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  • Clinical impact of genomic testing in patients with suspected monogenic kidney disease
    Genet. Med. (IF 8.904) Pub Date : 2020-09-17
    Kushani Jayasinghe; Zornitza Stark; Peter G. Kerr; Clara Gaff; Melissa Martyn; John Whitlam; Belinda Creighton; Elizabeth Donaldson; Matthew Hunter; Anna Jarmolowicz; Lilian Johnstone; Emma Krzesinski; Sebastian Lunke; Elly Lynch; Kathleen Nicholls; Chirag Patel; Yael Prawer; Jessica Ryan; Emily J. See; Andrew Talbot; Alison Trainer; Rigan Tytherleigh; Giulia Valente; Mathew Wallis; Louise Wardrop;

    Purpose To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease. Methods We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia. Results ES identified a molecular diagnosis in

    更新日期:2020-09-18
  • Correction: Aminoacyl-tRNA synthetase deficiencies in search of common themes
    Genet. Med. (IF 8.904) Pub Date : 2020-09-15
    Sabine A. Fuchs; Imre F. Schene; Gautam Kok; Jurriaan M. Jansen; Peter G. J. Nikkels; Koen L. I. van Gassen; Suzanne W. J. Terheggen-Lagro; Saskia N. van der Crabben; Sanne E. Hoeks; Laetitia E. M. Niers; Nicole I. Wolf; Maaike C. de Vries; David A. Koolen; Roderick H. J. Houwen; Margot F. Mulder; Peter M. van Hasselt

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-09-15
  • Correction: DOORS syndrome and a recurrent truncating ATP6V1B2 variant
    Genet. Med. (IF 8.904) Pub Date : 2020-09-15
    Eliane Beauregard-Lacroix; Guillermo Pacheco-Cuellar; Norbert F. Ajeawung; Jessica Tardif; Klaus Dieterich; Tabib Dabir; Dina Vind-Kezunovic; Susan M. White; Denes Zadori; Claudia Castiglioni; Lisbeth Tranebjærg; Pernille Mathiesen Tørring; Ed Blair; Marzena Wisniewska; Maria Vittoria Camurri; Yolande van Bever; Sirinart Molidperee; Juliet Taylor; Alexandre Dionne-Laporte; Sanjay M. Sisodiya; Raoul

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-09-15
  • The NHGRI Short Course in Genomics: energizing genetics and genomics education in classrooms through direct engagement between educators and scientists
    Genet. Med. (IF 8.904) Pub Date : 2020-09-15
    Sarah M. Robbins; Christina R. Daulton; Belen Hurle; Carla Easter

    Purpose The National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH) recognizes an urgent need for educator resources on cutting edge scientific topics due to increased public interest in genetics and genomics. We developed a Short Course in Genomics (“Short Course”) to inspire new teaching materials through collaborative course development sessions and lectures,

    更新日期:2020-09-15
  • Clinical and psychological outcomes of receiving a variant of uncertain significance from multigene panel testing or genomic sequencing: a systematic review and meta-analysis
    Genet. Med. (IF 8.904) Pub Date : 2020-09-14
    Chloe Mighton; Salma Shickh; Elizabeth Uleryk; Petros Pechlivanoglou; Yvonne Bombard

    This study systematically reviewed and synthesized the literature on psychological and clinical outcomes of receiving a variant of uncertain significance (VUS) from multigene panel testing or genomic sequencing. MEDLINE and EMBASE were searched. Two reviewers screened studies and extracted data. Data were synthesized through meta-analysis and meta-aggregation. The search identified 4539 unique studies

    更新日期:2020-09-14
  • Genomic and sequence variants of protein kinase A regulatory subunit type 1β (PRKAR1B) in patients with adrenocortical disease and Cushing syndrome
    Genet. Med. (IF 8.904) Pub Date : 2020-09-08
    Ludivine Drougat; Nikolaos Settas; Cristina L. Ronchi; Kerstin Bathon; Davide Calebiro; Andrea Gutierrez Maria; Sara Haydar; Antonios Voutetakis; Edra London; Fabio R. Faucz; Constantine A. Stratakis

    Purpose Protein kinase A (PKA) subunit defects (in PRKAR1A and PRKACA) are known to contribute to adrenal tumor pathogenesis. We studied the PRKAR1B gene for any genetic changes in bilateral adrenocortical hyperplasia (BAH) and cortisol-producing adrenal adenomas (CPA). Methods Exome sequencing and PRKAR1B copy-number variant (CNV) analysis were performed in 74 patients with BAH and 21 with CPA. PKA

    更新日期:2020-09-08
  • Predicting the risk of cardiac myxoma in Carney complex.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-07
    Georgia Pitsava,Chunming Zhu,Rajeshwari Sundaram,James L Mills,Constantine A Stratakis

