当前期刊: Genetics in Medicine Go to current issue    加入关注    本刊投稿指南
显示样式:        排序: IF: - GO 导出
我的关注
我的收藏
您暂时未登录!
登录
  • A state-based approach to genomics for rare disease and population screening
    Genet. Med. (IF 8.904) Pub Date : 2020-11-27
    Kelly M. East; Whitley V. Kelley; Ashley Cannon; Meagan E. Cochran; Irene P. Moss; Thomas May; Mariko Nakano-Okuno; Stephen O. Sodeke; Jeffrey C. Edberg; James J. Cimino; Mona Fouad; William A. Curry; Anna C. E. Hurst; Kevin M. Bowling; Michelle L. Thompson; E. Martina Bebin; Robert D. Johnson; Gregory M. Cooper; Matthew Might; Gregory S. Barsh; Bruce R. Korf

    Purpose The Alabama Genomic Health Initiative (AGHI) is a state-funded effort to provide genomic testing. AGHI engages two distinct cohorts across the state of Alabama. One cohort includes children and adults with undiagnosed rare disease; a second includes an unselected adult population. Here we describe findings from the first 176 rare disease and 5369 population cohort AGHI participants. Methods

    更新日期:2020-11-27
  • De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females
    Genet. Med. (IF 8.904) Pub Date : 2020-11-27
    Dong Li; Alanna Strong; Kaitlyn M. Shen; David Cassiman; Maria Van Dyck; Natalia Duarte Linhares; Eugenia Ribeiro Valadares; Tiancheng Wang; Sergio D. J. Pena; Jaak Jaeken; Samantha Vergano; Elaine Zackai; Anne Hing; Penny Chow; Arupa Ganguly; Tasja Scholz; Tatjana Bierhals; Deindl Philipp; Hakon Hakonarson; Elizabeth Bhoj

    Purpose Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic

    更新日期:2020-11-27
  • De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females
    Genet. Med. (IF 8.904) Pub Date : 2020-11-27
    D. L. Polla; E. J. Bhoj; J. B. G. M. Verheij; J. S. Klein Wassink-Ruiter; A. Reis; C. Deshpande; A. Gregor; K. Hill-Karfe; A. T. Vulto-van Silfhout; R. Pfundt; E. M. H. F. Bongers; H. Hakonarson; S. Berland; G. Gradek; S. Banka; K. Chandler; L. Gompertz; S. C. Huffels; C. T. R. M. Stumpel; R. Wennekes; A. P. A. Stegmann; W. Reardon; E. K. S. M. Leenders; B. B. A. de Vries; D. Li; E. Zackai; N. Ragge;

    Purpose MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes. Methods By international matchmaking we assembled variant and clinical

    更新日期:2020-11-27
  • An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids
    Genet. Med. (IF 8.904) Pub Date : 2020-11-26
    Sacha Ferdinandusse; Kirsty McWalter; Heleen te Brinke; Lodewijk IJlst; Petra M. Mooijer; Jos P. N. Ruiter; Alida E. M. van Lint; Mia Pras-Raves; Eric Wever; Francisca Millan; Maria J. Guillen Sacoto; Amber Begtrup; Mark Tarnopolsky; Lauren Brady; Roger L. Ladda; Susan L. Sell; Catherine B. Nowak; Jessica Douglas; Cuixia Tian; Elizabeth Ulm; Seth Perlman; Arlene V. Drack; Karen Chong; Nicole Martin;

    Purpose In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). Methods Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients’ fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics

    更新日期:2020-11-27
  • Neurofilament light chain levels correlate with clinical measures in CLN3 disease
    Genet. Med. (IF 8.904) Pub Date : 2020-11-26
    An N. Dang Do; Ninet Sinaii; Ruturaj R. Masvekar; Eva H. Baker; Audrey E. Thurm; Ariane G. Soldatos; Simona E. Bianconi; Bibiana Bielekova; Forbes D. Porter

    Purpose CLN3 disease is a neurodegenerative disorder with onset in childhood. It affects multiple functions at different developmental stages. Incomplete understanding of the pathophysiology hampers identification of cell and tissue biochemical compounds reflective of the disease process. As treatment approaches are being explored, more sensitive, objective, quantifiable, and clinically relevant biomarkers

