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NPJ Genomic Medicine

Shicai Fan, Jianxiong Tang, Nan Li, Ying Zhao, Rizi Ai, Kai Zhang, Mengchi Wang, Wei Du, Wei Wang
The integration of genomic and DNA methylation data has been demonstrated as a powerful strategy in understanding cancer mechanisms and identifying therapeutic targets. The TCGA consortium has mapped DNA methylation in thousands of cancer samples using Illumina Infinium Human Methylation 450 K BeadChip (Illumina 450 K array) that only covers about 1.5% of CpGs in the human genome. Therefore, increasing the coverage of the DNA methylome would significantly leverage the usage of the TCGA data. Here, we present a new model called EAGLING that can expand the Illumina 450 K array data 18 times to cover about 30% of the CpGs in the human genome...
2019: NPJ Genomic Medicine
Claire S Leblond, Freddy Cliquet, Coralie Carton, Guillaume Huguet, Alexandre Mathieu, Thomas Kergrohen, Julien Buratti, Nathalie Lemière, Laurence Cuisset, Thierry Bienvenu, Anne Boland, Jean-François Deleuze, Tormodur Stora, Rannva Biskupstoe, Jónrit Halling, Guðrið Andorsdóttir, Eva Billstedt, Christopher Gillberg, Thomas Bourgeron
The number of genes associated with autism is increasing, but few studies have been performed on epidemiological cohorts and in isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 individuals with autism, 136 of their relatives and 185 non-autism controls. Data from SNP array and whole exome sequencing revealed that individuals with autism had a higher burden of rare exonic copy-number variants altering autism associated genes (deletions ( p   =  0.0352) or duplications ( p   =  0...
2019: NPJ Genomic Medicine
Musa AlHarbi, Nahla Mubarak, Latifa AlMubarak, Rasha Aljelaify, Mariam AlSaeed, Amal Almutairi, Weal AlJabarat, Fatimah Alqubaishi, Lamia Al-Subaie, Nada AlTassan, Cynthia L Neben, Alicia Y Zhou, Malak Abedalthagafi
Li-Fraumeni syndrome (LFS) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors at an early age. Approximately 70% of families with classic LFS have pathogenic variants in the tumor suppressor gene TP53 that disrupt protein function or stability. While more than 70% of pathogenic variants in TP53 are missense variants, the vast majority occur very infrequently, and thus their clinical significance is uncertain or conflicting. Here, we report an extremely rare TP53 missense variant, c...
2018: NPJ Genomic Medicine
Hindrek Teder, Mariann Koel, Priit Paluoja, Tatjana Jatsenko, Kadri Rekker, Triin Laisk-Podar, Viktorija Kukuškina, Agne Velthut-Meikas, Olga Fjodorova, Maire Peters, Juha Kere, Andres Salumets, Priit Palta, Kaarel Krjutškov
Targeted next-generation sequencing (NGS) methods have become essential in medical research and diagnostics. In addition to NGS sensitivity and high-throughput capacity, precise biomolecule counting based on unique molecular identifier (UMI) has potential to increase biomolecule detection accuracy. Although UMIs are widely used in basic research its introduction to clinical assays is still in progress. Here, we present a robust and cost-effective TAC-seq (Targeted Allele Counting by sequencing) method that uses UMIs to estimate the original molecule counts of mRNAs, microRNAs, and cell-free DNA...
2018: NPJ Genomic Medicine
Mark A Corbett, Clare L van Eyk, Dani L Webber, Stephen J Bent, Morgan Newman, Kelly Harper, Jesia G Berry, Dimitar N Azmanov, Karen J Woodward, Alison E Gardner, Jennie Slee, Luís A Pérez-Jurado, Alastair H MacLennan, Jozef Gecz
Cerebral palsy (CP) is the most frequent movement disorder of childhood affecting 1 in 500 live births in developed countries. We previously identified likely pathogenic de novo or inherited single nucleotide variants (SNV) in 14% (14/98) of trios by exome sequencing and a further 5% (9/182) from evidence of outlier gene expression using RNA sequencing. Here, we detected copy number variants (CNV) from exomes of 186 unrelated individuals with CP (including our original 98 trios) using the CoNIFER algorithm...
2018: NPJ Genomic Medicine
D Gareth Evans, Sacha J Howell, Ian M Frayling, Juha Peltonen
No abstract text is available yet for this article.
