Similarities and Differences in Patterns of Germline Mutation Between Mice and Humans
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Next-Generation Sequencing for Identifying a Novel/De Novo
Martínez-Hernández et al. BMC Medical Genomics (2019) 12:68 https://doi.org/10.1186/s12920-019-0528-1 CASE REPORT Open Access Next-generation sequencing for identifying a novel/de novo pathogenic variant in a Mexican patient with cystic fibrosis: a case report Angélica Martínez-Hernández1, Julieta Larrosa2, Francisco Barajas-Olmos1, Humberto García-Ortíz1, Elvia C. Mendoza-Caamal3, Cecilia Contreras-Cubas1, Elaheh Mirzaeicheshmeh1, José Luis Lezana4 and Lorena Orozco1* Abstract Background: Mexico is among the countries showing the highest heterogeneity of CFTR variants. However, no de novo variants have previously been reported in Mexican patients with cystic fibrosis (CF). Case presentation: Here, we report the first case of a novel/de novo variant in a Mexican patient with CF. Our patient was an 8-year-old male who had exhibited the clinical onset of CF at one month of age, with steatorrhea, malabsorption, poor weight gain, anemia, and recurrent respiratory tract infections. Complete sequencing of the CFTR gene by next generation sequencing (NGS) revealed two different variants in trans, including the previously reported CF-causing variant c.3266G > A (p.Trp1089*, W1089*), that was inherited from the mother, and the novel/ de novo CFTR variant c.1762G > T (p.Glu588*). Conclusion: Our results demonstrate the efficiency of targeted NGS for making a rapid and precise diagnosis in patients with clinically suspected CF. This method can enable the provision of accurate genetic counselling, and improve our understanding of the molecular basis of genetic diseases. Keywords: Cystic fibrosis, Next generation sequencing, P.Trp1089*, P.Glu588*, Novel/de novo variant Background been detected, with the deletion of phenylalanine at pos- Cystic fibrosis (CF, MIM# 219700) is the most common ition 508 (c.1521_1523delCTT, p.Phe508del, F508del) autosomal recessive disorder among Caucasians. -
Gene Therapy Glossary of Terms
GENE THERAPY GLOSSARY OF TERMS A • Phase 3: A phase of research to describe clinical trials • Allele: one of two or more alternative forms of a gene that that gather more information about a drug’s safety and arise by mutation and are found at the same place on a effectiveness by studying different populations and chromosome. different dosages and by using the drug in combination • Adeno-Associated Virus: A single stranded DNA virus that has with other drugs. These studies typically involve more not been found to cause disease in humans. This type of virus participants.7 is the most frequently used in gene therapy.1 • Phase 4: A phase of research to describe clinical trials • Adenovirus: A member of a family of viruses that can cause occurring after FDA has approved a drug for marketing. infections in the respiratory tract, eye, and gastrointestinal They include post market requirement and commitment tract. studies that are required of or agreed to by the study • Adeno-Associated Virus Vector: Adeno viruses used as sponsor. These trials gather additional information about a vehicles for genes, whose core genetic material has been drug’s safety, efficacy, or optimal use.8 removed and replaced by the FVIII- or FIX-gene • Codon: a sequence of three nucleotides in DNA or RNA • Amino Acids: building block of a protein that gives instructions to add a specific amino acid to an • Antibody: a protein produced by immune cells called B-cells elongating protein in response to a foreign molecule; acts by binding to the • CRISPR: a family of DNA sequences that can be cleaved by molecule and often making it inactive or targeting it for specific enzymes, and therefore serve as a guide to cut out destruction and insert genes. -
Human Germline Genome Editing: Fact Sheet
