri A, Rieter E, Fiedler K, van Hasselt PM, Triffaux EM, van Haelst MM, Nijman IJ, Kloosterman WP, Nieuwenhuis EE, Muise AM, Cuppen E, Houwen RH, Coffer PJ

Abstract
Infantile-onset inflammatory bowel disease (IO IBD) is an invalidating illness with an onset before two years of age and has a complex pathophysiology in which genetic factors are important. Homozygosity mapping and whole exome sequencing in an IO IBD patient and subsequent sequencing of the candidate gene in twelve additional IO IBD patients revealed two patients with two mutated Ankyrin Repeat and Zinc Finger Domain containing 1 (ANKZF1) alleles (homozygous ANKZF1 R585Q mutation and compound heterozygous ANKZF1 E152K and V32_Q87del mutations respectively) and two patients with one mutated ANKZF1 allele. While the function of ANKZF1 in mammals had not been previously evaluated, we show that ANKZF1 has an indispensible role in the mitochondrial response to cellular stress. ANKZF1 is located diffusely in the cytoplasm and translocates to the mitochondria upon cellular stress. ANKZF1 depletion reduces mitochondrial integrity and mitochondrial respiration under conditions of cellular stress. The ANKZF1 mutations identified in IO IBD patients with two mutated ANKZF1 alleles result in dysfunctional ANKZF1, as shown by an increased level of apoptosis in patients' lymphocytes, a decrease in mitochondrial respiration in patient fibroblasts with a homozygous ANKZF1 R585Q mutation and an inability of ANKZF1 R585Q and E152K to rescue the phenotype of yeast deficient in Vms1, the yeast homologue of ANKZF1. These data indicate that loss-of-function mutations in ANKZF1 result in deregulation of mitochondrial integrity and this may play a pathogenic role in the development of IO IBD.

PMID: 28302725 [PubMed - as supplied by publisher]

Identification and Characterization of a Missense Mutation in the O-GlcNAc Transferase Gene that Segregates with X-Linked Intellectual Disability.

J Biol Chem. 2017 Mar 16;:

Authors: Vaidyanathan K, Niranjan T, Selvan N, Teo CF, May M, Patel S, Weatherly B, Skinner C, Opitz J, Carey J, Viskochil D, Gecz J, Shaw M, Peng Y, Alexov E, Wang T, Schwartz C, Wells L

Abstract
O-GlcNAc is a regulatory post-translational modification of nucleocytoplasmic proteins that has been implicated in multiple biological processes including transcription. In humans, single genes encode enzymes for its attachment [O-GlcNAc transferase (OGT)] and removal [O-GlcNAcase (OGA)]. An X-chromosome exome screen identified a missense mutation, that encodes an amino acid in the tetratricopeptide repeat, in OGT (759G>T (p.L254F)) that segregates with X-linked intellectual disability (XLID) in an affected family. A decrease in steady-state OGT protein levels were observed in isolated lymphoblastoid cell lines from affected individuals consistent with molecular modeling experiments. Recombinant expression of L254F-OGT demonstrated that the enzyme is active as both a glycosyltransferase and as a HCF-1 protease. Despite the reduction in OGT levels seen in the L254F-OGT individual cells, we observed that steady-state global O-GlcNAc levels remain grossly unaltered. Surprisingly, lymphoblastoids from affected individuals display a marked decrease in steady-state OGA protein and mRNA levels. We observed an enrichment of the OGT-containing transcriptional repressor complex mSin3A-HDAC1 at the proximal promoter region of OGA and correspondingly decreased OGA promoter activity in affected cells. Global transcriptome analysis of L254F-OGT lymphoblastoids compared to controls revealed a small subset of genes that are differentially expressed. Thus, we have begun to unravel the molecular consequences of the 759G>T (p.L254F) mutation in OGT that uncovered a compensation mechanism, albeit imperfect given the phenotype of affected individuals, to maintain steady-state O-GlcNAc levels. Thus, a single amino acid substitution in the regulatory domain (TPR domain) of OGT, which catalyzes the O-GlcNAc post-translational modification of nuclear and cytosolic proteins, appears causal for XLID.

PMID: 28302723 [PubMed - as supplied by publisher]

Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease.