2018: NPJ Genomic Medicine
Cynthia Sanchez, Matthew W Snyder, Rita Tanos, Jay Shendure, Alain R Thierry
Circulating cell-free DNA (cfDNA) has received increasing interest as an apparent breakthrough approach in diagnostics, personalized medicine, and tumor biology. However, the structural features of cfDNA are poorly characterized. Specifically, the literature has discrepancies with regards to cfDNA size profile. We performed a blinded study of the distribution of cfDNA fragment sizes in cancer patient plasma ( n  = 11), by various ultra-deep-sequencing approaches and quantitative PCR (Q-PCR). Whole-genome sequencing of single-stranded DNA library preparation (SSP-S) revealed that nearly half of the total cfDNA fragment number are below 120 nucleotides, which are not readily detectable by standard double-stranded DNA library preparation (DSP) protocols...
2018: NPJ Genomic Medicine
Sock Hoai Chan, Winston Chew, Nur Diana Binte Ishak, Weng Khong Lim, Shao-Tzu Li, Sheng Hui Tan, Jing Xian Teo, Tarryn Shaw, Kenneth Chang, Yong Chen, Prasad Iyer, Enrica Ee Kar Tan, Michaela Su-Fern Seng, Mei Yoke Chan, Ah Moy Tan, Sharon Yin Yee Low, Shui Yen Soh, Amos Hong Pheng Loh, Joanne Ngeow
Assessment of cancer predisposition syndromes (CPS) in childhood tumours is challenging to paediatric oncologists due to inconsistent recognizable clinical phenotypes and family histories, especially in cohorts with unknown prevalence of germline mutations. Screening checklists were developed to facilitate CPS detection in paediatric patients; however, their clinical value have yet been validated. Our study aims to assess the utility of clinical screening checklists validated by genetic sequencing in an Asian cohort of childhood tumours...
2018: NPJ Genomic Medicine
Rahul Gajbhiye, Jenny N Fung, Grant W Montgomery
Variation in reproductive lifespan and female fertility have implications for health, population size and ageing. Fertility declines well before general signs of menopause and is also adversely affected by common reproductive diseases, including polycystic ovarian syndrome (PCOS) and endometriosis. Understanding the factors that regulate the timing of puberty and menopause, and the relationships with fertility are important for individuals and for policy. Substantial genetic variation exists for common traits associated with reproductive lifespan and for common diseases influencing female fertility...
2018: NPJ Genomic Medicine
Frank Luh, Yun Yen
No abstract text is available yet for this article.
2018: NPJ Genomic Medicine
Ny Hoang, Janet A Buchanan, Stephen W Scherer
No abstract text is available yet for this article.
2018: NPJ Genomic Medicine
Gouri Mukerjee, Andrea Huston, Boyko Kabakchiev, Micheline Piquette-Miller, Ron van Schaik, Ruslan Dorfman
Pharmacogenomic (PGx) testing is gaining recognition from physicians, pharmacists and patients as a tool for evidence-based medication management. However, seemingly similar PGx testing panels (and PGx-based decision support tools) can diverge in their technological specifications, as well as the genetic factors that determine test specificity and sensitivity, and hence offer different values for users. Reluctance to embrace PGx testing is often the result of unfamiliarity with PGx technology, a lack of knowledge about the availability of curated guidelines/evidence for drug dosing recommendations, and an absence of wide-spread institutional implementation efforts and educational support...
2018: NPJ Genomic Medicine
Bhupesh K Prusty, Nitish Gulve, Suvagata Roy Chowdhury, Michael Schuster, Sebastian Strempel, Vincent Descamps, Thomas Rudel
Human herpesvirus 6A and 6B frequently acquires latency. HHV-6 activation has been associated with various human diseases. Germ line inheritance of chromosomally integrated HHV-6 makes viral DNA-based analysis difficult for determination of early stages of viral activation. We characterized early stages of HHV-6 activation using high throughput transcriptomics studies and applied the results to understand virus activation under clinical conditions. Using a latent HHV-6A cell culture model in U2OS cells, we identified an early stage of viral reactivation, which we define as transactivation that is marked by transcription of several viral small non-coding RNAs (sncRNAs) in the absence of detectable increase in viral replication and proteome...
2018: NPJ Genomic Medicine
Jean Xavier, Bo Zhou, Frédéric Bilan, Xianglong Zhang, Brigitte Gilbert-Dussardier, Sylvie Viaux-Savelon, Reenal Pattni, Steve S Ho, David Cohen, Douglas F Levinson, Alexander E Urban, Claudine Laurent-Levinson
Microduplication of chromosome 1q21.1 is observed in ~0.03% of adults. It has a highly variable, incompletely penetrant phenotype that can include intellectual disability, global developmental delay, specific learning disabilities, autism, schizophrenia, heart anomalies and dysmorphic features. We evaluated a 10-year-old-male with a 1q21.1 duplication by CGH microarray. He presented with major attention deficits, phonological dysphasia, poor fine motor skills, dysmorphia and mild autistic features, but not the typical macrocephaly...