    Purpose Carney complex (CNC), is an autosomal dominant multiple neoplasia and lentiginosis syndrome. We aimed to identify risk factors associated with the occurrence and recurrence of cardiac myxomas, the predominant cause of death in CNC patients. Methods Patients with CNC were monitored prospectively between 1995 and 2020 for the development of cardiac myxomas. Results Of the 319 patients studied

    更新日期:2020-09-06
  • Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-07
    Roddy Walsh,Najim Lahrouchi,Rafik Tadros,Florence Kyndt,Charlotte Glinge,Pieter G Postema,Ahmad S Amin,Eline A Nannenberg,James S Ware,Nicola Whiffin,Francesco Mazzarotto,Doris Škorić-Milosavljević,Christian Krijger,Elena Arbelo,Dominique Babuty,Hector Barajas-Martinez,Britt M Beckmann,Stéphane Bézieau,J Martijn Bos,Jeroen Breckpot,Oscar Campuzano,Silvia Castelletti,Candan Celen,Sebastian Clauss,Anniek

    Purpose Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative

    更新日期:2020-09-06
  • Correction: A longitudinal footprint of genetic epilepsies using automated electronic medical record interpretation.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-04
    Shiva Ganesan,Peter D Galer,Katherine L Helbig,Sarah E McKeown,Margaret O'Brien,Alexander K Gonzalez,Alex S Felmeister,Pouya Khankhanian,Colin A Ellis,Ingo Helbig

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-09-05
  • Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-04
    Kaitlyn Zenner,Dana M Jensen,Tori T Cook,Victoria Dmyterko,Randall A Bly,Sheila Ganti,Ghayda M Mirzaa,William B Dobyns,Jonathan A Perkins,James T Bennett

    Purpose Vascular malformations (VM) are primarily caused by somatic activating pathogenic variants in oncogenes. Targeted pharmacotherapies are emerging but require molecular diagnosis. Since variants are currently only detected in malformation tissue, patients may be ineligible for clinical trials prior to surgery. We hypothesized that cell-free DNA (cfDNA) could provide molecular diagnoses for patients

    更新日期:2020-09-05
  • A novel statistical method for interpreting the pathogenicity of rare variants.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-04
    Jun Wang,Hehe Liu,Renae Elaine Bertrand,Alejandro Sarrion-Perdigones,Yezabel Gonzalez,Koen J T Venken,Rui Chen

    Purpose To achieve the ultimate goal of personalized treatment of patients, accurate molecular diagnosis and precise interpretation of the impact of genetic variants on gene function is essential. With sequencing cost becoming increasingly affordable, the accurate distinguishing of benign from pathogenic variants becomes the major bottleneck. Although large normal population sequence databases have

    更新日期:2020-09-05
  • A randomized controlled trial of an online health tool about Down syndrome.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-03
    Jeanhee Chung,Karen Donelan,Eric A Macklin,Alison Schwartz,Ibrahim Elsharkawi,Amy Torres,Yichuan Grace Hsieh,Holly Parker,Stephen Lorenz,Vasiliki Patsiogiannis,Stephanie L Santoro,Mark Wylie,Lloyd Clarke,Greg Estey,Sandra Baker,Patricia E Bauer,Marilyn Bull,Brian Chicoine,Sarah Cullen,Ariel Frey-Vogel,Maureen Gallagher,Reem Hasan,Ashley Lamb,Lisa Majewski,Jawanda Mast,Travis Riddell,Karen Sepucha,Melissa

    Purpose We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We also sought to determine if primary care providers (PCPs) and caregivers are satisfied with this personalized online health tool. Methods In a national, randomized controlled trial of 230 caregivers who had children or dependents

    更新日期:2020-09-03
  • DOORS syndrome and a recurrent truncating ATP6V1B2 variant.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-02
    Eliane Beauregard-Lacroix,Guillermo Pacheco-Cuellar,Norbert F Ajeawung,Jessica Tardif,Klaus Dieterich,Tabib Dabir,Dina Vind-Kezunovic,Susan M White,Denes Zadori,Claudia Castiglioni,Lisbeth Tranebjærg,Pernille Mathiesen Tørring,Ed Blair,Marzena Wisniewska,Maria Vittoria Camurri,Yolande van Bever,Sirinart Molidperee,Juliet Taylor,Alexandre Dionne-Laporte,Sanjay M Sisodiya,Raoul C M Hennekam,Philippe