    更新日期:2020-11-27
  • Correction: Assessment of plasma lyso-Gb 3 for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease
    Genet. Med. (IF 8.904) Pub Date : 2020-11-20
    Daniel G. Bichet; Johannes M. Aerts; Christiane Auray-Blais; Hiroki Maruyama; Atul B. Mehta; Nina Skuban; Eva Krusinska; Raphael Schiffmann

    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:2020-11-21
  • Impact of prenatal exome sequencing for fetal genetic diagnosis on maternal psychological outcomes and decisional conflict in a prospective cohort
    Genet. Med. (IF 8.904) Pub Date : 2020-11-20
    Asha N. Talati; Kelly L. Gilmore; Emily E. Hardisty; Anne D. Lyerly; Christine Rini; Neeta L. Vora

    Purpose To evaluate associations between prenatal trio exome sequencing (trio-ES) and psychological outcomes among women with an anomalous pregnancy. Methods Trio-ES study enrolling patients with major fetal anomaly and normal microarray. Women completed self-reported measures and free response interviews at two timepoints: pre- (1) and post- (2) sequencing. Pre-sequencing responses were compared with

    更新日期:2020-11-21
  • Evaluating the resource implications of different service delivery models for offering additional genomic findings
    Genet. Med. (IF 8.904) Pub Date : 2020-11-20
    Martin Vu; Koen Degeling; Melissa Martyn; Elly Lynch; Belinda Chong; Clara Gaff; Maarten J. IJzerman

    Purpose To evaluate the resource implications of different delivery models for the provision of additional findings (AF) in genomics from a health-care purchaser perspective. Methods Data from the Additional Findings study were used to develop and validate a discrete event simulation model that represented the pathway of delivering AF. Resource implications were estimated by microcosting the consultations

    更新日期:2020-11-21
  • Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots
    Genet. Med. (IF 8.904) Pub Date : 2020-11-20
    Xinying Hong; Jessica Daiker; Martin Sadilek; Nicole Ruiz-Schultz; Arun Babu Kumar; Stevie Norcross; Warunee Dansithong; Teryn Suhr; Maria L. Escolar; C. Ronald Scott; Andreas Rohrwasser; Michael H. Gelb

    Purpose Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA), which results in the accumulation of sulfatides. Newborn screening for MLD may be considered in the future as innovative treatments are advancing. We carried out a research study to assess the feasibility of screening MLD using dried blood spots (DBS) from de-identified newborns

    更新日期:2020-11-21
  • Cardiovascular risk factors and body composition in adults with achondroplasia
    Genet. Med. (IF 8.904) Pub Date : 2020-11-18
    Svein O. Fredwall; Jennifer Linge; Olof Dahlqvist Leinhard; Lisa Kjønigsen; Heidi Beate Eggesbø; Harald Weedon-Fekjær; Ingeborg Beate Lidal; Grethe Månum; Ravi Savarirayan; Serena Tonstad

    Purpose An increased cardiovascular mortality has been reported in achondroplasia. This population-based, case–control study investigated cardiovascular risk factors and body composition in Norwegian adults with achondroplasia. Methods We conducted anthropometric, clinical, and laboratory assessments in 49 participants with achondroplasia, of whom 40 completed magnetic resonance imaging (MRI) for body

    更新日期:2020-11-18
  • High-throughput fetal fraction amplification increases analytical performance of noninvasive prenatal screening
    Genet. Med. (IF 8.904) Pub Date : 2020-11-15
    Noah C. Welker; Albert K. Lee; Rachel A. S. Kjolby; Helen Y. Wan; Mark R. Theilmann; Diana Jeon; James D. Goldberg; Kevin R. Haas; Dale Muzzey; Clement S. Chu

    Purpose The percentage of a maternal cell-free DNA (cfDNA) sample that is fetal-derived (the fetal fraction; FF) is a key driver of the sensitivity and specificity of noninvasive prenatal screening (NIPS). On certain NIPS platforms, >20% of women with high body mass index (and >5% overall) receive a test failure due to low FF (<4%). Methods A scalable fetal fraction amplification (FFA) technology was