Human germline genome editing: fact sheet Purpose • To contribute to evidence-informed discussions about human germline genome editing. KEY TAKEAWAYS • Gene editing offers the potential to improve human health in ways not previously possible. • Making changes to human genes that can be passed on to future generations is prohibited in Australia. • Unresolved questions remain on the possible long-term impacts, unintended consequences, and ethical issues associated with introducing heritable changes by editing of the genome of human gametes (sperm and eggs) and embryos. • AusBiotech believes the focus of human gene editing should remain on non-inheritable changes until such time as the scientific evidence, regulatory frameworks and health care models have progressed sufficiently to warrant consideration of any heritable genetic edits. Gene editing Gene editing is the insertion, deletion, or modification of DNA to modify an organism’s specific genetic characteristics. New and evolving gene editing techniques and tools (e.g. CRISPR) allow editing of genes with a level of precision that increases its applications across the health, agricultural, and industrial sectors. These breakthrough techniques potentially offer a range of different options for treating devastating human diseases and delivering environmentally sustainable food production systems that can feed the world’s growing population, which is expected to exceed nine billion by 2050. The current primary application of human gene editing is on non-reproductive cells (‘somatic’ cells) -
Multi-Omics Analysis Defines Core Genomic Alterations in Pheochromocytomas and Paragangliomas
ARTICLE Received 11 Aug 2014 | Accepted 5 Dec 2014 | Published 27 Jan 2015 DOI: 10.1038/ncomms7044 OPEN Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas Luis Jaime Castro-Vega1,2,*, Eric Letouze´3,*, Nelly Burnichon1,2,4,*, Alexandre Buffet1,2,4, Pierre-He´lie Disderot1,2, Emmanuel Khalifa1,2,4,Ce´line Loriot1,2, Nabila Elarouci3, Aure´lie Morin1,2,Me´lanie Menara1,2, Charlotte Lepoutre-Lussey1,2,5,Ce´cile Badoual1,2,6, Mathilde Sibony2,7, Bertrand Dousset2,8,9,10, Rossella Libe´2,9,10,11,12, Franck Zinzindohoue2,13, Pierre Franc¸ois Plouin1,2,5,12,Je´roˆme Bertherat2,9,10,11,12, Laurence Amar1,2,5, Aure´lien de Reynie`s3, Judith Favier1,2,y & Anne-Paule Gimenez-Roqueplo1,2,4,12,y Pheochromocytomas and paragangliomas (PCCs/PGLs) are neural crest-derived tumours with a very strong genetic component. Here we report the first integrated genomic examination of a large collection of PCC/PGL. SNP array analysis reveals distinct copy-number patterns associated with genetic background. Whole-exome sequencing shows a low mutation rate of 0.3 mutations per megabase, with few recurrent somatic mutations in genes not previously associated with PCC/PGL. DNA methylation arrays and miRNA sequencing identify DNA methylation changes and miRNA expression clusters strongly associated with messenger RNA expression profiling. Overexpression of the miRNA cluster 182/96/183 is specific in SDHB-mutated tumours and induces malignant traits, whereas silencing of the imprinted DLK1-MEG3 miRNA cluster appears as a potential driver in a subgroup of sporadic tumours. -
High-Efficiency CRISPR/Cas9 Mutagenesis of the White Gene in the Milkweed Bug Oncopeltus Fasciatus
| INVESTIGATION High-Efficiency CRISPR/Cas9 Mutagenesis of the white Gene in the Milkweed Bug Oncopeltus fasciatus Katie Reding and Leslie Pick1 Department of Entomology, University of Maryland, College Park, Maryland 20742 ORCID IDs: 0000-0003-2067-4232 (K.R.); 0000-0002-4505-5107 (L.P.) ABSTRACT In this manuscript, we report that clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 is highly efficient in the hemipteran Oncopeltus fasciatus. The white gene is well characterized in Drosophila where mutation causes loss of eye pigmentation; white is a reliable marker for transgenesis and other genetic manipulations. Accordingly, white has been targeted in a number of nonmodel insects to establish tools for genetic studies. Here, we generated mutations in the Of-white (Of-w) locus using CRISPR/Cas9. We found that Of-w is required for pigmentation throughout the body of Oncopeltus, not just the ommatidia. High rates of somatic mosaicism were observed in the injected generation, reflecting biallelic mutations, and a high rate of germline mutation was evidenced by the large proportion of heterozygous G1s. However, Of-w mutations are homozygous lethal; G2 homozygotes lacked pigment dispersion throughout the body and did not hatch, precluding the establishment of a stable mutant line. Embryonic and parental RNA interference (RNAi) were subsequently performed to rule out off-target mutations producing the observed phenotype and to evaluate the efficacy of RNAi in ablating gene function compared to a loss-of-function mutation. RNAi knockdowns phe- nocopied Of-w homozygotes, with an unusual accumulation of orange granules observed in unhatched embryos. This is, to our knowledge, the first CRISPR/Cas9-targeted mutation generated in Oncopeltus. -