    Purpose Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant

    更新日期:2020-09-02
  • Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-02
    Amy K Dickey,Corbin Quick,Sarah Ducamp,Zhaozhong Zhu,Yen-Chen A Feng,Hetanshi Naik,Manisha Balwani,Karl E Anderson,Xihong Lin,John E Phillips,Lina Rebeiz,Herbert L Bonkovsky,Brendan M McGuire,Bruce Wang,Daniel I Chasman,Jordan W Smoller,Mark D Fleming,David C Christiani

    Purpose Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.05). The estimated prevalence of EPP derived from the number of diagnosed individuals in

    更新日期:2020-09-02
  • Reassessment of causality of ABCC6 missense variants associated with pseudoxanthoma elasticum based on Sherloc.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-02
    Shana Verschuere,Nastassia Navassiolava,Ludovic Martin,Pasi I Nevalainen,Paul J Coucke,Olivier M Vanakker

    Purpose Pseudoxanthoma elasticum (PXE) is a heritable disorder affecting elastic fibers in the skin, eyes, and cardiovascular system. It is caused by biallelic pathogenic variants in the ABCC6 gene. To date, over 300 ABCC6 variants are associated with PXE, more than half being missense variants. Correct variant interpretation is essential for establishing a direct link between the variant and the patient’s

    更新日期:2020-09-02
  • Response to Faulkner et al.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-02
    Paul S Appelbaum,Erik Parens,Sara M Berger,Wendy K Chung,Wylie Burke

    更新日期:2020-09-02
  • Correspondence on "Is there a duty to reinterpret genetic data? The ethical dimensions" by Appelbaum et al.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-02
    Nicole Faulkner,Swaroop Aradhya,Kerry W Aradhya,Robert L Nussbaum

    更新日期:2020-09-02
  • Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-28
    Sandy Elbitar,Marjolijn Renard,Pauline Arnaud,Nadine Hanna,Marie-Paule Jacob,Dong-Chuan Guo,Ko Tsutsui,Marie-Sylvie Gross,Ketty Kessler,Laurent Tosolini,Vincenzo Dattilo,Sebastien Dupont,Jeremie Jonquet,Maud Langeois,Louise Benarroch,Melodie Aubart,Youmna Ghaleb,Yara Abou Khalil,Mathilde Varret,Petra El Khoury,Benoit Ho-Tin-Noé,Yves Alembik,Sébastien Gaertner,Bertrand Isidor,Laurent Gouya,Olivier Milleron

    Purpose Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. Methods We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional

    更新日期:2020-08-28
  • The value of genomic sequencing in complex pediatric neurological disorders: a discrete choice experiment.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-25
    Ilias Goranitis,Stephanie Best,Zornitza Stark,Tiffany Boughtwood,John Christodoulou

    Purpose To estimate the value of genomic sequencing for complex pediatric neurological disorders of suspected genetic origin. Methods A discrete choice experiment (DCE) was undertaken to elicit societal preferences and values. A Bayesian D-efficient and explicit partial profile design was used. The design included 72 choice tasks, split across six blocks, with eight attributes (three overlapping per

    更新日期:2020-08-25
  • Alaska Native genomic research: perspectives from Alaska Native leaders, federal staff, and biomedical researchers.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-25
    Vanessa Y Hiratsuka,Michael J Hahn,R Brian Woodbury,Sara Chandros Hull,David R Wilson,Vence L Bonham,Denise A Dillard,,Jaedon P Avey,Andrea C Beckel-Mitchener,Juliana Blome,Katrina Claw,Elizabeth D Ferucci,Francine C Gachupin,Armen Ghazarian,Lucia Hindorff,Sonya Jooma,Susan B Trinidad,Jennifer Troyer,Hina Walajahi

    Meaningful engagement of Alaska Native (AN) tribes and tribal health organizations is essential in the conduct of socially responsible and ethical research. As genomics becomes increasingly important to advancements in medicine, there is a risk that populations not meaningfully included in genomic research will not benefit from the outcomes of that research. AN people have historically been underrepresented

    更新日期:2020-08-25
  • Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-21
    Eva S van Walree,Gregor Dombrowsky,Iris E Jansen,Maša Umićević Mirkov,Rob Zwart,Aho Ilgun,Dongchuan Guo,Sally-Ann B Clur,Ahmed S Amin,Jeanne E Savage,Allard C van der Wal,Quinten Waisfisz,Alessandra Maugeri,Anna Wilsdon,Frances A Bu'Lock,Matthew E Hurles,Sven Dittrich,Felix Berger,Enrique Audain Martinez,Vincent M Christoffels,Marc-Philip Hitz,Dianna M Milewicz,Daniëlle Posthuma,Hanne Meijers-Heijboer

    Purpose In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. Methods Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment

    更新日期:2020-08-21
  • Limited diagnostic impact of duplications <1 Mb of uncertain clinical significance: a 10-year retrospective analysis of reporting practices at the Mayo Clinic.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-21
    Cherisse A Marcou,Beth Pitel,Clinton E Hagen,Nicole J Boczek,Ross A Rowsey,Linda B Baughn,Nicole L Hoppman,Erik C Thorland,Hutton M Kearney

    Purpose Copy-number variants (CNVs) of uncertain clinical significance are routinely reported in a clinical setting only when exceeding predetermined reporting thresholds, typically based on CNV size. Given that very few genes are associated with triplosensitive phenotypes, it is not surprising that many interstitial duplications <1 Mb are found to be inherited and anticipated to be of limited or no

    更新日期:2020-08-21
  • Health-care practitioners' preferences for the return of secondary findings from next-generation sequencing: a discrete choice experiment.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-21
    Shan Jiang,Aslam H Anis,Ian Cromwell,Tima Mohammadi,Kasmintan A Schrader,Janet Lucas,Christine M Armour,Marc Clausen,Yvonne Bombard,Dean A Regier

    Purpose Health-care practitioners’ (HCPs) preferences for returning secondary findings (SFs) will influence guideline compliance, shared decision-making, and patient health outcomes. This study aimed to estimate HCPs’ preferences and willingness to support the return (WTSR) of SFs in Canada. Methods A discrete choice experiment estimated HCPs’ preferences for the following attributes: disease risk

    更新日期:2020-08-21
  • Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-21
    Daisy Rymen,Martijn Lindhout,Maria Spanou,Farah Ashrafzadeh,Ira Benkel,Cornelia Betzler,Christine Coubes,Hans Hartmann,Julie D Kaplan,Diana Ballhausen,Johannes Koch,Jan Lotte,Mohammad Hasan Mohammadi,Marianne Rohrbach,Argirios Dinopoulos,Marieke Wermuth,Daniel Willis,Karin Brugger,Ron A Wevers,Eugen Boltshauser,Jörgen Bierau,Johannes A Mayr,Saskia B Wortmann

    Purpose Biallelic CAD variants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment. Methods Retrospective case series of 20 patients. Results Our study confirms CAD deficiency as a progressive EIEE

    更新日期:2020-08-21
  • Response to Mounts and Besser.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-20
    Gordana Raca,Marwan Shinawi,Daniela Del Gaudio,

    更新日期:2020-08-20
  • Correction: KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-19
    Joanna Kennedy,David Goudie,Edward Blair,Kate Chandler,Shelagh Joss,Victoria McKay,Andrew Green,Ruth Armstrong,Melissa Lees,Benjamin Kamien,Bruce Hopper,Tiong Yang Tan,Patrick Yap,Zornitza Stark,Nobuhiko Okamoto,Noriko Miyake,Naomichi Matsumoto,Ellen Macnamara,Jennifer L Murphy,Elizabeth McCormick,Hakon Hakonarson,Marni J Falk,Dong Li,Patrick Blackburn,Eric Klee,Dusica Babovic-Vuksanovic,Susan Schelley

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-08-19
  • 更新日期:2020-08-19
  • Galactokinase deficiency: lessons from the GalNet registry.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-18
    M Estela Rubio-Gozalbo,Britt Derks,Anibh Martin Das,Uta Meyer,Dorothea Möslinger,M Luz Couce,Aurélie Empain,Can Ficicioglu,Natalia Juliá Palacios,Mariela M De Los Santos De Pelegrin,Isabel A Rivera,Sabine Scholl-Bürgi,Annet M Bosch,David Cassiman,Didem Demirbas,Matthias Gautschi,Ina Knerr,Philippe Labrune,Anastasia Skouma,Patrick Verloo,Saskia B Wortmann,Eileen P Treacy,David J Timson,Gerard T Berry

    Purpose Galactokinase (GALK1) deficiency is a rare hereditary galactose metabolism disorder. Beyond cataract, the phenotypic spectrum is questionable. Data from affected patients included in the Galactosemias Network registry were collected to better characterize the phenotype. Methods Observational study collecting medical data of 53 not previously reported GALK1 deficient patients from 17 centers

    更新日期:2020-08-18
  • Assessment of technical heterogeneity among diagnostic tests to detect germline risk variants for hematopoietic malignancies.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-18
    Gregory W Roloff,Lucy A Godley,Michael W Drazer

    Purpose To determine the degree of testing consistency among commercially available diagnostic assays for hereditary hematopoietic malignancies (HHMs). Methods Next-generation sequencing assays designed for the diagnosis of HHMs were studied to determine which genes were sequenced, their ability to detect variant types relevant for HHMs, and clinical-grade characteristics such as price, turnaround