    更新日期:2020-11-15
  • Biallelic variants in HPDL , encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition
    Genet. Med. (IF 8.904) Pub Date : 2020-11-14
    Shereen G. Ghosh; Sangmoon Lee; Rudy Fabunan; Guoliang Chai; Maha S. Zaki; Ghada Abdel-Salam; Tipu Sultan; Tawfeg Ben-Omran; Javeria Raza Alvi; Jennifer McEvoy-Venneri; Valentina Stanley; Aakash Patel; Danica Ross; Jeffrey Ding; Mohit Jain; Daqiang Pan; Philipp Lübbert; Bernd Kammerer; Nils Wiedemann; Nanda M. Verhoeven-Duif; Judith J. Jans; David Murphy; Mehran Beiraghi Toosi; Farah Ashrafzadeh; Shima

    Purpose Dioxygenases are oxidoreductase enzymes with roles in metabolic pathways necessary for aerobic life. 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), encoded by HPDL, is an orphan paralogue of 4-hydroxyphenylpyruvate dioxygenase (HPD), an iron-dependent dioxygenase involved in tyrosine catabolism. The function and association of HPDL with human diseases remain unknown. Methods We applied

    更新日期:2020-11-15
  • Defining the genotypic and phenotypic spectrum of X-linked MSL3 -related disorder
    Genet. Med. (IF 8.904) Pub Date : 2020-11-11
    Theresa Brunet; Kirsty McWalter; Katharina Mayerhanser; Grace M. Anbouba; Amy Armstrong-Javors; Ingrid Bader; Evan Baugh; Amber Begtrup; Caleb P. Bupp; Bert L. Callewaert; Anna Cereda; Margot A. Cousin; Juan C. Del Rey Jimenez; Laurie Demmer; Nikita R. Dsouza; Nicole Fleischer; Ralitza H. Gavrilova; Sumedha Ghate; Elisabeth Graf; Andrew Green; Sarah R. Green; Maria Iascone; Ameni Kdissa; Dirk Klee;

    Purpose We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome). Methods Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. Results We identified multiple variant types in MSL3 (ten

    更新日期:2020-11-12
  • Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease
    Genet. Med. (IF 8.904) Pub Date : 2020-11-10
    Miranda Durkie; Jiehan Chong; Manoj K. Valluru; Peter C. Harris; Albert C. M. Ong

    Purpose To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010–2020). Methods All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation

    更新日期:2020-11-12
  • Correction: A randomized controlled trial of an online health tool about Down syndrome
    Genet. Med. (IF 8.904) Pub Date : 2020-11-09
    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

    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:2020-11-12
  • Evaluating variants classified as pathogenic in ClinVar in the DDD Study
    Genet. Med. (IF 8.904) Pub Date : 2020-11-05
    Caroline F. Wright; Ruth Y. Eberhardt; Panayiotis Constantinou; Matthew E. Hurles; David R. FitzPatrick; Helen V. Firth

    Purpose Automated variant filtering is an essential part of diagnostic genome-wide sequencing but may generate false negative results. We sought to investigate whether some previously identified pathogenic variants may be being routinely excluded by standard variant filtering pipelines. Methods We evaluated variants that were previously classified as pathogenic or likely pathogenic in ClinVar in known

    更新日期:2020-11-05
  • New insights into the clinical and molecular spectrum of the novel CYFIP2 -related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics
    Genet. Med. (IF 8.904) Pub Date : 2020-11-05
    Anaïs Begemann; Heinrich Sticht; Amber Begtrup; Antonio Vitobello; Laurence Faivre; Siddharth Banka; Bader Alhaddad; Reza Asadollahi; Jessica Becker; Tatjana Bierhals; Kathleen E. Brown; Ange-Line Bruel; Theresa Brunet; Maryline Carneiro; Kirsten Cremer; Robert Day; Anne-Sophie Denommé-Pichon; Dave A. Dyment; Hartmut Engels; Rachel Fisher; Elaine S. Goh; M. J. Hajianpour; Lucia Ribeiro Machado Haertel;

    Purpose A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority. Methods We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling

