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  • Insuring patient access and affordability for treatments for rare and ultrarare diseases: a policy statement of the American College of Medical Genetics and Genomics
    Genet. Med. (IF 9.937) Pub Date : 2018-08-22

    Insuring patient access and affordability for treatments for rare and ultrarare diseases: a policy statement of the American College of Medical Genetics and GenomicsInsuring patient access and affordability for treatments for rare and ultrarare diseases: a policy statement of the American College of Medical Genetics and Genomics, Published online: 22 August 2018; doi:10.1038/s41436-018-0059-8Insuring patient access and affordability for treatments for rare and ultrarare diseases: a policy statement of the American College of Medical Genetics and Genomics

    更新日期:2018-08-22
  • Correction: DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes
    Genet. Med. (IF 9.937) Pub Date : 2018-08-20
    Marcy E. Richardson, Hansook Chong, Wenbo Mu, Blair R. Conner, Vickie Hsuan, Sara Willett, Stephanie Lam, Pei Tsai, Tina Pesaran, Adam C. Chamberlin, Min-Sun Park, Phillip Gray, Rachid Karam, Aaron Elliott

    Correction: DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes Correction: DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes, Published online: 20 August 2018; doi:10.1038/s41436-018-0276-1 Correction: DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes

    更新日期:2018-08-20
  • Development of an evidence-based algorithm that optimizes sensitivity and specificity in ES-based diagnostics of a clinically heterogeneous patient population
    Genet. Med. (IF 9.937) Pub Date : 2018-08-13
    Peter Bauer, Krishna Kumar Kandaswamy, Maximilian E. R. Weiss, Omid Paknia, Martin Werber, Aida M. Bertoli-Avella, Zafer Yüksel, Malgorzata Bochinska, Gabriela E. Oprea, Shivendra Kishore, Volkmar Weckesser, Ellen Karges, Arndt Rolfs

    Purpose Next-generation sequencing (NGS) is rapidly replacing Sanger sequencing in genetic diagnostics. Sensitivity and specificity of NGS approaches are not well-defined, but can be estimated from applying NGS and Sanger sequencing in parallel. Utilizing this strategy, we aimed at optimizing exome sequencing (ES)–based diagnostics of a clinically diverse patient population. Methods Consecutive DNA samples from unrelated patients with suspected genetic disease were exome-sequenced; comparatively nonstringent criteria were applied in variant calling. One thousand forty-eight variants in genes compatible with the clinical diagnosis were followed up by Sanger sequencing. Based on a set of variant-specific features, predictors for true positives and true negatives were developed. Results Sanger sequencing confirmed 81.9% of ES-derived variants. Calls from the lower end of stringency accounted for the majority of the false positives, but also contained ~5% of the true positives. A predictor incorporating three variant-specific features classified 91.7% of variants with 100% specificity and 99.75% sensitivity. Confirmation status of the remaining variants (8.3%) was not predictable. Conclusions Criteria for variant calling in ES-based diagnostics impact on specificity and sensitivity. Confirmatory sequencing for a proportion of variants, therefore, remains a necessity. Our study exemplifies how these variants can be defined on an empirical basis.

    更新日期:2018-08-13
  • Discovery of new susceptibility genes: proceed cautiously
    Genet. Med. (IF 9.937) Pub Date : 2018-08-13
    Tobias Else, Lauren Fishbein

    Discovery of new susceptibility genes: proceed cautiously Discovery of new susceptibility genes: proceed cautiously, Published online: 13 August 2018; doi:10.1038/s41436-018-0139-9 Discovery of new susceptibility genes: proceed cautiously

    更新日期:2018-08-13
  • Including ELSI research questions in newborn screening pilot studies
    Genet. Med. (IF 9.937) Pub Date : 2018-08-13
    Aaron J. Goldenberg, Michele Lloyd-Puryear, Jeffrey P. Brosco, Bradford Therrell, Lynn Bush, Susan Berry, Amy Brower, Natasha Bonhomme, Bruce Bowdish, Denise Chrysler, Angus Clarke, Thomas Crawford, Edward Goldman, Sally Hiner, R. Rodney Howell, David Orren, Benjamin S. Wilfond, Michael Watson

    Background The evidence review processes for adding new conditions to state newborn screening (NBS) panels rely on data from pilot studies aimed at assessing the potential benefits and harms of screening. However, the consideration of ethical, legal, and social implications (ELSI) of screening within this research has been limited. This paper outlines important ELSI issues related to newborn screening policy and practices as a resource to help researchers integrate ELSI into NBS pilot studies. Approach Members of the Bioethics and Legal Workgroup for the Newborn Screening Translational Research Network facilitated a series of professional and public discussions aimed at engaging NBS stakeholders to identify important existing and emerging ELSI challenges accompanying NBS. Results Through these engagement activities, we identified a set of key ELSI questions related to (1) the types of results parents may receive through newborn screening and (2) the initiation and implementation of NBS for a condition within the NBS system. Conclusion Integrating ELSI questions into pilot studies will help NBS programs to better understand the potential impact of screening for a new condition on newborns and families, and make crucial policy decisions aimed at maximized benefits and mitigating the potential negative medical or social implications of screening.

    更新日期:2018-08-13
  • Genomic sequencing in acutely ill infants: what will it take to demonstrate clinical value?
    Genet. Med. (IF 9.937) Pub Date : 2018-08-13
    Scott D. Grosse, Lauge Farnaes

    Genomic sequencing in acutely ill infants: what will it take to demonstrate clinical value? Genomic sequencing in acutely ill infants: what will it take to demonstrate clinical value?, Published online: 13 August 2018; doi:10.1038/s41436-018-0124-3 Genomic sequencing in acutely ill infants: what will it take to demonstrate clinical value?

    更新日期:2018-08-13
  • Correction: “Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals”
    Genet. Med. (IF 9.937) Pub Date : 2018-08-11
    Kai Lee Yap, Amy E. Knight Johnson, David Fischer, Priscilla Kandikatla, Jacea Deml, Viswateja Nelakuditi, Sara Halbach, George S. Jeha, Lindsay C. Burrage, Olaf Bodamer, Valeria C. Benavides, Andrea M. Lewis, Sian Ellard, Pratik Shah, Declan Cody, Alejandro Diaz, Aishwarya Devarajan, Lisa Truong, Siri Atma W. Greeley, Diva D. De Leon, Andrew C. Edmondson, Soma Das, Paul Thornton, Darrel Waggoner, Daniela del Gaudio

    Correction: “Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals” Correction: “Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals”, Published online: 11 August 2018; doi:10.1038/s41436-018-0126-1 Correction: “Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals”

    更新日期:2018-08-11
  • Medical genetics in developing countries in the Asia-Pacific region: challenges and opportunities
    Genet. Med. (IF 9.937) Pub Date : 2018-08-10
    Meow-Keong Thong, Yiling See-Toh, Jamiyah Hassan, Jaffar Ali

    Advances in genetic and genomic technology changed health-care services rapidly in low and middle income countries (LMICs) in the Asia-Pacific region. While genetic services were initially focused on population-based disease prevention strategies, they have evolved into clinic-based and therapeutics-oriented service. Many LMICs struggled with these noncommunicable diseases and were unprepared for the needs of a clinical genetic service. The emergence of a middle class population, the lack of regulatory oversight, and weak capacity-building in medical genetics expertise and genetic counseling services led to a range of genetic services of variable quality with minimal ethical oversight. Some of the current shortcomings faced include the lack of awareness of cultural values in genetic health care, the variable stages of socioeconomic development and educational background that led to increased demand and abuse of genetics, the role of women in society and the crisis of gender selection, the lack of preventive and care services for genetic and birth defects, the issues of gene ethics in medicine, and the lack of understanding of some religious controversies. These challenges provide opportunities for both developing and developed nations to work together to reduce the inequalities and to ensure a caring, inclusive, ethical, and cost-effective genetic service in the region.

    更新日期:2018-08-10
  • Paradigm shifts in newborn screening?
    Genet. Med. (IF 9.937) Pub Date : 2018-08-10
    Anne Marie Comeau

    Paradigm shifts in newborn screening? Paradigm shifts in newborn screening?, Published online: 10 August 2018; doi:10.1038/s41436-018-0130-5 Paradigm shifts in newborn screening?

    更新日期:2018-08-10
  • The landscape of epilepsy-related GATOR1 variants
    Genet. Med. (IF 9.937) Pub Date : 2018-08-10
    Sara Baldassari, Fabienne Picard, Nienke E. Verbeek, Marjan van Kempen, Eva H. Brilstra, Gaetan Lesca, Valerio Conti, Renzo Guerrini, Francesca Bisulli, Laura Licchetta, Tommaso Pippucci, Paolo Tinuper, Edouard Hirsch, Anne de Saint Martin, Jamel Chelly, Gabrielle Rudolf, Mathilde Chipaux, Sarah Ferrand-Sorbets, Georg Dorfmüller, Sanjay Sisodiya, Simona Balestrini, Natasha Schoeler, Laura Hernandez-Hernandez, S. Krithika, Renske Oegema, Eveline Hagebeuk, Boudewijn Gunning, Charles Deckers, Bianca Berghuis, Ilse Wegner, Erik Niks, Floor E. Jansen, Kees Braun, Daniëlle de Jong, Guido Rubboli, Inga Talvik, Valentin Sander, Peter Uldall, Marie-Line Jacquemont, Caroline Nava, Eric Leguern, Sophie Julia, Antonio Gambardella, Giuseppe d’Orsi, Giovanni Crichiutti, Laurence Faivre, Veronique Darmency, Barbora Benova, Pavel Krsek, Arnaud Biraben, Anne-Sophie Lebre, Mélanie Jennesson, Shifteh Sattar, Cécile Marchal, Douglas R Nordli Jr, Kristin Lindstrom, Pasquale Striano, Lysa Boissé L..