Kidney Int. 2017 Mar 14;:

Authors: McMahon GM, Hwang SJ, Clish CB, Tin A, Yang Q, Larson MG, Rhee EP, Li M, CKDGen Consortium, Levy D, O'Donnell CJ, Coresh J, Young JH, Gerszten RE, Fox CS

Abstract
We assessed the association between urinary metabolites, genetic variants, and incident chronic kidney disease (CKD) in the Framingham Offspring cohort. Among the participants, 193 individuals developed CKD (estimated glomerular filtration rate under 60 ml/min/1.73m(2)) between cohort examinations 6 (1995-1998) and 8 (2005-2008, mean follow-up 9.7 years). They were age- and sex-matched to 193 control individuals free of CKD. A total of 154 urinary metabolites were measured using mass spectrometry, and the association between metabolites and CKD was examined using logistic regression. Next, we tested the genetic associations of each metabolite with an Illumina exome chip. Urinary glycine and histidine were associated with a lower risk of incident CKD with an odds ratio of 0.59 (95% confidence interval [CI] 0.43-0.80) and 0.65 (0.50-0.85) respectively, per one standard deviation increase in metabolite concentration. Follow-up in the Atherosclerosis Risk in Communities cohort confirmed the association of urinary glycine with CKD. In exome chip analyses, 36 single nucleotide polymorphisms at 30 loci were significantly associated with 31 metabolites. We surveyed exome chip findings for associations with known renal function loci such as rs8101881 in SLC7A9 coding for an amino acid transporter, which has been associated with a lower risk of CKD. We found this polymorphism was significantly associated with higher levels of lysine and NG-monomethyl-L-arginine (NMMA). Increased urinary lysine and NMMA were associated with a lower risk of CKD (0.73 [0.50-0.90] and 0.66 [0.53-0.83], respectively) in the univariate model. Thus, low urinary glycine and histidine are associated with incident CKD. Furthermore, genomic association of urinary metabolomics identified lysine and NMMA as being linked with CKD and provided additional evidence for the association of SLC7A9 with kidney disease.

PMID: 28302371 [PubMed - as supplied by publisher]

Genomic landscape of colorectal cancer in Japan: clinical implications of comprehensive genomic sequencing for precision medicine.

Genome Med. 2016 12 22;8(1):136

Authors: Nagahashi M, Wakai T, Shimada Y, Ichikawa H, Kameyama H, Kobayashi T, Sakata J, Yagi R, Sato N, Kitagawa Y, Uetake H, Yoshida K, Oki E, Kudo SE, Izutsu H, Kodama K, Nakada M, Tse J, Russell M, Heyer J, Powers W, Sun R, Ring JE, Takabe K, Protopopov A, Ling Y, Okuda S, Lyle S

Abstract
BACKGROUND: Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC).
METHODS: Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC.
RESULTS: The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy.
CONCLUSIONS: Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.

PMID: 28007036 [PubMed - indexed for MEDLINE]

Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO).

PLoS One. 2017;12(3):e0169687

Authors: Cox AJ, Darbro BW, Laxer RM, Velez G, Bing X, Finer AL, Erives A, Mahajan VB, Bassuk AG, Ferguson PJ

Abstract
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.

PMID: 28301468 [PubMed - in process]

Whole exome sequencing in the Framingham Heart Study identifies rare variation in HYAL2 that influences platelet aggregation.

Thromb Haemost. 2017 Mar 16;:

Authors: Eicher JD, Chen MH, Pitsillides AN, Lin H, Veeraraghavan N, Brody JA, Metcalf GA, Muzny DM, Gibbs RA, Becker DM, Becker LC, Faraday N, Mathias RA, Yanek LR, Boerwinkle E, Cupples LA, Johnson AD