    更新日期:2020-08-18
  • Airmen and health-care providers' attitudes toward the use of genomic sequencing in the US Air Force: findings from the MilSeq Project.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-18
    Stacey Pereira,Rebecca L Hsu,Rubaiya Islam,Jill Oliver Robinson,Rishab Ramapriyan,Emily Sirotich,Megan D Maxwell,Mary Majumder,Carrie L Blout,Kurt D Christensen,Maxwell Mehlman,Efthimios Parasidis,Cubby L Gardner,Jacqueline M Killian,Mauricio De Castro,Robert C Green,,Amy L McGuire

    Purpose The use of genomic sequencing (GS) in military settings poses unique considerations, including the potential for GS to impact service members’ careers. The MilSeq Project investigated the use of GS in clinical care of active duty Airmen in the United States Air Force (USAF). Methods We assessed perceived risks, benefits, and attitudes toward use of GS in the USAF among patient participants

    更新日期:2020-08-18
  • Genome-wide noninvasive prenatal screening for carriers of balanced reciprocal translocations.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-18
    Nicola Jane Flowers,Trent Burgess,Olivia Giouzeppos,Grace Shi,Clare Jane Love,Clare Elizabeth Hunt,Katrina Louise Scarff,Alison Dalton Archibald,Mark Domenic Pertile

    Purpose Balanced reciprocal translocation carriers are at increased risk of producing gametes with unbalanced forms of the translocation leading to miscarriage, fetal anomalies, and birth defects. We sought to determine if genome-wide cell-free DNA based noninvasive prenatal screening (gw-NIPS) could provide an alternative to prenatal diagnosis for carriers of these chromosomal rearrangements. Methods

    更新日期:2020-08-18
  • When phenotype does not match genotype: importance of "real-time" refining of phenotypic information for exome data interpretation.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-17
    Lina Basel-Salmon,Noa Ruhrman-Shahar,Naama Orenstein,Yael Goldberg,Claudia Gonzaga-Jauregui,Alan R Shuldiner,Rivka Sukenik-Halevy,Idit Maya,Nurit Magal,Ofir Hagari,Noy Azulay,Gabriel Arie Lidzbarsky,Lily Bazak

    Purpose Clinical data provided to genetic testing laboratories are frequently scarce. Our purpose was to evaluate clinical scenarios where phenotypic refinement in proband’s family members might impact exome data interpretation. Methods Of 614 exomes, 209 were diagnostic and included in this study. Phenotypic information was gathered by the variant interpretation team from genetic counseling letters

    更新日期:2020-08-17
  • News.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-17
    V L Dengler

    更新日期:2020-08-17
  • In This Issue.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-17
    V L Dengler

    更新日期:2020-08-17
  • Role of POLE and POLD1 in familial cancer.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-14
    Pilar Mur,Sandra García-Mulero,Jesús Del Valle,Lorena Magraner-Pardo,August Vidal,Marta Pineda,Giacomo Cinnirella,Edgar Martín-Ramos,Tirso Pons,Adriana López-Doriga,Sami Belhadj,Lidia Feliubadaló,Pau M Munoz-Torres,Matilde Navarro,Elia Grau,Esther Darder,Gemma Llort,Judit Sanz,Teresa Ramón Y Cajal,Judith Balmana,Joan Brunet,Victor Moreno,Josep M Piulats,Xavier Matías-Guiu,Rebeca Sanz-Pamplona,Rosa

    Purpose Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study

    更新日期:2020-08-14
  • An Anti-Racism Toolkit for the Genetics Educator.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-13
    Shoumita Dasgupta

    更新日期:2020-08-13
  • Genotype-phenotype correlations in recessive titinopathies.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-11
    Marco Savarese,Anna Vihola,Emily C Oates,Rita Barresi,Chiara Fiorillo,Giorgio Tasca,Manu Jokela,Anna Sarkozy,Sushan Luo,Jordi Díaz-Manera,Christoffer Ehrstedt,Ricardo Rojas-García,Amets Sáenz,Nuria Muelas,Fortunato Lonardo,Heidi Fodstad,Talha Qureshi,Mridul Johari,Salla Välipakka,Helena Luque,Philippe Petiot,Adolfo López de Munain,Marika Pane,Eugenio Mercuri,Annalaura Torella,Vincenzo Nigro,Guja Astrea

    Purpose High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate

    更新日期:2020-08-11
  • Considerations in assessing germline variant pathogenicity using cosegregation analysis.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-10
    Sophie Belman,Michael T Parsons,Amanda B Spurdle,David E Goldgar,Bing-Jian Feng

    Purpose The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have developed guidelines for classifying germline variants as pathogenic or benign to interpret genetic testing results. Cosegregation analysis is an important component of the guidelines. There are two main approaches for cosegregation analysis: meiosis counting and Bayes factor–based