    Purpose To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway Methods We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. Results The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. Conclusion Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

    更新日期:2018-08-10
  • The New York pilot newborn screening program for lysosomal storage diseases: Report of the First 65,000 Infants
    Genet. Med. (IF 9.937) Pub Date : 2018-08-10
    Melissa P. Wasserstein, Michele Caggana, Sean M. Bailey, Robert J. Desnick, Lisa Edelmann, Lissette Estrella, Ian Holzman, Nicole R. Kelly, Ruth Kornreich, S. Gabriel Kupchik, Monica Martin, Suhas M. Nafday, Randi Wasserman, Amy Yang, Chunli Yu, Joseph J. Orsini

    Purpose We conducted a consented pilot newborn screening (NBS) for Pompe, Gaucher, Niemann–Pick A/B, Fabry, and MPS 1 to assess the suitability of these lysosomal storage disorders (LSDs) for public health mandated screening. Methods At five participating high–birth rate, ethnically diverse New York City hospitals, recruiters discussed the study with postpartum parents and documented verbal consent. Screening on consented samples was performed using multiplexed tandem mass spectrometry. Screen-positive infants underwent confirmatory enzymology, DNA testing, and biomarker quantitation when available. Affected infants are being followed for clinical management and long-term outcome. Results Over 4 years, 65,605 infants participated, representing an overall consent rate of 73%. Sixty-nine infants were screen-positive. Twenty-three were confirmed true positives, all of whom were predicted to have late-onset phenotypes. Six of the 69 currently have undetermined disease status. Conclusion Our results suggest that NBS for LSDs is much more likely to detect individuals at risk for late-onset disease, similar to results from other NBS programs. This work has demonstrated the feasibility of using a novel consented pilot NBS study design that can be modified to include other disorders under consideration for public health implementation as a means to gather critical evidence for evidence-based NBS practices.

    更新日期:2018-08-10
  • Correction: Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders
    Genet. Med. (IF 9.937) Pub Date : 2018-08-08
    Yasmin Bylstra, Jyn Ling Kuan, Weng Khong Lim, Jaydutt Digambar Bhalshankar, Jing Xian Teo, Sonia Davila, Bin Tean Teh, Steve Rozen, Ene-Choo Tan, Wendy Kein Meng Liew, Khung Keong Yeo, Patrick Tan, Seang Mei Saw, Ching-Yu Cheng, Stuart Cook, Roger Foo, Saumya Shekhar Jamuar

    Correction: Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders Correction: Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders, Published online: 08 August 2018; doi:10.1038/s41436-018-0142-1 Correction: Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders

    更新日期:2018-08-08
  • Ethical, social, and cultural issues related to clinical genetic testing and counseling in low- and middle-income countries: a systematic review
    Genet. Med. (IF 9.937) Pub Date : 2018-08-03
    Adrina Zhong, Benedict Darren, Bethina Loiseau, Li Qun Betty He, Trillium Chang, Jessica Hill, Helen Dimaras

    PurposeWe performed a systematic review of the ethical, social, and cultural issues associated with delivery of genetic services in low- and middle-income countries (LMICs).MethodsWe searched 11 databases for studies addressing ethical, social, and/or cultural issues associated with clinical genetic testing and/or counselling performed in LMICs. Narrative synthesis was employed to analyze findings, and resultant themes were mapped onto the social ecological model (PROSPERO #CRD42016042894).ResultsAfter reviewing 13,308 articles, 192 met inclusion criteria. Nine themes emerged: (1) genetic counseling has a tendency of being directive, (2) genetic services have psychosocial consequences that require improved support, (3) medical genetics training is inadequate, (4) genetic services are difficult to access, (5) social determinants affect uptake and understanding of genetic services, (6) social stigma is often associated with genetic disease, (7) family values are at risk of disruption by genetic services, (8) religious principles pose barriers to acceptability and utilization of genetic services, and (9) cultural beliefs and practices influence uptake of information and understanding of genetic disease.ConclusionWe identified a number of complex and interrelated ethical, cultural, and social issues with implications implications for further development of genetic services in LMICs.

    更新日期:2018-08-02
  • Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration
    Genet. Med. (IF 9.937) Pub Date : 2018-08-03
    Farzad Jamshidi, Emily M. Place, Sudeep Mehrotra, Daniel Navarro-Gomez, Mathew Maher, Kari E. Branham, Elise Valkanas, Timothy J. Cherry, Monkol Lek, Daniel MacArthur, Eric A. Pierce, Kinga M. Bujakowska

    PurposeWith the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis.MethodsIRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing.ResultsAmong 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro.ConclusionNoncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.

    更新日期:2018-08-02
  • Analysis of fetal DNA in maternal plasma with markers designed for forensic DNA mixture resolution
    Genet. Med. (IF 9.937) Pub Date : 2018-08-03
    Amandine Moriot, Diana Hall

    PurposeWith the description of circulating fetal DNA in maternal blood, noninvasive prenatal diagnostics became theoretically possible. As the presence of background maternal DNA interferes with the detection of fetal DNA, analytical methods require genetic markers capable of distinguishing by quantitative or targeted approaches the minor population of DNA molecules of the fetus. Here we evaluate the feasibility of analyzing fetal DNA with novel DIP-STR genetic markers, designed for the investigation of forensic mixed biological evidence.MethodsThe DIP-STR molecular approach is based on sequence-specific analysis of paternally inherited fetal alleles. These sequences are biallelic deletion/insertion polymorphisms (DIPs) located very close to short tandem repeat (STR) markers, for combined analysis. In this study, 48 women were tested with 28 DIP-STRs during the first, second, and third trimester of pregnancy.ResultsPositive results were obtained across markers, including longer ones (386 base-pairs) and with blood samples collected during early pregnancy, such as 10 weeks of gestational age.ConclusionThese data show that DIP-STR markers can be used to amplify specific genomic regions of circulating fetal DNA to obtain targeted genetic information. This method may contribute to developments in noninvasive prenatal paternity testing and diagnosis of certain genetic diseases.

    更新日期:2018-08-02
  • The power of heredity and the relevance of eugenic history
    Genet. Med. (IF 9.937) Pub Date : 2018-07-31
    Paul A. Lombardo

    The power of heredity and the relevance of eugenic historyThe power of heredity and the relevance of eugenic history, Published online: 31 July 2018; doi:10.1038/s41436-018-0123-4The power of heredity and the relevance of eugenic history

    更新日期:2018-07-31
  • Disease and subtype specific signatures enable precise diagnosis of the mucopolysaccharidoses
    Genet. Med. (IF 9.937) Pub Date : 2018-07-31
    Jennifer T. Saville, Belinda K. McDermott, Janice M. Fletcher, Maria Fuller

    PurposeExpanding treatments for the mucopolysaccharidoses—a family of genetic disorders—place unprecedented demands for accurate, timely diagnosis because best outcomes are seen with early initiation of appropriate therapies. Here we sought to improve the diagnostic odyssey by measuring specific glycosaminoglycan fragments with terminal residues complicit with the genetic defect resulting in precise diagnosis rather than the usual first-line, ambiguous total glycosaminoglycan determinations that return poor diagnostic yield.MethodsA derivatizing reagent was added to urine aliquots (0.5 μmol creatinine) before separation of the glycosaminoglycan fragments by liquid chromatography and quantification with electrospray ionization–tandem mass spectrometry using multiple reaction monitoring for 10 targeted fragments plus the internal standard.ResultsAll 93 mucopolysaccharidosis patients were correctly identified as 1 of 10 subtypes from a total of 723 de-identified subjects—blinded to diagnosis—based on the presence of specific “signature” glycosaminoglycan fragments. Employing reference intervals calculated from 630 unaffected urines, with 99% confidence intervals, provided a laboratory test with 100% specificity and sensitivity.ConclusionThis novel urine assay allows diagnosis of 10 mucopolysaccharidosis subtypes in a single test. The precise quantification of unique glycosaminoglycan fragments also enables longitudinal biochemical monitoring following therapeutic interventions.