    更新日期:2020-11-05
  • Impact of integrated translational research on clinical exome sequencing
    Genet. Med. (IF 8.904) Pub Date : 2020-11-04
    Eric W. Klee; Margot A. Cousin; Filippo Pinto e Vairo; Joel A. Morales-Rosado; Erica L. Macke; W. Garrett Jenkinson; Alejandro Ferrer; Laura E. Schultz-Rogers; Rory J. Olson; Gavin R. Oliver; Ashley N. Sigafoos; Tanya L. Schwab; Michael T. Zimmermann; Raul A. Urrutia; Charu Kaiwar; Aditi Gupta; Patrick R. Blackburn; Nicole J. Boczek; Carri A. Prochnow; Rebecca J. Lowy; Lindsay A. Mulvihill; Tammy M

    Purpose Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic

    更新日期:2020-11-04
  • NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns
    Genet. Med. (IF 8.904) Pub Date : 2020-11-04
    Hannah Stamberger; Trine B. Hammer; Elena Gardella; Danique R. M. Vlaskamp; Birgitte Bertelsen; Simone Mandelstam; Iris de Lange; Jing Zhang; Candace T. Myers; Christina Fenger; Zaid Afawi; Edith P. Almanza Fuerte; Danielle M. Andrade; Yunus Balcik; Bruria Ben Zeev; Mark F. Bennett; Samuel F. Berkovic; Bertrand Isidor; Arjan Bouman; Eva Brilstra; Øyvind L. Busk; Anita Cairns; Roseline Caumes; Nicolas

    Purpose Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. Methods Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. Results Sixty-three

    更新日期:2020-11-04
  • Analysis of laboratory reporting practices using a quality assessment of a virtual patient
    Genet. Med. (IF 8.904) Pub Date : 2020-10-30
    Danya F. Vears; Martin Elferink; Marjolein Kriek; Pascal Borry; Koen L. van Gassen

    Purpose Existing research suggests that while some laboratories report variants of uncertain significance, unsolicited findings (UF), and/or secondary findings (SF) when performing exome sequencing, others do not. Methods To investigate reporting differences, we created virtual patient–parent trio data by merging variants from patients into “normal” exomes. We invited laboratories worldwide to analyze

    更新日期:2020-10-30
  • Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities
    Genet. Med. (IF 8.904) Pub Date : 2020-10-28
    Lot Snijders Blok; Arianna Vino; Joery den Hoed; Hunter R. Underhill; Danielle Monteil; Hong Li; Francis Jeshira Reynoso Santos; Wendy K. Chung; Michelle D. Amaral; Rhonda E. Schnur; Teresa Santiago-Sim; Yue Si; Han G. Brunner; Tjitske Kleefstra; Simon E. Fisher

    Purpose Heterozygous pathogenic variants in various FOXP genes cause specific developmental disorders. The phenotype associated with heterozygous variants in FOXP4 has not been previously described. Methods We assembled a cohort of eight individuals with heterozygous and mostly de novo variants in FOXP4: seven individuals with six different missense variants and one individual with a frameshift variant

    更新日期:2020-10-28
  • Individuals with common diseases but with a low polygenic risk score could be prioritized for rare variant screening
    Genet. Med. (IF 8.904) Pub Date : 2020-10-28
    Tianyuan Lu; Sirui Zhou; Haoyu Wu; Vincenzo Forgetta; Celia M. T. Greenwood; J. Brent Richards

    Purpose Identifying rare genetic causes of common diseases can improve diagnostic and treatment strategies, but incurs high costs. We tested whether individuals with common disease and low polygenic risk score (PRS) for that disease generated from less expensive genome-wide genotyping data are more likely to carry rare pathogenic variants. Methods We identified patients with one of five common complex

    更新日期:2020-10-28
  • Cost-effectiveness of genome-wide sequencing for unexplained developmental disabilities and multiple congenital anomalies
    Genet. Med. (IF 8.904) Pub Date : 2020-10-28
    Chunmei Li; Stacey Vandersluis; Corinne Holubowich; Wendy J. Ungar; Elaine S. Goh; Kym M. Boycott; Nancy Sikich; Irfan Dhalla; Vivian Ng