Cfdna Deconvolution Via NIPT of a Pregnant Woman After Bone Marrow
Zhu et al. Human Genomics (2021) 15:14 https://doi.org/10.1186/s40246-021-00311-w PRIMARY RESEARCH Open Access cfDNA deconvolution via NIPT of a pregnant woman after bone marrow transplant and donor egg IVF Jianjiang Zhu1 , Feng Hui2, Xuequn Mao1, Shaoqin Zhang1, Hong Qi1* and Yang Du2* Abstract Cell-free DNA is known to be a mixture of DNA fragments originating from various tissue types and organs of the human body and can be utilized for several clinical applications and potentially more to be created. Non-invasive prenatal testing (NIPT), by high throughput sequencing of cell-free DNA (cfDNA), has been successfully applied in the clinical screening of fetal chromosomal aneuploidies, with more extended coverage under active research. In this study, via a quite unique and rare NIPT sample, who has undergone both bone marrow transplant and donor egg IVF, we investigated the sources of oddness observed in the NIPT result using a combination of molecular genetics and genomic methods and eventually had the case fully resolved. Along the process, we devised a clinically viable process to dissect the sample mixture. Eventually, we used the proposed scheme to evaluate the relatedness of individuals and the demultiplexed sample components following modified population genetics concepts, exemplifying a noninvasive prenatal paternity test prototype. For NIPT specific applicational concern, more thorough and detailed clinical information should therefore be collected prior to cfDNA-based screening procedure like NIPT and systematically reviewed when an abnormal report is obtained to improve genetic counseling and overall patient care. Keywords: NIPT, Target sequencing, Fetal fraction, IVF, Transplant, Prenatal diagnostic Introduction establishment of circulating tumor DNA (ctDNA) in the Cell-free DNA (cfDNA) is known to be a mixture from plasma of cancer patients [4]. -
Genetic Testing for Reproductive Carrier Screening and Prenatal Diagnosis
Medical Coverage Policy Effective Date ............................................. 7/15/2021 Next Review Date ......................................12/15/2021 Coverage Policy Number .................................. 0514 Genetic Testing for Reproductive Carrier Screening and Prenatal Diagnosis Table of Contents Related Coverage Resources Overview ........................................................ 2 Genetics Coverage Policy ............................................ 2 Genetic Testing Collateral File Genetic Counseling ...................................... 2 Recurrent Pregnancy Loss: Diagnosis and Treatment Germline Carrier Testing for Familial Infertility Services Disease .......................................................... 3 Preimplantation Genetic Testing of an Embryo........................................................... 4 Preimplantation Genetic Testing (PGT-A) .. 5 Sequencing–Based Non-Invasive Prenatal Testing (NIPT) ............................................... 5 Invasive Prenatal Testing of a Fetus .......... 6 Germline Mutation Reproductive Genetic Testing for Recurrent Pregnancy Loss ...... 6 Germline Mutation Reproductive Genetic Testing for Infertility ..................................... 7 General Background .................................... 8 Genetic Counseling ...................................... 8 Germline Genetic Testing ............................ 8 Carrier Testing for Familial Disease ........... 8 Preimplantation Genetic Testing of an Embryo.......................................................... -
The Genetic Complexity of Prostate Cancer