    更新日期:2018-07-31
  • DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes
    Genet. Med. (IF 9.937) Pub Date : 2018-07-28
    Marcy E. Richardson, Hansook Chong, Wenbo Mu, Blair R. Conner, Vickie Hsuan, Sara Willett, Stephanie Lam, Pei Tsai, Tina Pesaran, Adam C. Chamberlin, Min-Sun Park, Phillip Gray, Rachid Karam, Aaron Elliott

    PurposeGross duplications are ambiguous in terms of clinical interpretation due to the limitations of the detection methods that cannot infer their context, namely, whether they occur in tandem or are duplicated and inserted elsewhere in the genome. We investigated the proportion of gross duplications occurring in tandem in breast cancer predisposition genes with the intent of informing their classifications.MethodsThe DNA breakpoint assay (DBA) is a custom, paired-end, next-generation sequencing (NGS) method designed to capture and detect deep-intronic DNA breakpoints in gross duplications in BRCA1, BRCA2, ATM, CDH1, PALB2, and CHEK2.ResultsDBA allowed us to ascertain breakpoints for 44 unique gross duplications from 147 probands. We determined that the duplications occurred in tandem in 114 (78%) carriers from this cohort, while the remainder have unknown tandem status. Among the tandem gross duplications that were eligible for reclassification, 95% of them were upgraded to pathogenic.ConclusionDBA is a novel, high-throughput, NGS-based method that informs the tandem status, and thereby the classification of, gross duplications. This method revealed that most gross duplications in the investigated genes occurred in tandem and resulted in a pathogenic classification, which helps to secure the necessary treatment options for their carriers.

    更新日期:2018-07-28
  • Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma
    Genet. Med. (IF 9.937) Pub Date : 2018-07-27
    Susan Richter, Laura Gieldon, Ying Pang, Mirko Peitzsch, Thanh Huynh, Rocio Leton, Bruna Viana, Tonino Ercolino, Anastasios Mangelis, Elena Rapizzi, Mario Menschikowski, Daniela Aust, Matthias Kroiss, Felix Beuschlein, Volker Gudziol, Henri JLM Timmers, Jacques Lenders, Massimo Mannelli, Alberto Cascon, Karel Pacak, Mercedes Robledo, Graeme Eisenhofer, Barbara Klink

    PurposeMetabolic aberrations have been described in neoplasms with pathogenic variants (PV) in the Krebs cycle genes encoding succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH). In turn, accumulation of oncometabolites succinate, fumarate, and 2-hydroxyglutarate can be employed to identify tumors with those PV . Additionally, such metabolic readouts may aid in genetic variant interpretation and improve diagnostics.MethodsUsing liquid chromatography–mass spectrometry, 395 pheochromocytomas and paragangliomas (PPGLs) from 391 patients were screened for metabolites to indicate Krebs cycle aberrations. Multigene panel sequencing was applied to detect driver PV in cases with indicative metabolite profiles but undetermined genetic drivers.ResultsAberrant Krebs cycle metabolomes identified rare cases of PPGLs with germline PV in FH and somatic PV in IDHx and SDHx, including the first case of a somatic IDH2 PV in PPGL. Metabolomics also reliably identified PPGLs with SDHx loss-of-function (LOF) PV. Therefore we utilized tumor metabolite profiles to further classify variants of unknown significance in SDHx, thereby enabling missense variants associated with SDHx LOF to be distinguished from benign variants.ConclusionWe propose incorporation of metabolome data into the diagnostics algorithm in PPGLs to guide genetic testing and variant interpretation and to help identify rare cases with PV in FH and IDHx.

    更新日期:2018-07-26
  • The Gen-Equip Project: evaluation and impact of genetics e-learning resources for primary care in six European languages
    Genet. Med. (IF 9.937) Pub Date : 2018-07-27
    Leigh Jackson, Anita O’Connor, Milena Paneque, Vaclava Curtisova, Peter W. Lunt, Radka Kremlíková Pourova, Milan Macek Jr, Vigdis Stefansdottir, Daniela Turchetti, Mariana Campos, Lidewij Henneman, Lea Godino, Heather Skirton, Martina C. Cornel

    PurposeGenetic advances mean patients at risk of genetic conditions can be helped through testing, clinical screening, and preventive treatment, but they must first be identified to benefit. Ensuring quality of genetic care for patients requires genetic expertise in all health services, including primary care. To address an educational shortfall, a series of e-learning resources was developed in six languages to equip primary care professionals with genetic skills relevant for practice. The purpose of the study was to evaluate these resources using Kirkpatrick’s framework for educational outcomes.MethodsMixed methods (qualitative and quantitative) were used over four phases of the study.ResultsA high level of satisfaction with the resources was reported. Knowledge and skills improved significantly after using the education material. Participants reported changes in confidence and practice behavior, including family history taking, seeking advice from specialists and referring patients. The resources helped users to learn how to explain genetics. Many visited the resources repeatedly and some used them to educate colleagues or students.ConclusionGen-Equip modules are effective in improving genetic knowledge, skills, and attitudes for primary care professionals. They provide both continuing professional development and just-in-time learning for a potentially large global audience at a practical level.

    更新日期:2018-07-26
  • Response to Biesecker
    Genet. Med. (IF 9.937) Pub Date : 2018-07-27
    Bryce A. Mendelsohn, Marta Sabbadini

    Response to BieseckerResponse to Biesecker, Published online: 27 July 2018; doi:10.1038/s41436-018-0133-2Response to Biesecker

    更新日期:2018-07-26
  • Correction: Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions
    Genet. Med. (IF 9.937) Pub Date : 2018-07-26
    N. T. Leach, D. R. Wilson Mathews, L. S. Rosenblum, Z. Zhou, H. Zhu, R. A. Heim

    Correction: Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditionsCorrection: Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions, Published online: 26 July 2018; doi:10.1038/s41436-018-0128-zCorrection: Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions

    更新日期:2018-07-26
  • Next-generation sequencing and prenatal 'omics: advanced diagnostics and new insights into human development
    Genet. Med. (IF 9.937) Pub Date : 2018-07-22
    Neeta L. Vora, Lisa Hui

    Prenatal genetics has evolved over the last decade to include application of new 'omics technologies to improve perinatal care. The clinical utility of these technologies when applied to direct fetal specimens from amniocentesis or chorionic villus sampling is being explored. In this review, we provide an overview of use of prenatal exome sequencing and role in evaluation of the structurally abnormal fetus, potential applications of genome sequencing, and finally, use of transcriptomics to assess placental and fetal well-being.

    更新日期:2018-07-22
  • The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1–6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7–34 pathogenic variant
    Genet. Med. (IF 9.937) Pub Date : 2018-07-22
    Julie W. Rutten, Bastian J. Van Eijsden, Marco Duering, Eric Jouvent, Christian Opherk, Leonardo Pantoni, Antonio Federico, Martin Dichgans, Hugh S. Markus, Hugues Chabriat, Saskia A. J. Lesnik Oberstein

    Purpose CADASIL is a small-vessel disease caused by a cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. We recently found that pathogenic variant in EGFr domains 7–34 have an unexpectedly high frequency in the general population (1:300). We hypothesized that EGFr 7–34 pathogenic variant more frequently cause a much milder phenotype, thereby explaining an important part of CADASIL disease variability. Methods Age at first stroke, survival and white matter hyperintensity volume were compared between 664 CADASIL patients with either a NOTCH3 EGFr 1–6 pathogenic variant or an EGFr 7–34 pathogenic variant. The frequencies of NOTCH3 EGFr 1–6 and EGFr 7–34 pathogenic variant were compared between individuals in the genome Aggregation Database and CADASIL patients. Results CADASIL patients with an EGFr 1–6 pathogenic variant have a 12-year earlier onset of stroke than those with an EGFr 7–34 pathogenic variant, lower survival, and higher white matter hyperintensity volumes. Among diagnosed CADASIL patients, 70% have an EGFr 1–6 pathogenic variant, whereas EGFr 7–34 pathogenic variant strongly predominate in the population. Conclusion NOTCH3 pathogenic variant position is the most important determinant of CADASIL disease severity, with EGFr 7–34 pathogenic variant predisposing to a later onset of stroke and longer survival.

    更新日期:2018-07-22
  • Response to Mendelsohn and Sabbadini
    Genet. Med. (IF 9.937) Pub Date : 2018-07-19
    Leslie G. Biesecker

    Response to Mendelsohn and Sabbadini Response to Mendelsohn and Sabbadini, Published online: 19 July 2018; doi:10.1038/s41436-018-0134-1 Response to Mendelsohn and Sabbadini

    更新日期:2018-07-19
  • Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients
    Genet. Med. (IF 9.937) Pub Date : 2018-07-16
    Bruna Calsina, Maria Currás-Freixes, Alexandre Buffet, Tirso Pons, Laura Contreras, Rocío Letón, Iñaki Comino-Méndez, Laura Remacha, María Calatayud, Berta Obispo, Antoine Martin, Regis Cohen, Susan Richter, Judith Balmaña, Esther Korpershoek, Elena Rapizzi, Timo Deutschbein, Laurent Vroonen, Judith Favier, Ronald R. de Krijger, Martin Fassnacht, Felix Beuschlein, Henri J. Timmers, Graeme Eisenhofer, Massimo Mannelli, Karel Pacak, Jorgina Satrústegui, Cristina Rodríguez-Antona, Laurence Amar, Alberto Cascón, Nicole Dölker, Anne-Paule Gimenez-Roqueplo, Mercedes Robledo

    PurposeMDH2 (malate dehydrogenase 2) has recently been proposed as a novel potential pheochromocytoma/paraganglioma (PPGL) susceptibility gene, but its role in the disease has not been addressed. This study aimed to determine the prevalence of MDH2 pathogenic variants among PPGL patients and determine the associated phenotype.MethodsEight hundred thirty patients with PPGLs, negative for the main PPGL driver genes, were included in the study. Interpretation of variants of unknown significance (VUS) was performed using an algorithm based on 20 computational predictions, by implementing cell-based enzymatic and immunofluorescence assays, and/or by using a molecular dynamics simulation approach.ResultsFive variants with potential involvement in pathogenicity were identified: three missense (p.Arg104Gly, p.Val160Met and p.Ala256Thr), one in-frame deletion (p.Lys314del), and a splice-site variant (c.429+1G>T). All were germline and those with available biochemical data, corresponded to noradrenergic PPGL.ConclusionThis study suggests that MDH2 pathogenic variants may play a role in PPGL susceptibility and that they might be responsible for less than 1% of PPGLs in patients without pathogenic variants in other major PPGL driver genes, a prevalence similar to the one recently described for other PPGL genes. However, more epidemiological data are needed to recommend MDH2 testing in patients negative for other major PPGL genes.