    Purpose Genetic testing is routine practice for individuals with unexplained developmental disabilities and multiple congenital anomalies. However, current testing pathways can be costly and time consuming, and the diagnostic yield low. Genome-wide sequencing, including exome sequencing (ES) and genome sequencing (GS), can improve diagnosis, but at a higher cost. This study aimed to assess the cost-effectiveness

    更新日期:2020-10-28
  • Correction: Long-awaited progress in addressing genetic discrimination in the United States
    Genet. Med. (IF 8.904) Pub Date : 2020-10-27
    A. C. F. Lewis; R. C. Green; A. E. R. Prince

    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:2020-10-28
  • The broad phenotypic spectrum of PPP2R1A -related neurodevelopmental disorders correlates with the degree of biochemical dysfunction
    Genet. Med. (IF 8.904) Pub Date : 2020-10-27
    Lisa Lenaerts; Sara Reynhout; Iris Verbinnen; Frédéric Laumonnier; Annick Toutain; Frédérique Bonnet-Brilhault; Yana Hoorne; Shelagh Joss; Anna K. Chassevent; Constance Smith-Hicks; Bart Loeys; Pascal Joset; Katharina Steindl; Anita Rauch; Sarju G. Mehta; Wendy K. Chung; Koenraad Devriendt; Susan E. Holder; Tamison Jewett; Lauren M. Baldwin; William G. Wilson; Shelley Towner; Siddharth Srivastava;

    Purpose Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. Methods Most cases were identified through routine

    更新日期:2020-10-28
  • Exome sequencing analysis on products of conception: a cohort study to evaluate clinical utility and genetic etiology for pregnancy loss
    Genet. Med. (IF 8.904) Pub Date : 2020-10-26
    Chen Zhao; Hongyan Chai; Qinghua Zhou; Jiadi Wen; Uma M. Reddy; Rama Kastury; Yonghui Jiang; Winifred Mak; Allen E. Bale; Hui Zhang; Peining Li

    Purpose Pregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of exome sequencing (ES) in identifying the genetic etiology for pregnancy loss. Methods A cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy-number variants were

    更新日期:2020-10-28
  • Dopachrome tautomerase variants in patients with oculocutaneous albinism
    Genet. Med. (IF 8.904) Pub Date : 2020-10-26
    Perrine Pennamen; Angèle Tingaud-Sequeira; Iveta Gazova; Margaret Keighren; Lisa McKie; Sandrine Marlin; Souad Gherbi Halem; Josseline Kaplan; Cédric Delevoye; Didier Lacombe; Claudio Plaisant; Vincent Michaud; Eulalie Lasseaux; Sophie Javerzat; Ian Jackson; Benoit Arveiler

    Purpose Albinism is a clinically and genetically heterogeneous condition. Despite analysis of the 20 known genes, ~30% patients remain unsolved. We aimed to identify new genes involved in albinism. Methods We sequenced a panel of genes with known or predicted involvement in melanogenesis in 230 unsolved albinism patients. Results We identified variants in the Dopachrome tautomerase (DCT) gene in two

    更新日期:2020-10-28
  • Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science
    Genet. Med. (IF 8.904) Pub Date : 2020-10-23
    Kelly Schoch; Cecilia Esteves; Anna Bican; Rebecca Spillmann; Heidi Cope; Allyn McConkie-Rosell; Nicole Walley; Liliana Fernandez; Jennefer N. Kohler; Devon Bonner; Chloe Reuter; Nicholas Stong; John J. Mulvihill; Donna Novacic; Lynne Wolfe; Ayat Abdelbaki; Camilo Toro; Cyndi Tifft; May Malicdan; William Gahl; Pengfei Liu; John Newman; David B. Goldstein; Jason Hom; Jacinda Sampson; Matthew T. Wheeler;

    Purpose The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices. Methods We analyzed retrospective data from four

    更新日期:2020-10-28
  • The role of clinical response to treatment in determining pathogenicity of genomic variants
    Genet. Med. (IF 8.904) Pub Date : 2020-10-22
    Joseph J. Shen; Saskia B. Wortmann; Lonneke de Boer; Leo A. J. Kluijtmans; Marleen C. D. G. Huigen; Johannes Koch; Stephanie Ross; Christin D. Collins; Robin van der Lee; Clara D. M. van Karnebeek; Madhuri R. Hegde

