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Afshin Shirkani, Mohammad Shahrooei, Gholamreza Azizi, Hassan Rokni-Zadeh, Hassan Abolhassani, Shokrollah Farrokhi, Glynis Frans, Xavier Bossuyt, Asghar Aghamohammadi
ZAP-70 deficiency is a rare autosomal recessive form of combined immunodeficiency (CID) characterized by selective absence of circulating CD8 T cells with low, normal, or increased CD4 T cells in peripheral blood. Up to now, 14 unique mutations in the ZAP70 gene have been identified in patients with ZAP-70-related CID. We present a 3-year-old boy with a history of recurrent bacterial infections and autoimmunity. Initial laboratory findings showed a normal total lymphocyte count, but low levels of CD8 and CD4 T cells and an abnormal lymphocyte proliferation response...
October 19, 2016: Immunological Investigations
Dennis Wang, Nhu-An Pham, Jiefei Tong, Shingo Sakashita, Ghassan Allo, Lucia Kim, Naoki Yanagawa, Vibha Raghavan, Yuhong Wei, Christine To, Quang M Trinh, Maud H W Starmans, Michelle A Chan-Seng-Yue, Dianne Chadwick, Lei Li, Chang-Qi Zhu, Ni Liu, Ming Li, Sharon Lee, Vladimir Ignatchenko, Dan Strumpf, Paul Taylor, Nadeem Moghal, Geoffrey Liu, Paul C Boutros, Thomas Kislinger, Melania Pintilie, Igor Jurisica, Frances A Shepherd, John D McPherson, Lakshmi Muthuswamy, Michael F Moran, Ming-Sound Tsao
Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient-derived tumor xenograft (PDX) resource from surgically resected non-small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non-obese severe combined immune deficient (NOD SCID) gamma mice...
October 17, 2016: International Journal of Cancer. Journal International du Cancer
Linda M Slot, Robbert Hoogeboom, Laura A Smit, Thera A M Wormhoudt, Bart J Biemond, Monique E C M Oud, Esther J M Schilder-Tol, André B Mulder, Aldo Jongejan, Antoine H C van Kampen, Philip M Kluin, Jeroen E J Guikema, Richard J Bende, Carel J M van Noesel
Follicular lymphoma (FL) is an indolent B-cell non-Hodgkin lymphoma able to transform into germinal center-type diffuse large B-cell lymphoma. We describe four extraordinary cases of FL, which progressed to TdT(+)CD20(-) precursor B-lymphoblastic lymphoma (B-LBL). Fluorescence in situ hybridization analysis showed that all four B-LBLs had acquired a MYC translocation on transformation. Comparative genomic hybridization analysis of one case demonstrated that in addition to 26 numerical aberrations that were shared between the FL and B-LBL, deletion of CDKN2A/B and 17q11, 14q32 amplification, and copy-neutral loss of heterozygosity of 9p were gained in the B-LBL cells...
October 14, 2016: American Journal of Pathology
David S Lynch, Wei Jia Zhang, Rahul Lakshmanan, Justin A Kinsella, Günes Altiokka Uzun, Merih Karbay, Zeynep Tüfekçioglu, Hasmet Hanagasi, Georgina Burke, Nicola Foulds, Simon R Hammans, Anupam Bhattacharjee, Heather Wilson, Matthew Adams, Mark Walker, James A R Nicoll, Jeremy Chataway, Nick Fox, Indran Davagnanam, Rahul Phadke, Henry Houlden
Importance: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations...
October 17, 2016: JAMA Neurology
Amit R Majithia, Ben Tsuda, Maura Agostini, Keerthana Gnanapradeepan, Robert Rice, Gina Peloso, Kashyap A Patel, Xiaolan Zhang, Marjoleine F Broekema, Nick Patterson, Marc Duby, Ted Sharpe, Eric Kalkhoven, Evan D Rosen, Inês Barroso, Sian Ellard, Sekar Kathiresan, Stephen O'Rahilly, Krishna Chatterjee, Jose C Florez, Tarjei Mikkelsen, David B Savage, David Altshuler
Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions...
October 17, 2016: Nature Genetics
Bishoy M Faltas, Davide Prandi, Scott T Tagawa, Ana M Molina, David M Nanus, Cora Sternberg, Jonathan Rosenberg, Juan Miguel Mosquera, Brian Robinson, Olivier Elemento, Andrea Sboner, Himisha Beltran, Francesca Demichelis, Mark A Rubin
Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime...
October 17, 2016: Nature Genetics
Jia-Jie Hao, De-Chen Lin, Huy Q Dinh, Anand Mayakonda, Yan-Yi Jiang, Chen Chang, Ye Jiang, Chen-Chen Lu, Zhi-Zhou Shi, Xin Xu, Yu Zhang, Yan Cai, Jin-Wu Wang, Qi-Min Zhan, Wen-Qiang Wei, Benjamin P Berman, Ming-Rong Wang, H Phillip Koeffler
Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others...