    更新日期:2018-07-16
  • Clinical genome sequencing in an unbiased pediatric cohort
    Genet. Med. (IF 9.937) Pub Date : 2018-07-16
    Isabelle Thiffault, Emily Farrow, Lee Zellmer, Courtney Berrios, Neil Miller, Margaret Gibson, Raymond Caylor, Janda Jenkins, Deb Faller, Sarah Soden, Carol Saunders

    PurposeWe report for the first time, the use of clinical genome sequencing (GS) in an unbiased pediatric cohort. We describe the clinical validation, patient metrics, ordering patterns, results, reimbursement, and physician retrieval of results for the first consecutive 80 cases.MethodsClinical GS was performed for both inpatients and outpatients undergoing etiologic evaluations. Results were reported in the electronic medical record. Evidence of report retrieval by clinicians and whether interpretation was concordant with laboratory report was obtained through retrospective chart review.ResultsTwenty definitive diagnoses were made in 19 patients (24%; n = 80). Except for two partial gene deletions, all diagnostic variants would have been detectable by our exome methods. Surprisingly, there was no documentation of communication of results to the family in the medical record for 17.5% of patients, and in 7.5%, physician and laboratory interpretations were discordant. Average insurance reimbursement was 30.2%, with yield for commercial payers significantly higher, at 54.1%.ConclusionsThe detection rate of GS is equivalent and potentially superior to exome sequencing (ES). Reimbursement rates were variable but overall satisfactory for commercial insurers, and poor for government entities. In addition, we identify opportunities for improvement in the communication of results to families, likely translatable to other tests and other institutions.

    更新日期:2018-07-16
  • Health behaviors among unaffected participants following receipt of variants of uncertain significance in cardiomyopathy-associated genes
    Genet. Med. (IF 9.937) Pub Date : 2018-07-12
    Ilana M. Miller, Katie L. Lewis, Tokunbor A. Lawal, David Ng, Jennifer J. Johnston, Barbara B. Biesecker, Leslie G. Biesecker

    Purpose Studies on returning variants of uncertain significance (VUS) results have predominantly included patients with a personal or family history of cancer and cancer-associated gene VUS. This study examined health behaviors among participants with cardiomyopathy-associated gene VUS, but without a personal history of cardiomyopathy. Methods Sixty-eight eligible participants without apparent cardiomyopathy but with VUS in cardiomyopathy-associated genes completed a survey of health behaviors, disclosure, distress, uncertainty, positive experiences, decisional conflict, and perceived value. The medical records of participants who reported cardiac testing because of their VUS were reviewed for testing indication(s). Results Two participants had cardiac testing due to their VUS alone. Four had cardiac testing because of their VUS and other clinical indications. Twelve changed health behaviors, including one participant who was subsequently diagnosed with cardiomyopathy. Distress, uncertainty, and decisional conflict were low (means = 1.2, 4.2, and 24.5 (scale ranges = 0–30, 0–45, and 15–75), respectively), and positive experiences and perceived value were moderate (means = 12.4 and 14.4 (scale ranges = 0–20 and 4–20), respectively). Greater perceived value was associated with greater likelihood to engage in health behaviors (P = 0.04). Conclusion Positive VUS results can be returned to apparently unaffected individuals with modest use of healthcare resources, minimal behavioral changes, and favorable psychological reactions.

    更新日期:2018-07-12
  • microRNAs as biomarkers in Pompe disease
    Genet. Med. (IF 9.937) Pub Date : 2018-07-12
    Antonietta Tarallo, Annamaria Carissimo, Francesca Gatto, Edoardo Nusco, Antonio Toscano, Olimpia Musumeci, Marcella Coletta, Marianthi Karali, Emma Acampora, Carla Damiano, Nadia Minopoli, Simona Fecarotta, Roberto Della Casa, Tiziana Mongini, Liliana Vercelli, Lucio Santoro, Lucia Ruggiero, Federica Deodato, Roberta Taurisano, Bruno Bembi, Andrea Dardis, Sandro Banfi, WW Pim Pijnappel, Ans T van der Ploeg, Giancarlo Parenti

    Purpose We studied microRNAs as potential biomarkers for Pompe disease. Methods We analyzed microRNA expression by small RNA-seq in tissues from the disease murine model at two different ages (3 and 9 months), and in plasma from Pompe patients. Results In the mouse model we found 211 microRNAs that were differentially expressed in gastrocnemii and 66 in heart, with a different pattern of expression at different ages. In a preliminary analysis in plasma from six patients 55 microRNAs were differentially expressed. Sixteen of these microRNAs were common to those dysregulated in mouse tissues. These microRNAs are known to modulate the expression of genes involved in relevant pathways for Pompe disease pathophysiology (autophagy, muscle regeneration, muscle atrophy). One of these microRNAs, miR-133a, was selected for further quantitative real-time polymerase chain reaction analysis in plasma samples from 52 patients, obtained from seven Italian and Dutch biobanks. miR-133a levels were significantly higher in Pompe disease patients than in controls and correlated with phenotype severity, with higher levels in infantile compared with late-onset patients. In three infantile patients miR-133a decreased after start of enzyme replacement therapy and evidence of clinical improvement. Conclusion Circulating microRNAs may represent additional biomarkers of Pompe disease severity and of response to therapy.

    更新日期:2018-07-12
  • Exome sequencing in congenital ataxia identifies two new candidate genes and highlights a pathophysiological link between some congenital ataxias and early infantile epileptic encephalopathies
    Genet. Med. (IF 9.937) Pub Date : 2018-07-12
    Stéphanie Valence, Emmanuelle Cochet, Christelle Rougeot, Catherine Garel, Sandra Chantot-Bastaraud, Elodie Lainey, Alexandra Afenjar, Marie-Anne Barthez, Nathalie Bednarek, Diane Doummar, Laurence Faivre, Cyril Goizet, Damien Haye, Bénédicte Heron, Isabelle Kemlin, Didier Lacombe, Mathieu Milh, Marie-Laure Moutard, Florence Riant, Stéphanie Robin, Agathe Roubertie, Pierre Sarda, Annick Toutain, Laurent Villard, Dorothée Ville, Thierry Billette de Villemeur, Diana Rodriguez, Lydie Burglen

    Purpose To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. Methods Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes. Results We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant. Conclusion Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).

    更新日期:2018-07-12
  • Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network
    Genet. Med. (IF 9.937) Pub Date : 2018-07-12
    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 Ginsburg

    Purpose While there is growing scientific evidence for and significant advances in the use of genomic technologies in medicine, there is a significant lag in the clinical adoption and sustainability of genomic medicine. Here we describe the findings from the National Human Genome Research Institute’s (NHGRI) Implementing GeNomics In pracTicE (IGNITE) Network in identifying key constructs, opportunities, and challenges associated with driving sustainability of genomic medicine in clinical practice. Methods Network members and affiliates were surveyed to identify key drivers associated with implementing and sustaining a genomic medicine program. Tallied results were used to develop and weigh key constructs/drivers required to support sustainability of genomic medicine programs. Results The top three driver–stakeholder dyads were (1) genomic training for providers, (2) genomic clinical decision support (CDS) tools embedded in the electronic health record (EHR), and (3) third party reimbursement for genomic testing. Conclusion Priorities may differ depending on healthcare systems when comparing the current state of key drivers versus projected needs for supporting genomic medicine sustainability. Thus we provide gap-filling guidance based on IGNITE members’ experiences. Although results are limited to findings from the IGNITE network, their implementation, scientific, and clinical experience may be used as a road map by others considering implementing genomic medicine programs.