    更新日期:2020-08-10
  • Constitutional mismatch repair deficiency is the diagnosis in 0.41% of pathogenic NF1/SPRED1 variant negative children suspected of sporadic neurofibromatosis type 1.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-10
    Juan A Perez-Valencia,Richard Gallon,Yunjia Chen,Jakob Koch,Markus Keller,Klaus Oberhuber,Alicia Gomes,Johannes Zschocke,John Burn,Michael S Jackson,Mauro Santibanez-Koref,Ludwine Messiaen,Katharina Wimmer

    Purpose Biallelic germline mismatch repair (MMR) gene pathogenic variants (PVs) cause constitutional MMR deficiency (CMMRD), a highly penetrant childhood cancer syndrome phenotypically overlapping with neurofibromatosis type 1 (NF1). CMMRD testing in suspected NF1 children without NF1/SPRED1 PVs enables inclusion of CMMRD positives into monitoring programs prior to tumor onset. However, testing is

    更新日期:2020-08-10
  • A longitudinal footprint of genetic epilepsies using automated electronic medical record interpretation.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-10
    Shiva Ganesan,Peter D Galer,Katherine L Helbig,Sarah E McKeown,Margaret O'Brien,Alexander K Gonzalez,Alex S Felmeister,Pouya Khankhanian,Colin A Ellis,Ingo Helbig

    Purpose Childhood epilepsies have a strong genetic contribution, but the disease trajectory for many genetic etiologies remains unknown. Electronic medical record (EMR) data potentially allow for the analysis of longitudinal clinical information but this has not yet been explored. Methods We analyzed provider-entered neurological diagnoses made at 62,104 patient encounters from 658 individuals with

    更新日期:2020-08-10
  • A cost-effectiveness analysis of genomic sequencing in a prospective versus historical cohort of complex pediatric patients.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-10
    Alison Yeung,Natalie B Tan,Tiong Y Tan,Zornitza Stark,Natasha Brown,Matthew F Hunter,Martin Delatycki,Chloe Stutterd,Ravi Savarirayan,George Mcgillivray,Rachel Stapleton,Smitha Kumble,Lilian Downie,Matthew Regan,Sebastian Lunke,Belinda Chong,Dean Phelan,Gemma R Brett,Anna Jarmolowicz,Yael Prawer,Giulia Valente,Yana Smagarinsky,Melissa Martyn,Callum McEwan,Ilias Goranitis,Clara Gaff,Susan M White

    Purpose Cost-effectiveness evaluations of first-line genomic sequencing (GS) in the diagnosis of children with genetic conditions are limited by the lack of well-defined comparative cohorts. We sought to evaluate the cost-effectiveness of early GS in pediatric patients with complex monogenic conditions compared with a matched historical cohort. Methods Data, including investigation costs, were collected

    更新日期:2020-08-10
  • DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-05
    Anjali Vig,James A Poulter,Daniele Ottaviani,Erika Tavares,Katerina Toropova,Anna Maria Tracewska,Antonio Mollica,Jasmine Kang,Oshini Kehelwathugoda,Tara Paton,Jason T Maynes,Gabrielle Wheway,Gavin Arno,,Kamron N Khan,Martin McKibbin,Carmel Toomes,Manir Ali,Matteo Di Scipio,Shuning Li,Jamie Ellingford,Graeme Black,Andrew Webster,Małgorzata Rydzanicz,Piotr Stawiński,Rafał Płoski,Ajoy Vincent,Michael

    Purpose Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD). Methods Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay). Results Four

    更新日期:2020-08-05
  • Application of exome sequencing for prenatal diagnosis: a rapid scoping review.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-04
    Misty Pratt,Chantelle Garritty,Micere Thuku,Leila Esmaeilisaraji,Candyce Hamel,Taila Hartley,Kathryn Millar,Becky Skidmore,Shelley Dougan,Christine M Armour

    Genetic diagnosis provides important information for prenatal decision-making and management. Promising results from exome sequencing (ES) for genetic diagnosis in fetuses with structural anomalies are emerging. The objective of this scoping review was to identify what is known about the use of ES for genetic testing in prenatal cases with known or suspected genetic disease. A rapid scoping review

    更新日期:2020-08-04
  • Correction: Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-03
    Amber L Beitelshees,James M Stevenson,Nihal El Rouby,Chrisly Dillon,Philip E Empey,Elliot M Fielstein,Julie A Johnson,Nita A Limdi,Henry H Ong,Francesco Franchi,Dominick J Angiolillo,Joshua F Peterson,Marc B Rosenman,Todd C Skaar,Sony Tuteja,Larisa H Cavallari,