G C A T T A C G G C A T genes Review The Genetic Complexity of Prostate Cancer Eva Compérat 1,2,3,*, Gabriel Wasinger 3 , André Oszwald 3 , Renate Kain 3 , Geraldine Cancel-Tassin 1 and Olivier Cussenot 1,4 1 CeRePP/GRC5 Predictive Onco-Urology, Sorbonne University, 75020 Paris, France; [email protected] (G.C.-T.); [email protected] (O.C.) 2 Department of Pathology, Hôpital Tenon, Sorbonne University, 75020 Paris, France 3 Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria; [email protected] (G.W.); [email protected] (A.O.); [email protected] (R.K.) 4 Department of Urology, Hôpital Tenon, Sorbonne University, 75020 Paris, France * Correspondence: [email protected]; Tel.: +33-658246024 Received: 28 September 2020; Accepted: 23 November 2020; Published: 25 November 2020 Abstract: Prostate cancer (PCa) is a major concern in public health, with many genetically distinct subsets. Genomic alterations in PCa are extraordinarily complex, and both germline and somatic mutations are of great importance in the development of this tumor. The aim of this review is to provide an overview of genetic changes that can occur in the development of PCa and their role in potential therapeutic approaches. Various pathways and mechanisms proposed to play major roles in PCa are described in detail to provide an overview of current knowledge. Keywords: prostate cancer; germline mutations; somatic mutations; PTEN; TMPRSS2; ERG; androgen receptors 1. Introduction Prostate cancer (PCa) is a major concern in public health, with more than 1.1 million cases worldwide detected every year [1]. -
A Germline Or De Novo Mutation in Two Families with Gaucher Disease: Implications for Recessive Disorders
European Journal of Human Genetics (2013) 21, 115–117 & 2013 Macmillan Publishers Limited All rights reserved 1018-4813/13 www.nature.com/ejhg SHORT REPORT A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders Hamid Saranjam1, Sameer S Chopra2,3, Harvey Levy3, Barbara K Stubblefield1, Emerson Maniwang1, Ian J Cohen4,5, Hagit Baris4,5, Ellen Sidransky*,1 and Nahid Tayebi1 Gaucher disease (GD) is an autosomal recessive storage disorder that most commonly results from the inheritance of one identifiable mutant glucocerebrosidase (GBA1) allele from each parent. Here, we report two cases of type 2 GD resulting from the inheritance of one identifiable paternal mutant allele and one allele that likely resulted from a maternal germline mutation. Germline mutations or mosiacism are not generally associated with autosomal recessive disorders. The probands from the two unrelated families had the same maternal mutation, leu444pro, that we propose resulted from a de novo maternal germline mutation occurring at this known ‘hotspot’ for mutation. This first report of a germline mutation for a common point mutation leu444pro (c.1448 T4C;p.leu483pro) in GD has significant implications for molecular diagnostics and genetic counseling in recessive disorders. European Journal of Human Genetics (2013) 21, 115–117; doi:10.1038/ejhg.2012.105; published online 20 June 2012 Keywords: acute neuronopathic Gaucher disease; glucocerebrosidase; germline mutation; DNA mutational analysis; molecular diagnostic INTRODUCTION However, in both cases, the second mutant allele, leu444pro, was Gaucher disease (GD), the most common lysosomal storage disorder, not detected in the mother. This prompted us to explore whether the results from the autosomal recessively inherited deficiency of gluco- leu444pro mutation might have resulted from a maternal germline cerebrosidase (GCase, EC 3.2.1.45).1,2 GD is subdivided into three mutation in these families. -
Pedigree-Based and Phylogenetic Methods Support Surprising Patterns of Mutation Rate and Spectrum in the Gray Mouse Lemur
www.nature.com/hdy ARTICLE Pedigree-based and phylogenetic methods support surprising patterns of mutation rate and spectrum in the gray mouse lemur 1,2,8 1,8 1 1,6 1,7 3 C. Ryan Campbell , George P. Tiley , Jelmer W. Poelstra✉ , Kelsie E. Hunnicutt , Peter A. Larsen , Hui-Jie Lee , Jeffrey L. Thorne4, Mario dos Reis 5 and Anne D. Yoder1 © The Author(s), under exclusive licence to The Genetics Society 2021 Mutations are the raw material on which evolution acts, and knowledge of their frequency and genomic distribution is crucial for understanding how evolution operates at both long and short timescales. At present, the rate and spectrum of de novo mutations have been directly characterized in relatively few lineages. Our study