    更新日期:2018-07-12
  • Private payer coverage policies for exome sequencing (ES) in pediatric patients: trends over time and analysis of evidence cited
    Genet. Med. (IF 9.937) Pub Date : 2018-07-12
    Michael P. Douglas, Stephanie L. Parker, Julia R. Trosman, Anne M. Slavotinek, Kathryn A. Phillips

    Purpose Exome sequencing (ES) is being adopted for neurodevelopmental disorders in pediatric patients. However, little is known about current coverage policies or the evidence cited supporting these policies. Our study is the first in-depth review of private payer ES coverage policies for pediatric patients with neurodevelopmental disorders. Methods We reviewed private payer coverage policies and examined evidence cited in the policies of the 15 largest payers in 2017, and trends in coverage policies and evidence cited (2015–2017) for the five largest payers. Results There were four relevant policies (N = 5 payers) in 2015 and 13 policies (N = 15 payers) in 2017. In 2015, no payer covered ES, but by 2017, three payers from the original registry payers did. In 2017, 8 of the 15 payers covered ES. We found variations in the number and types of evidence cited. Positive coverage policies tended to include a larger number and range of citations. Conclusion We conclude that more systematic assessment of evidence cited in coverage policies can provide a greater understanding of coverage policies and how evidence is used. Such assessments could facilitate the ability of researchers to provide the needed evidence, and the ability of clinicians to provide the most appropriate testing for patients.

    更新日期:2018-07-12
  • Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria
    Genet. Med. (IF 9.937) Pub Date : 2018-07-12
    Sven F. Garbade, Nan Shen, Nastassja Himmelreich, Dorothea Haas, Friedrich K. Trefz, Georg F. Hoffmann, Peter Burgard, Nenad Blau

    Purpose The nature of phenylalanine hydroxylase (PAH) variants determines residual enzyme activity, which modifies the clinical phenotype in phenylketonuria (PKU). We exploited the statistical power of a large genotype database to determine the relationship between genotype and phenotype in PKU. Methods A total of 9336 PKU patients with 2589 different genotypes, carrying 588 variants, were investigated using an allelic phenotype value (APV) algorithm. Results We identified 251 0-variants encoding inactive PAH, and assigned APVs (0 = classic PKU; 5 = mild PKU; 10 = mild hyperphenylalaninaemia) to 88 variants in PAH-functional hemizygous patients. The genotypic phenotype values (GPVs) were set equal to the higher-APV allele, which was assumed to be dominant over the lower-APV allele and to determine the metabolic phenotype. GPVs for 8872 patients resulted in cut-off ranges of 0.0–2.7 for classic PKU, 2.8–6.6 for mild PKU and 6.7–10.0 for mild hyperphenylalaninaemia. Genotype-based phenotype prediction was 99.2% for classic PKU, 46.2% for mild PKU and 89.5% for mild hyperphenylalaninaemia. The relationships between known pretreatment blood phenylalanine levels and GPVs (n = 4217), as well as tetrahydrobiopterin responsiveness and GPVs (n = 3488), were significant (both P < 0.001). Conclusions APV and GPV are powerful tools to investigate genotype–phenotype associations, and can be used for genetic counselling of PKU families.

    更新日期:2018-07-12
  • Direct-to-consumer raw genetic data and third-party interpretation services: more burden than bargain?
    Genet. Med. (IF 9.937) Pub Date : 2018-07-12
    Tia Moscarello, Brittney Murray, Chloe M. Reuter, Erin Demo

    Direct-to-consumer raw genetic data and third-party interpretation services: more burden than bargain? Direct-to-consumer raw genetic data and third-party interpretation services: more burden than bargain?, Published online: 12 July 2018; doi:10.1038/s41436-018-0097-2 Direct-to-consumer raw genetic data and third-party interpretation services: more burden than bargain?

    更新日期:2018-07-12
  • Phrank measures phenotype sets similarity to greatly improve Mendelian diagnostic disease prioritization
    Genet. Med. (IF 9.937) Pub Date : 2018-07-12
    Karthik A. Jagadeesh, Johannes Birgmeier, Harendra Guturu, Cole A. Deisseroth, Aaron M. Wenger, Jonathan A. Bernstein, Gill Bejerano

    Purpose Exome sequencing and diagnosis is beginning to spread across the medical establishment. The most time-consuming part of genome-based diagnosis is the manual step of matching the potentially long list of patient candidate genes to patient phenotypes to identify the causative disease. Methods We introduce Phrank (for phenotype ranking), an information theory–inspired method that utilizes a Bayesian network to prioritize candidate diseases or genes, as a stand-alone module that can be run with any underlying knowledgebase and any variant filtering scheme. Results Phrank outperforms existing methods at ranking the causative disease or gene when applied to 169 real patient exomes with Mendelian diagnoses. Phrank’s greatest improvement is in disease space, where across all 169 patients it ranks only 3 diseases on average ahead of the true diagnosis, whereas Phenomizer ranks 32 diseases ahead of the causal one. Conclusions Using Phrank to rank all patient candidate genes or diseases, as they start working through a new case, will save the busy clinician much time in deriving a genetic diagnosis.

    更新日期:2018-07-12
  • The functional impact of variants of uncertain significance in BRCA2
    Genet. Med. (IF 9.937) Pub Date : 2018-07-10
    Romy L. S. Mesman, Fabienne M. G. R. Calléja, Giel Hendriks, Bruno Morolli, Branislav Misovic, Peter Devilee, Christi J. van Asperen, Harry Vrieling, Maaike P. G. Vreeswijk

    Purpose Genetic testing has uncovered large numbers of variants in the BRCA2 gene for which the clinical significance is unclear. Cancer risk prediction of these variants of uncertain significance (VUS) can be improved by reliable assessment of the extent of impairment of the tumor suppressor function(s) of BRCA2. Methods Here, we evaluated the performance of the mouse embryonic stem cell (mESC)-based functional assay on an extensive set of BRCA2 missense variants. Results Whereas all 20 nonpathogenic (class 1/2) variants were able to complement the cell lethal phenotype induced by loss of endogenous mouse Brca2, only 1 out of 15 pathogenic (class 4/5) variants (p.Gly2609Asp) was able to do so. However, in this variant the major tumor suppressive activity of BRCA2, i.e., homology directed repair (HDR), was severely abrogated. Among 43 evaluated VUS (class 3), 7 were unable to complement the lethal phenotype of mouse Brca2 loss while 7 other variants displayed a more severe reduction of HDR activity than observed for class 1/ 2 variants. Conclusion The mESC-based BRCA2 functional assay can reliably determine the functional impact of VUS, distinguish between pathogenic and nonpathogenic variants, and may contribute to improved cancer risk estimation for BRCA2 VUS carriers.

    更新日期:2018-07-10
  • Navigating the nuances of clinical sequence variant interpretation in Mendelian disease
    Genet. Med. (IF 9.937) Pub Date : 2018-07-10
    Natasha T. Strande, Sarah E. Brnich, Tamara S. Roman, Jonathan S. Berg

    Understanding clinical genetic test results in the era of next-generation sequencing has become increasingly complex, necessitating clear and thorough guidelines for sequence variant interpretation. To meet this need the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for a systematic approach for sequence variant interpretation in 2015. This framework is intended to be adaptable to any Mendelian condition, promoting transparency and consistency in variant interpretation, yet its comprehensive nature yields important challenges and caveats that end users must understand. In this review, we address some of these nuances and discuss the evolving efforts to refine and adapt this framework. We also consider the added complexity of distinguishing between variant-level interpretations and case-level conclusions, particularly in the context of the large gene panel approach to clinical diagnostics.

    更新日期:2018-07-10
  • Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families
    Genet. Med. (IF 9.937) Pub Date : 2018-07-10
    Laurent Castéra, Valentin Harter, Etienne Muller, Sophie Krieger, Nicolas Goardon, Agathe Ricou, Antoine Rousselin, Germain Paimparay, Angelina Legros, Olivia Bruet, Céline Quesnelle, Florian Domin, Chankannira San, Baptiste Brault, Robin Fouillet, Caroline Abadie, Odile Béra, Pascaline Berthet, Thierry Frébourg, Dominique Vaur

    Purpose Integration of gene panels in the diagnosis of hereditary breast and ovarian cancer (HBOC) requires a careful evaluation of the risk associated with pathogenic or likely pathogenic variants (PVs) detected in each gene. Here we analyzed 34 genes in 5131 suspected HBOC index cases by next-generation sequencing. Methods Using the Exome Aggregation Consortium data sets plus 571 individuals from the French Exome Project, we simulated the probability that an individual from the Exome Aggregation Consortium carries a PV and compared it to the estimated frequency within the HBOC population. Results Odds ratio conferred by PVs within BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, BRIP1, CHEK2, and MSH6 were estimated at 13.22 [10.01–17.22], 8.61 [6.78–10.82], 8.22 [4.91–13.05], 4.54 [2.55–7.48], 5.23 [1.46–13.17], 3.20 [2.14–4.53], 2.49 [1.42–3.97], 1.67 [1.18–2.27], and 2.50 [1.12–4.67], respectively. PVs within RAD51C, RAD51D, and BRIP1 were associated with ovarian cancer family history (OR = 11.36 [5.78–19.59], 12.44 [2.94–33.30] and 3.82 [1.66–7.11]). PALB2 PVs were associated with bilateral breast cancer (OR = 16.17 [5.48–34.10]) and BARD1 PVs with triple-negative breast cancer (OR = 11.27 [3.37–25.01]). Burden tests performed in both patients and the French Exome Project population confirmed the association of PVs of BRCA1, BRCA2, PALB2, and RAD51C with HBOC. Conclusion Our results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of HBOC and suggest that the other genes are involved in an oligogenic determinism.