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-08-03
  • Assessing non-Mendelian inheritance in inherited axonopathies.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-03
    Dana M Bis-Brewer,Ziv Gan-Or,Patrick Sleiman,,Hakon Hakonarson,Sarah Fazal,Steve Courel,Vivian Cintra,Feifei Tao,Mehrdad A Estiar,Mark Tarnopolsky,Kym M Boycott,Grace Yoon,Oksana Suchowersky,Nicolas Dupré,Andrew Cheng,Thomas E Lloyd,Guy Rouleau,Rebecca Schüle,Stephan Züchner

    Purpose Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot–Marie–Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not

    更新日期:2020-08-03
  • Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-03
    Hailey Findlay Black,Galen E B Wright,Jennifer A Collins,Nicholas Caron,Chris Kay,Qingwen Xia,Larissa Arning,Emilia K Bijlsma,Ferdinando Squitieri,Huu Phuc Nguyen,Michael R Hayden

    Purpose In some Huntington disease (HD) patients, the “loss of interruption” (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency

    更新日期:2020-08-03
  • Treatment of mucopolysaccharidosis type II (Hunter syndrome): a Delphi derived practice resource of the American College of Medical Genetics and Genomics (ACMG).
    Genet. Med. (IF 8.904) Pub Date : 2020-08-03
    Kim L McBride,Susan A Berry,Nancy Braverman,

    Mucopolysaccharidosis, type II (MPS II, MIM 309900) is a severe lysosomal storage disease with multisystem involvement. There is one product approved by the FDA, an enzyme replacement therapy, based on a phase III trial in older, attenuated MPS II individuals. Guidance on treatment of MPS II is lacking, not only in general, but for specific clinical situations. A previous systematic evidence-based

    更新日期:2020-08-03
  • Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-03
    Csilla Krausz,Antoni Riera-Escamilla,Daniel Moreno-Mendoza,Kaylee Holleman,Francesca Cioppi,Ferran Algaba,Marc Pybus,Corinna Friedrich,Margot J Wyrwoll,Elena Casamonti,Sara Pietroforte,Liina Nagirnaja,Alexandra M Lopes,Sabine Kliesch,Adrian Pilatz,Douglas T Carrell,Donald F Conrad,Elisabet Ars,Eduard Ruiz-Castañé,Kenneth I Aston,Willy M Baarends,Frank Tüttelmann

    Purpose Azoospermia affects 1% of men and it can be the consequence of spermatogenic maturation arrest (MA). Although the etiology of MA is likely to be of genetic origin, only 13 genes have been reported as recurrent potential causes of MA. Methods Exome sequencing in 147 selected MA patients (discovery cohort and two validation cohorts). Results We found strong evidence for five novel genes likely

    更新日期:2020-08-03
  • Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-03
    Essa Alharby,Eissa A Faqeih,Mohammed Saleh,Seham Alameer,Makki Almuntashri,Annalisa Pastore,Manar A Samman,Abdullah M Alnawfal,Mais Hashem,Dimah Zaytuni,Ghadeer Alharbi,Mohammed Almannai,Ali Alasmari,Adel A Mahmoud,Ali H Alwadei,Lamya Jad,Ali AlOtaibi,Fahad Al-Hakami,Wafaa Eyaid,Fowzan S Alkuraya,Majid Alfadhel,Roy W A Peake,Naif A M Almontashiri

    Purpose Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD. Methods

    更新日期:2020-08-03
  • Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-03
    Samantha E Greenberg,Michelle F Jacobs,Heather Wachtel,Amanda Anson,Luke Buchmann,Debbie L Cohen,Maria Bonanni,Bonita Bennett,Anne Naumer,Amanda M Schaefer,Wendy Kohlmann,Katherine L Nathanson,Tobias Else,Lauren Fishbein

    Purpose Minimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma–pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols. Methods A multicenter retrospective longitudinal observational study was conducted. Individuals

    更新日期:2020-08-03
  • In This Issue.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-01
    V L Dengler

    更新日期:2020-08-01
  • News.
    Genet. Med. (IF 8.904) Pub Date : 2020-08-01
    V L Dengler

    更新日期:2020-08-01
  • Correction: Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.
    Genet. Med. (IF 8.904) Pub Date : 2020-07-29
    Siddharth Srivastava,Jamie A Love-Nichols,Kira A Dies,David H Ledbetter,Christa L Martin,Wendy K Chung,Helen V Firth,Thomas Frazier,Robin L Hansen,Lisa Prock,Han Brunner,Ny Hoang,Stephen W Scherer,Mustafa Sahin,David T Miller,