provides the first direct mutation-rate estimate for a strepsirrhine (i.e., the lemurs and lorises), which comprises nearly half of the primate clade. Using high-coverage linked-read sequencing for a focal quartet of gray mouse lemurs (Microcebus murinus), we estimated the mutation rate to be among the highest calculated for a mammal at 1.52 × 10–8 (95% credible interval: 1.28 × 10−8–1.78 × 10−8) mutations/site/generation. Further, we found an unexpectedly low count of paternal mutations, and only a modest overrepresentation of mutations at CpG sites. Despite the surprising nature of these results, we found both the rate and spectrum to be robust to the manipulation of a wide range of computational filtering criteria. We also sequenced a technical replicate to estimate a false-negative and false-positive rate for our data and show that any point estimate of a de novo mutation rate should be considered with a large degree of uncertainty. -
The Male Germline-Specific Protein MAPS Is Indispensable for Pachynema Progression and Fertility
The male germline-specific protein MAPS is indispensable for pachynema progression and fertility Miao Lia,b, Jiahuan Zhenga,b, Gaopeng Lic, Zexiong Lina, Dongliang Lia, Dongteng Liua,b, Haiwei Fenga,b, Dandan Caoa, Ernest H. Y. Nga,b, Raymond H. W. Lia,b, Chunsheng Hand,e,f, William S. B. Yeunga,b, Louise T. Chowc,1, Hengbin Wangc,1, and Kui Liua,b,1 aShenzhen Key Laboratory of Fertility Regulation, Center of Assisted Reproduction and Embryology, The University of Hong Kong–Shenzhen Hospital, 518053 Shenzhen, Guangdong, China; bDepartment of Obstetrics and Gynecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; cDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024; dState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China; eInstitute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101 Beijing, China; and fUniversity of Chinese Academy of Sciences, Chinese Academy of Sciences, 100049 Beijing, China Contributed by Louise T. Chow, January 12, 2021 (sent for review December 10, 2020; reviewed by Anders Hofer, Kazuhiro Kawamura, and Mingxi Liu) Meiosis is a specialized cell division that creates haploid germ cells to transient transcriptional silencing in a process termed meiotic from diploid progenitors. Through differential RNA expression sex chromosome inactivation (MSCI) (6, 7). analyses, we previously identified a number of mouse genes that Over the past decades, the underlying molecular aspects of were dramatically elevated in spermatocytes, relative to their very meiosis prophase I have been widely studied. Various mutant low expression in spermatogonia and somatic organs. -
Guide to Interpreting Genomic Reports: a Genomics Toolkit
Guide to Interpreting Genomic Reports: A Genomics Toolkit A guide to genomic test results for non-genetics providers Created by the Practitioner Education Working Group of the Clinical Sequencing Exploratory Research (CSER) Consortium Genomic Report Toolkit Authors Kelly East, MS, CGC, Wendy Chung MD, PhD, Kate Foreman, MS, CGC, Mari Gilmore, MS, CGC, Michele Gornick, PhD, Lucia Hindorff, PhD, Tia Kauffman, MPH, Donna Messersmith , PhD, Cindy Prows, MSN, APRN, CNS, Elena Stoffel, MD, Joon-Ho Yu, MPh, PhD and Sharon Plon, MD, PhD About this resource This resource was created by a team of genomic testing experts. It is designed to help non-geneticist healthcare providers to understand genomic medicine and genome sequencing. The CSER Consortium1 is an NIH-funded group exploring genomic testing in clinical settings. Acknowledgements This work was conducted as part of the Clinical Sequencing Exploratory Research (CSER) Consortium, grants U01 HG006485, U01 HG006485, U01 HG006546, U01 HG006492, UM1 HG007301, UM1 HG007292, UM1 HG006508, U01 HG006487, U01 HG006507, R01 HG006618, and U01 HG007307. Special thanks to Alexandria Wyatt and Hugo O’Campo for graphic design and layout, Jill Pope for technical editing, and the entire CSER Practitioner Education Working Group for their time, energy, and support in developing this resource. Contents 1 Introduction and Overview ................................................................ 3 2 Diagnostic Results Related to Patient Symptoms: Pathogenic and Likely Pathogenic Variants . 8 3 Uncertain Results