    更新日期:2018-07-10
  • Accelerating evidence gathering and approval of precision medicine therapies: the FDA takes aim at rare mutations
    Genet. Med. (IF 9.937) Pub Date : 2018-07-10
    Amalia M. Issa, Adrian Thorogood, Yann Joly, Bartha M. Knoppers

    Accelerating evidence gathering and approval of precision medicine therapies: the FDA takes aim at rare mutations Accelerating evidence gathering and approval of precision medicine therapies: the FDA takes aim at rare mutations, Published online: 10 July 2018; doi:10.1038/s41436-018-0099-0 Accelerating evidence gathering and approval of precision medicine therapies: the FDA takes aim at rare mutations

    更新日期:2018-07-10
  • Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background
    Genet. Med. (IF 9.937) Pub Date : 2018-07-06
    Kelly E. Ormond, Miranda L. G. Hallquist, Adam H. Buchanan, Danielle Dondanville, Mildred K. Cho, Maureen Smith, Myra Roche, Kyle B. Brothers, Curtis R. Coughlin II, Laura Hercher, Louanne Hudgins, Seema Jamal, Howard P. Levy, Misha Raskin, Melissa Stosic, Wendy Uhlmann, Karen E. Wain, Erin Currey, W. Andrew Faucett

    PurposeIn response to genetic testing being widely ordered by nongenetics clinicians, the Consent and Disclosure Recommendations (CADRe) Workgroup of the Clinical Genome Resource (ClinGen; clinicalgenome.org) developed guidance to facilitate communication about genetic testing and efficiently improve the patient experience. Considering ethical, legal, and social implications, and medical factors, CADRe developed and pilot tested two rubrics addressing consent for genetic testing and results disclosure. The CADRe rubrics allow for adjusting the communication approach based on circumstances specific to patients and ordering clinicians.MethodsWe present results of a formative survey of 66 genetics clinicians to assess the consent rubric for nine genes (MLH1, CDH1, TP53, GJB2, OTC; DMD, HTT, and CYP2C9/VKORC1). We also conducted interviews and focus groups with family and patient stakeholders (N = 18), nongenetics specialists (N = 27), and genetics clinicians (N = 32) on both rubrics.ResultsFormative evaluation of the CADRe rubrics suggests key factors on which to make decisions about consent and disclosure discussions for a “typical” patient.ConclusionWe propose that the CADRe rubrics include the primary issues necessary to guide communication recommendations, and are ready for pilot testing by nongenetics clinicians. Consultation with genetics clinicians can be targeted toward more complex or intensive consent and disclosure counseling.

    更新日期:2018-07-08
  • Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study
    Genet. Med. (IF 9.937) Pub Date : 2018-07-04
    Mahim Jain, Allison Tam, Jay R. Shapiro, Robert D. Steiner, Peter A. Smith, Michael B. Bober, Tracy Hart, David Cuthbertson, Jeff Krischer, Mary Mullins, Sunil Bellur, Peter H. Byers, Melanie Pepin, Michaela Durigova, Francis H. Glorieux, Frank Rauch, Brendan Lee, V. Reid Sutton, Sandesh C. S. Nagamani

    Purpose Osteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI. Methods Using data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves. Results In children, the median z-scores for height in OI types I, III, and IV were −0.66, −6.91, and −2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was −4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05). Conclusion From the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves.

    更新日期:2018-07-04
  • Normative and conceptual ELSI research: what it is, and why it’s important
    Genet. Med. (IF 9.937) Pub Date : 2018-07-04
    Lisa S. Parker, Pamela L. Sankar, Joy Boyer, JD Jean McEwen, David Kaufman

    The Ethical, Legal, and Social Implications (ELSI) Research Program of the National Human Genome Research Institute sponsors research examining ethical, legal, and social issues arising in the context of genetics/genomics. The ELSI Program endorses an understanding of research not as the sole province of empirical study, but instead as systematic study or inquiry, of which there are many types and methods. ELSI research employs both empirical and nonempirical methods. Because the latter remain relatively unfamiliar to biomedical and translational scientists, this paper seeks to elucidate the relationship between empirical and nonempirical methods in ELSI research. It pays particular attention to the research questions and methods of normative and conceptual research, which examine questions of value and meaning, respectively. To illustrate the distinct but interrelated roles of empirical and nonempirical methods in ELSI research, including normative and conceptual research, the paper demonstrates how a range of methods may be employed both to examine the evolution of the concept of incidental findings (including the recent step toward terming them ‘secondary findings’), and to address the normative question of how genomic researchers and clinicians should manage incidental such findings.

    更新日期:2018-07-04
  • Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy
    Genet. Med. (IF 9.937) Pub Date : 2018-07-02
    Andre E. Minoche, Claire Horvat, Renee Johnson, Velimir Gayevskiy, Sarah U. Morton, Alexander P. Drew, Kerhan Woo, Aaron L. Statham, Ben Lundie, Richard D. Bagnall, Jodie Ingles, Christopher Semsarian, J. G. Seidman, Christine E. Seidman, Marcel E. Dinger, Mark J. Cowley, Diane Fatkin

    PurposeWe evaluated genome sequencing (GS) as an alternative to multigene panel sequencing (PS) for genetic testing in dilated cardiomyopathy (DCM).MethodsForty-two patients with familial DCM underwent PS and GS, and detection rates of rare single-nucleotide variants and small insertions/deletions in panel genes were compared. Loss-of-function variants in 406 cardiac-enriched genes were evaluated, and an assessment of structural variation was performed.ResultsGS provided broader and more uniform coverage than PS, with high concordance for rare variant detection in panel genes. GS identified all PS-identified pathogenic or likely pathogenic variants as well as two additional likely pathogenic variants: one was missed by PS due to low coverage, the other was a known disease-causing variant in a gene not included on the panel. No loss-of-function variants in the extended gene set met clinical criteria for pathogenicity. One BAG3 structural variant was classified as pathogenic.ConclusionOur data support the use of GS for genetic testing in DCM, with high variant detection accuracy and a capacity to identify structural variants. GS provides an opportunity to go beyond suites of established disease genes, but the incremental yield of clinically actionable variants is limited by a paucity of genetic and functional evidence for DCM association.

    更新日期:2018-07-03
  • Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders
    Genet. Med. (IF 9.937) Pub Date : 2018-07-02
    Yasmin Bylstra, Jyn Ling Kuan, Weng Khong Lim, Jaydutt Digambar Bhalshankar, Jing Xian Teo, Sonia Davila, Bin Tean Teh, Steve Rozen, Ene-Choo Tan, Wendy Kein Meng Liew, Khung Keong Yeo, Patrick Tan, Seang Mei Saw, Ching-Yu Cheng, Stuart Cook, Roger Foo, Saumya Shekhar Jamuar

    PurposeGenomic studies have demonstrated the necessity of ethnicity-specific population data to ascertain variant pathogenicity for disease diagnosis and treatment. This study examined the carrier prevalence of treatable inherited disorders (TIDs), where early diagnosis of at-risk offspring can significantly improve clinical outcomes.MethodsExisting exome/ genome sequencing data of 831 Singaporeans were aggregated and examined for disease causing variants in 104 genes associated with 80 TIDs.ResultsAmong the 831 Singaporean participants, genomic variant filtering and analysis identified 1 in 18 individuals (6%) to be carriers amongst one of 13 TIDs. Citrin deficiency and Wilson disease had the highest carrier frequency of 1 in 41, and 1 in 103 individuals, respectively. The pathogenic variants associated with citrin deficiency were 24 times more prevalent in our local cohorts when compared to Western cohorts.ConclusionThis study demonstrates the value of a population specific genomic database to determine true disease prevalence and has enabled the discovery of carrier frequencies of treatable genetic conditions specific to South East Asian populations, which are currently underestimated in existing data sources. This study framework can be adapted to other population groups and expanded to multiple genetic conditions to inform health policies directing precision medicine.

    更新日期:2018-07-03
  • Beyond the panel: preconception screening in consanguineous couples using the TruSight One “clinical exome”
    Genet. Med. (IF 9.937) Pub Date : 2018-07-02
    Edwin P. Kirk, Kristine Barlow-Stewart, Arthavan Selvanathan, Sarah Josephi-Taylor, Lisa Worgan, Sulekha Rajagopalan, Mark J. Cowley, Velimir Gayevskiy, Alan Bittles, Leslie Burnett, George Elakis, William Lo, Michael Buckley, Alison Colley, Tony Roscioli

    PurposeTo provide proof of concept by broadening preconception screening beyond targeted testing to inform reproductive risk in consanguineous couples.MethodsConsanguineous couples were screened for autosomal recessive and X-linked disorders using the TruSight One panel of 4,813 genes associated with human disease.ResultsWe recruited 22 couples, of whom 15 elected to have sequencing. We found four couples to be at risk of autosomal recessive disorders, including one with a child affected by Poretti–Boltshauser syndrome (a diagnosis not made prior to the study) and another previously known to carry a β-globin variant. Two couples were found to carry variants unrelated to known family history. These variants were in the genes C5orf42 (associated with Joubert syndrome and orofaciodigital syndrome) and GYS2 (associated with glycogen synthase deficiency). One known variant was not detected—a single exon deletion in FAM20C. We would not expect to identify this variant with the methodology employed. Of the four variants identified, only the β-globin variant would have been found using available commercial preconception screening panels.ConclusionPreconception screening of consanguineous couples for recessive and X-linked disorders using genomic sequencing is practicable, and is likely to detect many more at-risk couples than any targeted panel could achieve. A couples-based approach greatly reduces the associated analysis and counselling burden.