    Purpose The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease

    更新日期:2020-10-28
  • Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance
    Genet. Med. (IF 8.904) Pub Date : 2020-10-22
    Paulo C. M. Lyra; Thales C. Nepomuceno; Marcele L. M. de Souza; Géssica F. Machado; Mariana F. Veloso; Taciane B. Henriques; Diandra Z. dos Santos; Iuly G. Ribeiro; Roberto S. Ribeiro; Leticia B. A. Rangel; Marcy Richardson; Edwin S. Iversen; David Goldgar; Fergus J. Couch; Marcelo A. Carvalho; Alvaro N. A. Monteiro

    Purpose BRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for

    更新日期:2020-10-28
  • Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies
    Genet. Med. (IF 8.904) Pub Date : 2020-10-21
    Julian Schröter; Jan H. Döring; Sven F. Garbade; Georg F. Hoffmann; Stefan Kölker; Markus Ries; Steffen Syrbe

    Purpose TUBA1A and TUBB2B tubulinopathies are rare neurodevelopmental disorders characterized by cortical and extracortical malformations and heterogenic phenotypes. There is a need for quantitative clinical endpoints that will be beneficial for future diagnostic and therapeutic trials. Methods Quantitative natural history modeling of individuals with TUBA1A and TUBB2B tubulinopathies from clinical

    更新日期:2020-10-28
  • Geleophysic and acromicric dysplasias: natural history, genotype–phenotype correlations, and management guidelines from 38 cases
    Genet. Med. (IF 8.904) Pub Date : 2020-10-21
    Pauline Marzin; Briac Thierry; Andrea Dancasius; Anne Cavau; Caroline Michot; Sophie Rondeau; Geneviève Baujat; Gilles Phan; Maryse Bonnière; Muriel Le Bourgeois; Diala Khraiche; Zagorka Pejin; Damien Bonnet; Christophe Delacourt; Valérie Cormier-Daire

    Purpose Geleophysic dysplasia (GD) and acromicric dysplasia (AD) are characterized by short stature, short extremities, and progressive joint limitation. In GD, cardiorespiratory involvement can result in poor prognosis. Dominant variants in the FBN1 and LTBP3 genes are responsible for AD or GD, whereas recessive variants in the ADAMTSL2 gene are responsible for GD only. The aim of this study was to

    更新日期:2020-10-28
  • A systematic review of monogenic etiologies of nonimmune hydrops fetalis
    Genet. Med. (IF 8.904) Pub Date : 2020-10-21
    Andrea M. Quinn; Breanna N. Valcarcel; Mona M. Makhamreh; Huda B. Al-Kouatly; Seth I. Berger

    Hydrops fetalis (HF), accumulation of fluid in two or more fetal compartments, is life-threatening to the fetus. Genetic etiologies include many chromosomal and monogenic disorders. Despite this, the clinical workup typically evaluates limited genetic targets. To support broader molecular testing of pregnancies with HF, we cataloged the spectrum of monogenic disorders associated with nonimmune hydrops

    更新日期:2020-10-28
  • Correction: 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 : 2020-10-20
    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

    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:2020-10-20
  • Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy
    Genet. Med. (IF 8.904) Pub Date : 2020-10-20
    Renae Elaine Bertrand; Jun Wang; Kaitlyn H. Xiong; Chinthana Thangavel; Xinye Qian; Rola Ba-Abbad; Qingnan Liang; Renata T. Simões; Shirley A. M. Sampaio; Keren J. Carss; F. Lucy Raymond; Anthony G. Robson; Andrew R. Webster; Gavin Arno; Fernanda Belga Ottoni Porto; Rui Chen

    Purpose Previous studies suggest that ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. However, no pathogenic variant in ceramide synthases has been identified in human patients and knockout of various ceramide synthases in mice has not led to photoreceptor degeneration. Methods Exome sequencing was used to identify candidate

    更新日期:2020-10-20
  • Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results
    Genet. Med. (IF 8.904) Pub Date : 2020-10-20
    Ramakrishnan Rajagopalan; Melissa A. Gilbert; Deborah A. McEldrew; James A. Nassur; Kathleen M. Loomes; David A. Piccoli; Ian D. Krantz; Laura K. Conlin; Nancy B. Spinner