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-07-29
  • Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism.
    Genet. Med. (IF 8.904) Pub Date : 2020-07-29
    James S Acierno,Cheng Xu,Georgios E Papadakis,Nicolas J Niederländer,Jesse D Rademaker,Jenny Meylan,Andrea Messina,Zofia Kolesinska,Richard Quinton,Mariarosaria Lang-Muritano,Deborah Bartholdi,Irene Halperin,Christian De Geyter,Jérôme Bouligand,Lucia Bartoloni,Jacques Young,Federico A Santoni,Nelly Pitteloud

    Purpose Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder resulting in absent puberty and infertility. The genetic architecture is complex with multiple loci involved, variable expressivity, and incomplete penetrance. The majority of cases are sporadic, consistent with a disease affecting fertility. The current study aims to investigate mosaicism as a genetic mechanism for CHH, focusing

    更新日期:2020-07-29
  • A genomics approach to male infertility.
    Genet. Med. (IF 8.904) Pub Date : 2020-07-28
    Naif Alhathal,Sateesh Maddirevula,Serdar Coskun,Hamed Alali,Mirna Assoum,Thomas Morris,Hesham A Deek,Soha A Hamed,Shaheed Alsuhaibani,Abdulmalik Mirdawi,Nour Ewida,Mashael Al-Qahtani,Niema Ibrahim,Firdous Abdulwahab,Waleed Altaweel,Majed J Dasouki,Abdullah Assiri,Wafa Qabbaj,Fowzan S Alkuraya

    Purpose Male infertility remains poorly understood at the molecular level. We aimed in this study to investigate the yield of a “genomics first” approach to male infertility. Methods Patients with severe oligospermia and nonobstructive azoospermia were investigated using exome sequencing (ES) in parallel with the standard practice of chromosomal analysis. Results In 285 patients, 10.5% (n = 30) had

    更新日期:2020-07-28
  • Parental experiences of ultrarapid genomic testing for their critically unwell infants and children.
    Genet. Med. (IF 8.904) Pub Date : 2020-07-28
    Gemma R Brett,Melissa Martyn,Fiona Lynch,Michelle G de Silva,Samantha Ayres,Lyndon Gallacher,Kirsten Boggs,Anne Baxendale,Sarah Schenscher,Sarah King-Smith,Lindsay Fowles,Amanda Springer,Sebastian Lunke,Anand Vasudevan,Emma Krzesinski,Jason Pinner,Sarah A Sandaradura,Christopher Barnett,Chirag Patel,Meredith Wilson,Zornitza Stark

    Purpose To explore parental experiences of ultrarapid genomic testing for their critically unwell infants and children. Methods Parents of critically unwell children who participated in a national ultrarapid genomic diagnosis program were surveyed >12 weeks after genomic results return. Surveys consisted of custom questions and validated scales, including the Decision Regret Scale and Genomics Outcome

    更新日期:2020-07-28
  • Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes.
    Genet. Med. (IF 8.904) Pub Date : 2020-07-28
    Lu Qiao,Julia Wynn,Lan Yu,Rebecca Hernan,Xueya Zhou,Vincent Duron,Gudrun Aspelund,Christiana Farkouh-Karoleski,Annette Zygumunt,Usha S Krishnan,Shannon Nees,Julie Khlevner,Foong Yen Lim,Timothy Crombleholme,Robert Cusick,Kenneth Azarow,Melissa Ellen Danko,Dai Chung,Brad W Warner,George B Mychaliska,Douglas Potoka,Amy J Wagner,Samuel Soffer,David Schindel,David J McCulley,Yufeng Shen,Wendy K Chung

    Purpose Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes. Methods We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 trios to identify

    更新日期:2020-07-28
  • Correction: Developing a common framework for evaluating the implementation of genomic medicine interventions in clinical care: the IGNITE Network's Common Measures Working Group.
    Genet. Med. (IF 8.904) Pub Date : 2020-07-27
    Lori A Orlando,Nina R Sperber,Corrine Voils,Marshall Nichols,Rachel A Myers,R Ryanne Wu,Tejinder Rakhra-Burris,Kenneth D Levy,Mia Levy,Toni I Pollin,Yue Guan,Carol R Horowitz,Michelle Ramos,Stephen E Kimmel,Caitrin W McDonough,Ebony B Madden,Laura J Damschroder,

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-07-27
  • Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.
    Genet. Med. (IF 8.904) Pub Date : 2020-07-27
    Kenneth D Levy,Kathryn Blake,Colette Fletcher-Hoppe,James Franciosi,Diasuke Goto,James K Hicks,Ann M Holmes,Sri Harsha Kanuri,Ebony B Madden,Michael D Musty,Lori Orlando,Victoria M Pratt,Michelle Ramos,Ryanne Wu,Geoffrey S Ginsburg

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-07-27