    更新日期:2018-07-03
  • Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer
    Genet. Med. (IF 9.937) Pub Date : 2018-07-02
    Matthew B. Yurgelun, Anu B. Chittenden, Vicente Morales-Oyarvide, Douglas A. Rubinson, Richard F. Dunne, Margaret M. Kozak, Zhi Rong Qian, Marisa W. Welch, Lauren K. Brais, Annacarolina Da Silva, Justin L. Bui, Chen Yuan, Tingting Li, Wanwan Li, Atsuhiro Masuda, Mancang Gu, Andrea J. Bullock, Daniel T. Chang, Thomas E. Clancy, David C. Linehan, Jennifer J. Findeis-Hosey, Leona A. Doyle, Aaron R. Thorner, Matthew D. Ducar, Bruce M. Wollison, Natalia Khalaf, Kimberly Perez, Sapna Syngal, Andrew J. Aguirre, William C. Hahn, Matthew L. Meyerson, Charles S. Fuchs, Shuji Ogino, Jason L. Hornick, Aram F. Hezel, Albert C. Koong, Jonathan A. Nowak, Brian M. Wolpin

    PurposeGermline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses.MethodsUsing a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression.ResultsWe found that 28/289 (9.7%; 95% confidence interval [CI] 6.5–13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30–0.99; P = 0.05).ConclusionNearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

    更新日期:2018-07-03
  • Response to Nakaguma et al.
    Genet. Med. (IF 9.937) Pub Date : 2018-06-30
    Leslie G. Biesecker

    Response to Nakaguma et al. Response to Nakaguma et al., Published online: 30 June 2018; doi:10.1038/s41436-018-0042-4 Response to Nakaguma et al.

    更新日期:2018-06-30
  • Noonan syndrome associated with growth hormone deficiency with biallelic LZTR1 variants
    Genet. Med. (IF 9.937) Pub Date : 2018-06-30
    Marilena Nakaguma, Alexander A. L. Jorge, Ivo J. P. Arnhold

    Noonan syndrome associated with growth hormone deficiency with biallelic LZTR1 variants Noonan syndrome associated with growth hormone deficiency with biallelic LZTR1 variants, Published online: 30 June 2018; doi:10.1038/s41436-018-0041-5 Noonan syndrome associated with growth hormone deficiency with biallelic LZTR1 variants

    更新日期:2018-06-30
  • Genomic characterization of the RH locus detects complex and novel structural variation in multi-ethnic cohorts
    Genet. Med. (IF 9.937) Pub Date : 2018-06-29
    Marsha M. Wheeler, Kerry W. Lannert, Haley Huston, Shelley N. Fletcher, Samantha Harris, Gayle Teramura, Helena J. Maki, Chris Frazar, Jason G. Underwood, Tristan Shaffer, Adolfo Correa, Meghan Delaney, Alex P. Reiner, James G. Wilson, Deborah A. Nickerson, Jill M. Johnsen

    Purpose Rh antigens can provoke severe alloimmune reactions, particularly in high-risk transfusion contexts, such as sickle cell disease. Rh antigens are encoded by the paralogs, RHD and RHCE, located in one of the most complex genetic loci. Our goal was to characterize RH genetic variation in multi-ethnic cohorts, with the focus on detecting RH structural variation (SV). Methods We customized analytical methods to estimate paralog-specific copy number from next-generation sequencing (NGS) data. We applied these methods to clinically characterized samples, including four World Health Organization (WHO) genotyping references and 1135 Asian and Native American blood donors. Subsequently, we surveyed 1715 African American samples from the Jackson Heart Study. Results Most samples in each dataset exhibited SV. SV detection enabled prediction of the immunogenic RhD and RhC antigens in concordance (>99%) with serological phenotyping. RhC antigen expression was associated with exon 2 hybrid alleles (RHCE*CE-D(2)-CE). Clinically relevant exon 4–7 hybrid alleles (RHD*D-CE(4-7)-D) and exon 9 hybrid alleles (RHCE*CE-D(9)-CE) were prevalent in African Americans. Conclusion This study shows custom NGS methods can accurately detect RH SV, and that SV is important to inform prediction of relevant RH alleles. Additionally, this study provides the first large NGS survey of RH alleles in African Americans.

    更新日期:2018-06-30
  • Addressing the accuracy of direct-to-consumer genetic testing
    Genet. Med. (IF 9.937) Pub Date : 2018-06-29
    Shirley Wu, Jeffrey Pollard, Arnab Chowdry, Richard Scheller, Robert Gentleman

    Addressing the accuracy of direct-to-consumer genetic testing Addressing the accuracy of direct-to-consumer genetic testing, Published online: 29 June 2018; doi:10.1038/s41436-018-0094-5 Addressing the accuracy of direct-to-consumer genetic testing

    更新日期:2018-06-30
  • Advocating for the consumer: clinical confirmation of all direct-to-consumer raw data alterations remains critical
    Genet. Med. (IF 9.937) Pub Date : 2018-06-27
    Stephany Tandy-Connor, Kate Krempely, Tina Pesaran, Holly LaDuca, Jenna Guiltinan, Brigette Tippin Davis

    Advocating for the consumer: clinical confirmation of all direct-to-consumer raw data alterations remains criticalAdvocating for the consumer: clinical confirmation of all direct-to-consumer raw data alterations remains critical, Published online: 27 June 2018; doi:10.1038/s41436-018-0095-4Advocating for the consumer: clinical confirmation of all direct-to-consumer raw data alterations remains critical

    更新日期:2018-06-28
  • MOVR—NeuroMuscular ObserVational Research, a unified data hub for neuromuscular diseases
    Genet. Med. (IF 9.937) Pub Date : 2018-06-22
    R. Rodney Howell, Stephan Zuchner

    MOVR—NeuroMuscular ObserVational Research, a unified data hub for neuromuscular diseases MOVR—NeuroMuscular ObserVational Research, a unified data hub for neuromuscular diseases, Published online: 22 June 2018; doi:10.1038/s41436-018-0086-5 MOVR—NeuroMuscular ObserVational Research, a unified data hub for neuromuscular diseases

    更新日期:2018-06-22
  • Gene modification therapies: views of parents of people with Down syndrome
    Genet. Med. (IF 9.937) Pub Date : 2018-06-21
    Marsha Michie, Megan Allyse

    Purpose In considering gene modification technologies, the priorities of patient communities must be a central consideration. The purpose of this study is to assess views of families with Down syndrome (DS) regarding potential genome-based interventions. Methods We constructed an anonymous online survey for family members of people with DS. Participants were asked to agree or disagree with scenarios describing hypothetical interventions to silence or significantly alter the physical and cognitive effects of a trisomy 21, and also with scenarios depicting currently available physical interventions. Results All 532 respondents were parents of people with DS. For each of the five scenarios, over half said they would approve the intervention or would advise their children with DS to do so. Responses to hypothetical prenatal and pediatric cognitive interventions were significantly affected by participants’ assessments of the impact of DS on their children’s and their families’ lives, while physical and adult cognitive scenarios were not. Conclusion Future interventions to address genetic conditions will impact patient communities and cannot succeed without their input and support. While many parents of people with DS indicated approval for hypothetical genetic therapies, these results indicate a need for continuing dialogue about benefits and drawbacks of gene modification technologies.

    更新日期:2018-06-22
  • Clinical and genetic spectrum of a large cohort of children with epilepsy in China
    Genet. Med. (IF 9.937) Pub Date : 2018-06-21
    Lin Yang, Yanting Kong, Xinran Dong, Liyuan Hu, Yifeng Lin, Xiang Chen, Qi Ni, Yulan Lu, Bingbing Wu, Huijun Wang, Q. Richard Lu, Wenhao Zhou

    Purpose Genetic diagnosis for children suffering from epilepsy has important implications for treatment, prognosis, and development of precision medicine strategies. Methods We performed exome sequencing (ES) or targeted sequencing on 733 children with epilepsy onset within the first year of life. We subgrouped our patients based on the onset age of seizure into neonatal and before 1 year (1–12 months), to compare the clinical and genetic features. Results The subgroups with different onset age of seizure showed different pathogenic variant spectrum, and the 1-year age group was more likely to have developmental delays than the neonate group (p = 0.000614). The diagnostic rate was 26.7% for targeted sequencing using a 2742-gene panel, and 42% for ES. We identified 12 genes, which covered 48.7% of diagnostic cases. Our data revealed that 41.9% of patients in the neonate group and 49.7% patients in the 1-year group had treatment options based on molecular diagnosis. Conclusion The 12 most commonly implicated genes in this cohort and the genes with treatment options should be considered as part of the essential panel for early diagnosis of epilepsy onset, if large medical exome analyses or ES are not feasible as first-tier analysis. Genetic results are beginning to improve therapy by antiepileptic medication selections and precision medicine approaches.