Abstract
Inhibition of platelet reactivity is a common therapeutic strategy in secondary prevention of cardiovascular disease. Genetic and environmental factors influence inter-individual variation in platelet reactivity. Identifying genes that contribute to platelet reactivity can reveal new biological mechanisms and possible therapeutic targets. Here, we examined rare coding variation to identify genes associated with platelet reactivity in a population-based cohort. To do so, we performed whole exome sequencing in the Framingham Heart Study and conducted single variant and gene-based association tests against platelet reactivity to collagen, adenosine diphosphate (ADP), and epinephrine agonists in up to 1,211 individuals. Single variant tests revealed no significant associations (p<1.44×10(-7)), though we observed a suggestive association with previously implicated MRVI1 (rs11042902, p = 1.95×10(-7)). Using gene-based association tests of rare and low-frequency variants, we found significant associations of HYAL2 with increased ADP-induced aggregation (p = 1.07×10(-7)) and GSTZ1 with increased epinephrine-induced aggregation (p = 1.62×10(-6)). HYAL2 also showed suggestive associations with epinephrine-induced aggregation (p = 2.64×10(-5)). The rare variants in the HYAL2 gene-based association included a missense variant (N357S) at a known N-glycosylation site and a nonsense variant (Q406*) that removes a glycophosphatidylinositol (GPI) anchor from the resulting protein. These variants suggest that improper membrane trafficking of HYAL2 influences platelet reactivity. We also observed suggestive associations of AR (p = 7.39×10(-6)) and MAPRE1 (p = 7.26×10(-6)) with ADP-induced reactivity. Our study demonstrates that gene-based tests and other grouping strategies of rare variants are powerful approaches to detect associations in population-based analyses of complex traits not detected by single variant tests and possible new genetic influences on platelet reactivity.

PMID: 28300864 [PubMed - as supplied by publisher]

Complex interaction between HNRNPD mutations and risk polymorphisms is associated with discordant Crohn's disease in monozygotic twins.

Autoimmunity. 2017 Mar 16;:1-2

Authors: Prakash T, Veerappa A, B Ramachandra N

Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) affecting the lining of digestive tracts of the colon and ileum. To investigate the reasons behind the presence of CD phenotype in one of the monozygotic (MZ) twins, we utilized the whole exome sequence (WES) datasets of CD tissue biopsy and CD blood of affected twin and the exome dataset of blood from healthy twin. We report the presence of discordant and rare damaging mutation in HNRNPD and other risk polymorphisms such as, rs12103, rs2241880, rs3810936, rs7076156, rs1042058 and rs1292053. HNRNPD was found carrying two novel heterozygous mutations - a stop gain mutation that truncated the protein at 249th and 268th amino acid position and a single base missense mutation replacing Aspartate with Valine at 300th amino acid. The identified risk polymorphisms were found conferring susceptibility to CD and IBD. Discordant deleterious and damaging mutation was detected in HNRNPD that have been implicated in inflammatory pathways. Integrating these variants led to the elucidation of pathophysiology of CD in the affected twin involving the causal processes of macrophage activation, tissue death, autophagy, immune response, cell-migration and T-cell activation.

PMID: 28300425 [PubMed - as supplied by publisher]

Screening of gene mutations associated with bone metastasis in nonsmall cell lung cancer.

J Cancer Res Ther. 2016 Dec;12(Supplement):C186-C190

Authors: Zhang K, Zhang M, Zhu J, Hong W

Abstract
OBJECTIVE: The objective of this study is to assess the gene mutation of advanced nonsmall cell lung cancer (NSCLC) patients with bone metastasis using next-generation sequencing (NGS), and screen for the driver genes which are associated with bone metastasis of lung cancer.
MATERIALS AND METHODS: Eight clinicopathologic samples from advanced NSCLC combined with bone metastasis patients were collected. Exome sequencing was conducted within 483 tumor-associated genes using Hiseq 2000_PE75 NGS platform.
RESULTS: Three thousand six hundred and twenty gene mutations were identified, including point mutation, insertion, and deletion. Among all genes associated with lung cancer signaling pathways, fibroblast growth factor receptor (FGFR), and cyclin-dependent kinase 12 (CDK12) were found to be mutated in all eight patients. The top three genes were FGFR, ataxia telangiectasia mutated, and CDK12, according to mutation frequency. In the meanwhile, hepatocyte nuclear factor 1 alpha, adenomatous polyposis coli, and CD22 were found to be mutated in all eight patients with an over 50% mutation frequency (75%, 62.5%, and 50%, respectively), which would be the most potential genes accounting for bone metastasis in lung cancer patients.
CONCLUSION: Our findings shed light on several important signalling pathways involved in NSCLC, and suggest new potential molecular targets for treatment of NSCLC patients with bone metastasis.

PMID: 28230015 [PubMed - indexed for MEDLINE]

GRIN3B missense mutation as an inherited risk factor for schizophrenia: whole-exome sequencing in a family with a familiar history of psychotic disorders.