October 17, 2016: Nature Genetics
Yael Haberman, Ayelet Di Segni, Nurit Loberman-Nachum, Ortal Barel, Vered Kunik, Eran Eyal, Nitzan Kol, Goni Hout-Siloni, Brigitte Kochavi, Camila Avivi, Michael Schvimer, Gideon Rechavi, Yair Anikster, Iris Barshack, Batia Weiss
OBJECTIVES: Congenital chronic diarrhea (CCD) is a group of inherited enteropathies presenting in early life and requiring parenteral nutrition. In most cases, genetics may be the key for precise diagnosis. We present an infant girl with CCD that resolved after introduction of fructose-based formula but had no identified mutation in the SLC5A1 gene. Using whole exome sequencing (WES) we identified other mutations that better dictated dietary adjustments. METHODS: WES of the patient and her parents was performed...
October 4, 2016: Journal of Pediatric Gastroenterology and Nutrition
Anna Maria Pinto, Valentina Imperatore, Laura Bianciardi, Margherita Baldassarri, Paolo Galluzzi, Simone Furini, Giovanni Centini, Alessandra Renieri, Francesca Mari
Orofacial clefts are the most common congenital craniofacial anomalies and can occur as an isolated defect or be associated with other anomalies such as posterior fossa anomalies as a part of several genetic syndromes. We report two consecutive voluntary pregnancy interruptions in a nonconsanguineous couple following the fetal ultrasound finding of cleft lip and palate and posterior fossa anomalies confirmed by means of post-termination examination on the second fetus. The quantitative fluorescent PCR, the karyotype, and the comparative genomic hybridization-array analysis after amniocentesis were normal...
October 4, 2016: Clinical Dysmorphology
Youn Hee Jee, Nadine Sowada, Thomas C Markello, Iraj Rezvani, Guntram Borck, Jeffrey Baron
Linear growth failure can be caused by many different genetic abnormalities. In many cases, the genetic defect affects not only the growth plate, causing short stature, but also other organs/tissues causing additional clinical abnormalities. The proband was evaluated at 10 years of age for impaired postnatal linear growth (height 113.3 cm, -4.6 SDS), a bone age that was delayed by 5 years, dysmorphic facies, cognitive impairment, and central nervous system anomalies. His younger brother, presented only with growth failure at 10 months of age...
October 17, 2016: Clinical Genetics
Jiali Li, Xueshan Xiao, Shiqiang Li, Xiaoyun Jia, Xiangming Guo, Qingjiong Zhang
It has been previously reported that mutations in retinal G protein coupled receptor (RGR) are associated with retinitis pigmentosa. The present study aims to systemically analyze the potential role of variants of RGR in retinal diseases. Variants in coding regions and splice sites of RGR were selected from a whole exome sequencing dataset of 820 probands with various forms of genetic ocular diseases. Potential variants of RGR were further confirmed by Sanger sequencing and analyzed in available family members...
October 13, 2016: Molecular Medicine Reports
Farah R Zahir, Tracy Tucker, Sonia Mayo, Carolyn J Brown, Emilia L Lim, Jonathan Taylor, Marco A Marra, Fadi F Hamdan, Jacques L Michaud, Jan M Friedman
The disruption of genes involved in epigenetic regulation is well known to cause Intellectual Disability (ID). We reported a custom microarray study that interrogated among others, the epigenetic regulatory gene-class, at single exon resolution. Here we elaborate on identified intragenic CNVs involving epigenetic regulatory genes; specifically discussing those in three genes previously unreported in ID etiology-ARID2, KDM3A, and ARID4B. The changes in ARID2 and KDM3A are likely pathogenic while the ARID4B variant is uncertain...
November 2016: American Journal of Medical Genetics. Part A
Hanna Mandel, Morad Khayat, Elana Chervinsky, Orly Elpeleg, Stavit Shalev
There is a significant level of genetic heterogeneity underlying the phenotype of nonspecific hypotonia with severe intellectual disability. Exome sequencing has proven to be a powerful tool for identifying the underlying molecular basis of such nonspecific, abnormal neurological phenotypes. Mutations in the TBCK gene have been reported associated with very poor, if any, psychomotor development, poor speech, and inability to walk independently. We describe the long-term phenotypic evolution of a severe nonspecific neurodevelopmental disorder in two siblings born to an Arab-Moslem family living in northern Israel...