2018: NPJ Genomic Medicine
Adi Ovadia, Nigel Sharfe, Cynthia Hawkins, Suzanne Laughlin, Chaim M Roifman
Signal transducer and activator of transcription 1 (STAT1) regulates multiple biological processes downstream of a variety of cytokine receptors in many cell types. Heterozygous gain-of-function (GOF) mutations in STAT1 have been associated with a diverse phenotype encompassing chronic mucocutaneous candidiasis (CMCC) and declining immunity. There is no clear correlation between STAT1 domain-specific mutations and phenotype, and it remains unclear why GOF mutations in STAT1 result in such a wide spectrum of clinical presentations...
2018: NPJ Genomic Medicine
Alireza Haghighi, Joel B Krier, Agnes Toth-Petroczy, Christopher A Cassa, Natasha Y Frank, Nikkola Carmichael, Elizabeth Fieg, Andrew Bjonnes, Anwoy Mohanty, Lauren C Briere, Sharyn Lincoln, Stephanie Lucia, Vandana A Gupta, Onuralp Söylemez, Sheila Sutti, Kameron Kooshesh, Haiyan Qiu, Christopher J Fay, Victoria Perroni, Jamie Valerius, Meredith Hanna, Alexander Frank, Jodie Ouahed, Scott B Snapper, Angeliki Pantazi, Sameer S Chopra, Ignaty Leshchiner, Nathan O Stitziel, Anna Feldweg, Michael Mannstadt, Joseph Loscalzo, David A Sweetser, Eric Liao, Joan M Stoler, Catherine B Nowak, Pedro A Sanchez-Lara, Ophir D Klein, Hazel Perry, Nikolaos A Patsopoulos, Soumya Raychaudhuri, Wolfram Goessling, Robert C Green, Christine E Seidman, Calum A MacRae, Shamil R Sunyaev, Richard L Maas, Dana Vuzman
Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan...
2018: NPJ Genomic Medicine
Haixia Zou, Qian Liu, Li Meng, Jingye Zhou, Chenxiao Da, Xikun Wu, Lichun Jiang, Jianyong Shou, Haiqing Hua
Insulin resistance is a pathophysiological hallmark of type 2 diabetes and nonalcoholic fatty liver disease. Under the condition of fat accumulation in the liver, suppression of hepatic glucose production by insulin is diminished. In order to gain deeper understanding of dysregulation of glucose production in metabolic diseases, in the present study, we performed an unbiased phenotypic screening in primary human hepatocytes to discover novel mechanisms that regulate gluconeogenesis in the presence of insulin...
2018: NPJ Genomic Medicine
Betsy E P Ostrander, Russell J Butterfield, Brent S Pedersen, Andrew J Farrell, Ryan M Layer, Alistair Ward, Chase Miller, Tonya DiSera, Francis M Filloux, Meghan S Candee, Tara Newcomb, Joshua L Bonkowsky, Gabor T Marth, Aaron R Quinlan
Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE...
2018: NPJ Genomic Medicine
Christopher Cy Mak, Gordon Kc Leung, Gary Tk Mok, Kit San Yeung, Wanling Yang, Cheuk-Wing Fung, Sophelia Hs Chan, So-Lun Lee, Ni-Chung Lee, Rolph Pfundt, Yu-Lung Lau, Brian Hy Chung
Currently, offering whole-exome sequencing (WES) via collaboration with an external laboratory is increasingly common. However, the receipt of a WES report can be merely the beginning of a continuing exploration process rather than the end of the diagnostic odyssey. The laboratory often does not have the information the physician has, and any discrepancies in variant interpretation must be addressed by a medical geneticist. In this study, we performed diagnostic WES of 104 patients with paediatric-onset genetic diseases...
2018: NPJ Genomic Medicine
Ben Lawrence, Cherie Blenkiron, Kate Parker, Peter Tsai, Sandra Fitzgerald, Paula Shields, Tamsin Robb, Mee Ling Yeong, Nicole Kramer, Sarah James, Mik Black, Vicky Fan, Nooriyah Poonawala, Patrick Yap, Esther Coats, Braden Woodhouse, Reena Ramsaroop, Masato Yozu, Bridget Robinson, Kimiora Henare, Jonathan Koea, Peter Johnston, Richard Carroll, Saxon Connor, Helen Morrin, Marianne Elston, Christopher Jackson, Papaarangi Reid, John Windsor, Andrew MacCormick, Richard Babor, Adam Bartlett, Dragan Damianovich, Nicholas Knowlton, Sean Grimmond, Michael Findlay, Cristin Print
Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome...
2018: NPJ Genomic Medicine
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