    更新日期:2018-06-22
  • TRPV1 variants impair intracellular Ca2+ signaling and may confer susceptibility to malignant hyperthermia
    Genet. Med. (IF 9.937) Pub Date : 2018-06-21
    Fabien Vanden Abeele, Sabine Lotteau, Sylvie Ducreux, Charlotte Dubois, Nicole Monnier, Amy Hanna, Dimitra Gkika, Caroline Romestaing, Lucile Noyer, Matthieu Flourakis, Nolwenn Tessier, Ribal Al-Mawla, Christophe Chouabe, Etienne Lefai, Joël Lunardi, Susan Hamilton, Julien Fauré, Fabien Van Coppenolle, Natalia Prevarskaya

    Purpose Malignant hyperthermia (MH) is a pharmacogenetic disorder arising from uncontrolled muscle calcium release due to an abnormality in the sarcoplasmic reticulum (SR) calcium-release mechanism triggered by halogenated inhalational anesthetics. However, the molecular mechanisms involved are still incomplete. Methods We aimed to identify transient receptor potential vanilloid 1 (TRPV1) variants within the entire coding sequence in patients who developed sensitivity to MH of unknown etiology. In vitro and in vivo functional studies were performed in heterologous expression system, trpv1−/− mice, and a murine model of human MH. Results We identified TRPV1 variants in two patients and their heterologous expression in muscles of trpv1−/− mice strongly enhanced calcium release from SR upon halogenated anesthetic stimulation, suggesting they could be responsible for the MH phenotype. We confirmed the in vivo significance by using mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation associated with MH in humans. We showed that the TRPV1 antagonist capsazepine slows the heat-induced hypermetabolic response in this model. Conclusion We propose that TRPV1 contributes to MH and could represent an actionable therapeutic target for prevention of the pathology and also be responsible for MH sensitivity when mutated.

    更新日期:2018-06-22
  • Bioinformatics for medical students: a 5-year experience using OMIM® in medical student education
    Genet. Med. (IF 9.937) Pub Date : 2018-06-21
    Jasmine Lee-Barber, Violet Kulo, Harold Lehmann, Ada Hamosh, Joann Bodurtha

    Purpose Given advances in genomic medicine, medical students need increased confidence in clinical genetics skills to address multiple genetic conditions. After success of first-year medical school instruction in the Online Mendelian Inheritance in Man (OMIM®) database, we report the impact on gaining confidence in broad clinical genetics skills in 5 subsequent years. Methods We collected 5 years of successive pre- and postintervention survey based self-assessments on medical student use of genetic medicine information resources and confidence in genetic medicine skills. To assess retention of confidence in these skills, we administered a follow-up survey to students after 1–2 years of clinical rotations. Results We found a consistent, statistically significant increase in students’ confidence in clinical genetics skills after the first-year OMIM educational session, with confidence retention above baseline up to 2 years after the educational exposure. Skills include ability to generate a differential diagnosis for genetic conditions, share information with patients and families, and find accurate information on genetic conditions. The majority agreed that increased use of OMIM will better prepare students to achieve these skills. Conclusion Integration of the OMIM database in first-year education is an effective instructional tool that may provide a lasting increase in confidence in clinical genetics skills.

    更新日期:2018-06-22
  • MYLK pathogenic variants aortic disease presentation, pregnancy risk, and characterization of pathogenic missense variants
    Genet. Med. (IF 9.937) Pub Date : 2018-06-20
    Stephanie E. Wallace, Ellen S. Regalado, Limin Gong, Alexandra L. Janda, Dong-chuan Guo, Claudio F. Russo, Richard J. Kulmacz, Nadine Hanna, Guillaume Jondeau, Catherine Boileau, Pauline Arnaud, Kwanghyuk Lee, Suzanne M. Leal, Matias Hannuksela, Bo Carlberg, Tami Johnston, Christian Antolik, Ellen M. Hostetler, Roberto Colombo, Dianna M. Milewicz

    Purpose Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited. Methods Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed. Results Twenty-three individuals (39%) experienced an aortic event (defined as aneurysm repair or dissection); the majority of these events (87%) were aortic dissections. Aortic diameters were minimally enlarged at the time of dissection in many cases. Time-to-aortic-event curves showed that missense pathogenic variant (PV) carriers have earlier-onset aortic events than null PV carriers. An MYLK missense variant segregated with aortic disease over five generations but decreases MYLK kinase acitivity marginally. Functional Assays fail to identify all pathogenic variants in MYLK. Conclusion These data further define the aortic phenotype associated with MYLK pathogenic variants. Given minimal aortic enlargement before dissection, an alternative approach to guide the timing of aortic repair is proposed based on the probability of a dissection at a given age.

    更新日期:2018-06-20
  • Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency
    Genet. Med. (IF 9.937) Pub Date : 2018-06-19
    Hassan Abolhassani, Asghar Aghamohammadi, Mingyan Fang, Nima Rezaei, Chongyi Jiang, Xiao Liu, Qiang Pan-Hammarström, Lennart Hammarström

    Purpose The etiology of 80% of patients with primary antibody deficiency (PAD), the second most common type of human immune system disorder after human immunodeficiency virus infection, is yet unknown. Methods Clinical/immunological phenotyping and exome sequencing of a cohort of 126 PAD patients (55.5% male, 95.2% childhood onset) born to predominantly consanguineous parents (82.5%) with unknown genetic defects were performed. The American College of Medical Genetics and Genomics criteria were used for validation of pathogenicity of the variants. Results This genetic approach and subsequent immunological investigations identified potential disease-causing variants in 86 patients (68.2%); however, 27 of these patients (31.4%) carried autosomal dominant (24.4%) and X-linked (7%) gene defects. This genetic approach led to the identification of new phenotypes in 19 known genes (38 patients) and the discovery of a new genetic defect (CD70 pathogenic variants in 2 patients). Medical implications of a definite genetic diagnosis were reported in ~50% of the patients. Conclusion Due to misclassification of the conventional approach for targeted sequencing, employing next-generation sequencing as a preliminary step of molecular diagnostic approach to patients with PAD is crucial for management and treatment of the patients and their family members.

    更新日期:2018-06-19
  • Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes
    Genet. Med. (IF 9.937) Pub Date : 2018-06-18
    Miao Sun, Amy Knight Johnson, Viswateja Nelakuditi, Lucia Guidugli, David Fischer, Kelly Arndt, Lan Ma, Erin Sandford, Vikram Shakkottai, Kym Boycott, Jodi Warman Chardon, Zejuan Li, Daniela del Gaudio, Margit Burmeister, Christopher M. Gomez, Darrel J. Waggoner, Soma Das

    Purpose To examine the impact of a targeted exome approach for the molecular diagnosis of patients nationwide with a wide range of ataxia-related phenotypes. Methods One hundred and seventy patients with ataxia of unknown etiology referred from clinics throughout the United States and Canada were studied using a targeted exome approach. Patients ranged in age from 2 to 88 years. Analysis was focused on 441 curated genes associated with ataxia and ataxia-like conditions. Results Pathogenic and suspected diagnostic variants were identified in 88 of the 170 patients, providing a positive molecular diagnostic rate of 52%. Forty-six different genes were implicated, with the six most commonly mutated genes being SPG7, SYNE1, ADCK3, CACNA1A, ATP1A3, and SPTBN2, which accounted for >40% of the positive cases. In many cases a diagnosis was provided for conditions that were not suspected and resulted in the broadening of the clinical spectrum of several conditions. Conclusion Exome sequencing with targeted analysis provides a high-yield approach for the genetic diagnosis of ataxia-related conditions. This is the largest targeted exome study performed to date in patients with ataxia and ataxia-like conditions and represents patients with a wide range of ataxia phenotypes typically encountered in neurology and genetics clinics.

    更新日期:2018-06-19
  • A genotype-specific surgical approach for patients with Pfeiffer syndrome due to W290C pathogenic variant in FGFR2 is associated with improved developmental outcomes and reduced mortality
    Genet. Med. (IF 9.937) Pub Date : 2018-06-18
    Tara L. Wenger, Richard A. Hopper, Anna Rosen, Hannah M. Tully, Michael L. Cunningham, Amy Lee

    Purpose Among children with FGFR2-associated Pfeiffer syndrome, those with the W290C pathogenic variant (PV) are reported to have the worst clinical outcomes. Mortality is high, and severe neurocognitive impairment has been reported in all surviving patients. However, it is unclear whether these poor outcomes are an unavoidable consequence of the PV itself, or could be improved with a genotype-specific treatment approach. The purpose of this report is to describe the more intensive surgical approach used for each of the three patients with W290C PV in FGFR2 at our center, all of whom survived and have normal neurocognitive functioning. Methods Retrospective chart review. Results In contrast to other patients with Pfeiffer syndrome at our center, all three patients who were subsequently found to have a W290C PV required a similar and more aggressive approach based on early cephalocranial disproportion. In contrast to previously reported W290C cases, each of our three patients survived and demonstrate normal neurocognitive functioning. Conclusion While previously reported outcomes in W290C-associated Pfeiffer syndrome have been extremely poor, we present three patients who underwent an intensive surgical approach and have normal development. This suggests that a personalized and aggressive surgical approach for children with W290C PV may dramatically improve clinical outcome.

    更新日期:2018-06-19
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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