October 17, 2016: American Journal of Medical Genetics. Part A
Samara L Potter, Rajkumar Venkatramani, Scott Wenderfer, Brett H Graham, Sanjeev A Vasudevan, Andrew Sher, Hao Wu, David A Wheeler, Yaping Yang, Christine M Eng, Richard A Gibbs, Angshumoy Roy, Sharon E Plon, D Williams Parsons
Pediatric renal cell carcinoma (RCC) is a rare cancer that can be associated with inherited diseases including tuberous sclerosis complex (TSC) caused by germline mutations in TSC1 or TSC2. Somatic mutations in TSC1 and TSC2 have also been reported in adult RCC, which predict response to mTOR inhibitors. Here, we present the first case of RCC in a child with methylmalonic acidemia (MMA). Clinical whole exome sequencing of blood and tumor samples confirmed the diagnosis of MMA and revealed two somatic inactivating mutations in TSC2, suggesting the potential consideration of an mTOR inhibitor in the event of tumor recurrence...
October 17, 2016: Pediatric Blood & Cancer
Tasuku Suzuki, Yoji Sasahara, Atsuo Kikuchi, Humihiko Kakuta, Toshihiko Kashiwabara, Takashi Ishige, Yoshiko Nakayama, Masanori Tanaka, Akihiro Hoshino, Hirokazu Kanegane, Daiki Abukawa, Shigeo Kure
PURPOSE: Pediatric inflammatory bowel disease (IBD) is a heterogeneous disorder caused by multiple factors. Although genetic and immunological analyses are required for a definitive diagnosis, no reports of a comprehensive genetic study of a Japanese population are available. METHODS: In total, 35 Japanese patients <16 years of age suffering from IBD, including 27 patients aged <6 years with very early-onset IBD, were enrolled in this multicenter study. Exome and targeted gene panel sequencing was performed for all patients...
October 17, 2016: Journal of Clinical Immunology
Najaf Amin, Nadezhda M Belonogova, Olivera Jovanova, Rutger W W Brouwer, Jeroen G J van Rooij, Mirjam C G N van den Hout, Gulnara R Svishcheva, Robert Kraaij, Irina V Zorkoltseva, Anatoly V Kirichenko, Albert Hofman, André G Uitterlinden, Wilfred F J van IJcken, Henning Tiemeier, Tatiana I Axenovich, Cornelia M van Duijn
BACKGROUND: Despite high heritability, little success was achieved in mapping genetic determinants of depression-related traits by means of genome-wide association studies. METHODS: To identify genes associated with depressive symptomology, we performed a gene-based association analysis of nonsynonymous variation captured using exome-sequencing and exome-chip genotyping in a genetically isolated population from the Netherlands (n = 1999). Finally, we reproduced our significant findings in an independent population-based cohort (n = 1604)...
August 11, 2016: Biological Psychiatry
Luca Bello, Kevin M Flanigan, Robert B Weiss, Pietro Spitali, Annemieke Aartsma-Rus, Francesco Muntoni, Irina Zaharieva, Alessandra Ferlini, Eugenio Mercuri, Sylvie Tuffery-Giraud, Mireille Claustres, Volker Straub, Hanns Lochmüller, Andrea Barp, Sara Vianello, Elena Pegoraro, Jaya Punetha, Heather Gordish-Dressman, Mamta Giri, Craig M McDonald, Eric P Hoffman
The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers...
October 12, 2016: American Journal of Human Genetics
Wenqing Fu, Sharon R Browning, Brian L Browning, Joshua M Akey
Identifying and characterizing genomic regions that are shared identical by descent (IBD) among individuals can yield insight into population history, facilitate the identification of adaptively evolving loci, and be an important tool in disease gene mapping. Although increasingly large collections of exome sequences have been generated, it is challenging to detect IBD segments in exomes, precluding many potentially informative downstream analyses. Here, we describe an approach, ExIBD, to robustly detect IBD segments in exome-sequencing data, rigorously evaluate its performance, and apply this method to high-coverage exomes from 6,515 European and African Americans...
October 6, 2016: American Journal of Human Genetics
Bin Guan, James M Welch, Julie C Sapp, Hua Ling, Yulong Li, Jennifer J Johnston, Electron Kebebew, Leslie G Biesecker, William F Simonds, Stephen J Marx, Sunita K Agarwal
Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP...
October 13, 2016: American Journal of Human Genetics
Sirui Zhou, Amirthagowri Ambalavanan, Daniel Rochefort, Pingxing Xie, Cynthia V Bourassa, Pascale Hince, Alexandre Dionne-Laporte, Dan Spiegelman, Ziv Gan-Or, Cathy Mirarchi, Vessela Zaharieva, Nicolas Dupré, Hatasu Kobayashi, Toshiaki Hitomi, Kouji Harada, Akio Koizumi, Lan Xiong, Patrick A Dion, Guy A Rouleau
Intracranial aneurysms (IAs) are the result of focal weakness in the artery wall and have a complex genetic makeup. To date, genome-wide association and sequencing studies have had limited success in identifying IA risk factors. Distinct populations, such as the French-Canadian (FC) population, have increased IA prevalence. In our study, we used exome sequencing to prioritize risk variants in a discovery cohort of six FC families affected by IA, and the analysis revealed an increased variation burden for ring finger protein 213 (RNF213)...
September 30, 2016: American Journal of Human Genetics
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