Genet Res (Camb). 2017 01 30;99:e1

Authors: Hornig T, Grüning B, Kundu K, Houwaart T, Backofen R, Biber K, Normann C

Abstract
Glutamate is the most important excitatory neurotransmitter in the brain. The N-methyl-D-aspartate (NMDA) receptor is a glutamate-gated ionotropic cation channel that is composed of several subunits and modulated by a glycine binding site. Many forms of synaptic plasticity depend on the influx of calcium ions through NMDA receptors, and NMDA receptor dysfunction has been linked to a number of neuropsychiatric disorders, including schizophrenia. Whole-exome sequencing was performed in a family with a strong history of psychotic disorders over three generations. We used an iterative strategy to obtain condense and meaningful variants. In this highly affected family, we found a frameshift mutation (rs10666583) in the GRIN3B gene, which codes for the GluN3B subunit of the NMDA receptor in all family members with a psychotic disorder, but not in the healthy relatives. Matsuno et al., also reported this null variant as a risk factor for schizophrenia in 2015. In a broader sample of 22 patients with psychosis, the allele frequency of the rs10666583 mutation variant was increased compared to those of healthy population samples and unaffected relatives. Compared to the 1000 Genomes Project population, we found a significant increase of this variant with a large effect size among patients. The amino acid shift degrades the S1/S2 glycine binding domain of the dominant modulatory GluN3B subunit of the NMDA receptor, which subsequently affects the permeability of the channel pore to calcium ions. A decreased glycine affinity for the GluN3B subunit might cause impaired functional capability of the NMDA receptor and could be an important risk factor for the pathogenesis of psychotic disorders.

PMID: 28132660 [PubMed - indexed for MEDLINE]

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2017/03/16

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies.

Am J Hum Genet. 2017 Mar 06;:

Authors: Xu M, Xie YA, Abouzeid H, Gordon CT, Fiorentino A, Sun Z, Lehman A, Osman IS, Dharmat R, Riveiro-Alvarez R, Bapst-Wicht L, Babino D, Arno G, Busetto V, Zhao L, Li H, Lopez-Martinez MA, Azevedo LF, Hubert L, Pontikos N, Eblimit A, Lorda-Sanchez I, Kheir V, Plagnol V, Oufadem M, Soens ZT, Yang L, Bole-Feysot C, Pfundt R, Allaman-Pillet N, Nitschké P, Cheetham ME, Lyonnet S, Agrawal SA, Li H, Pinton G, Michaelides M, Besmond C, Li Y, Yuan Z, von Lintig J, Webster AR, Le Hir H, Stoilov P, UK Inherited Retinal Dystrophy Consortium, Amiel J, Hardcastle AJ, Ayuso C, Sui R, Chen R, Allikmets R, Schorderet DF

Abstract
Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

PMID: 28285769 [PubMed - as supplied by publisher]

Diagnosis with Multiple Epiphyseal Dysplasia Using Whole-exome Sequencing in a Chinese Family.

Chin Med J (Engl). 2017 5th Jan 2017;130(1):104-107

Authors: Liu HY, Xiao JF, Huang J, Wang Y, Wu D, Li T, Wang HD, Guo LJ, Guo QN, Xiao H, Lyu X, Yu ZH

PMID: 28051032 [PubMed - indexed for MEDLINE]

Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms.

Sci Rep. 2016 Mar 10;6:22760

Authors: Asai T, Hatlen MA, Lossos C, Ndiaye-Lobry D, Deblasio A, Murata K, Fleisher M, Cortizas EM, Verdun RE, Petrini J, Nimer SD

Abstract
Multiple myeloma is a plasma cell neoplasm with an extremely variable clinical course. Animal models are needed to better understand its pathophysiology and for preclinical testing of potential therapeutic agents. Hematopoietic cells expressing the hypermorphic Rad50(s) allele show hematopoietic failure, which can be mitigated by the lack of a transcription factor, Mef/Elf4. However, we find that 70% of Mef(-/-)Rad50(s/s) mice die from multiple myeloma or other plasma cell neoplasms. These mice initially show an abnormal plasma cell proliferation and monoclonal protein production, and then develop anemia and a decreased bone mineral density. Tumor cells can be serially transplanted and according to array CGH and whole exome sequencing, the pathogenesis of plasma cell neoplasms in these mice is not linked to activation of a specific oncogene, or inactivation of a specific tumor suppressor. This model recapitulates the systemic manifestations of human plasma cell neoplasms, and implicates cooperativity between the Rad50(s) and Mef/Elf4 pathways in initiating myelomagenic mutations that promote plasma cell transformation.

PMID: 26961797 [PubMed - indexed for MEDLINE]