    Purpose Detection of all major classes of genomic variants in a single test would decrease cost and increase the efficiency of genomic diagnostics. Genome sequencing (GS) has the potential to provide this level of comprehensive detection. We sought to demonstrate the utility of GS in the molecular diagnosis of 18 patients with clinically defined Alagille syndrome (ALGS), who had a negative or inconclusive

    更新日期:2020-10-20
  • A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism
    Genet. Med. (IF 8.904) Pub Date : 2020-10-20
    W. Reid Thompson; Brittany Hornby; Ryan Manuel; Elena Bradley; Janice Laux; Jim Carr; Hilary J. Vernon

    Purpose To evaluate effectiveness of elamipretide in Barth syndrome (BTHS), a genetic condition of defects in TAZ, which causes abnormal cardiolipin on the inner mitochondrial membrane. Methods We performed a randomized, double-blind, placebo-controlled crossover trial followed by an open-label extension in BTHS to test the effect of elamipretide, a mitochondrial tetrapeptide that interacts with cardiolipin

    更新日期:2020-10-20
  • JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome
    Genet. Med. (IF 8.904) Pub Date : 2020-10-20
    Eline A. Verberne; Shuxiang Goh; Jade England; Manon van Ginkel; Louise Rafael-Croes; Saskia Maas; Abeltje Polstra; Yuri A. Zarate; Katherine A. Bosanko; Kieran B. Pechter; Emma Bedoukian; Kosuke Izumi; Ayeshah Chaudhry; Nathaniel H. Robin; Megan Boothe; Natalie C. Lippa; Vimla Aggarwal; Darryl C. De Vivo; Anna Lehman; Causes Study; Sylvia Stockler; Ange-Line Bruel; Bertrand Isidor; Jennifer Lemons;

    Purpose JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22–p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion

    更新日期:2020-10-20
  • Laboratory analysis of acylcarnitines, 2020 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG)
    Genet. Med. (IF 8.904) Pub Date : 2020-10-19
    Marcus J. Miller; Kristina Cusmano-Ozog; Devin Oglesbee; Sarah Young

    Acylcarnitine analysis is a useful test for identifying patients with inborn errors of mitochondrial fatty acid β-oxidation and certain organic acidemias. Plasma is routinely used in the diagnostic workup of symptomatic patients. Urine analysis of targeted acylcarnitine species may be helpful in the diagnosis of glutaric acidemia type I and other disorders in which polar acylcarnitine species accumulate

    更新日期:2020-10-19
  • Individuals with Down syndrome hospitalized with COVID-19 have more severe disease
    Genet. Med. (IF 8.904) Pub Date : 2020-10-16
    Louise Malle; Cynthia Gao; Chin Hur; Han Q. Truong; Nicole M. Bouvier; Bethany Percha; Xiao-Fei Kong; Dusan Bogunovic

    Purpose Rare genetic conditions like Down syndrome (DS) are historically understudied. Infection is a leading cause of mortality in DS, along with cardiac anomalies. Currently, it is unknown how the COVID-19 pandemic affects individuals with DS. Herein, we report an analysis of individuals with DS who were hospitalized with COVID-19 in New York, New York, USA. Methods In this retrospective, dual-center

    更新日期:2020-10-16
  • Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions
    Genet. Med. (IF 8.904) Pub Date : 2020-10-13
    Xiaolei Zhang; Roddy Walsh; Nicola Whiffin; Rachel Buchan; William Midwinter; Alicja Wilk; Risha Govind; Nicholas Li; Mian Ahmad; Francesco Mazzarotto; Angharad Roberts; Pantazis I. Theotokis; Erica Mazaika; Mona Allouba; Antonio de Marvao; Chee Jian Pua; Sharlene M. Day; Euan Ashley; Steven D. Colan; Michelle Michels; Alexandre C. Pereira; Daniel Jacoby; Carolyn Y. Ho; Iacopo Olivotto; Gunnar T. Gunnarsson;

    Purpose Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning variant prioritization tools are imprecise and ignore important parameters defining gene–disease relationships, e.g., distinct consequences of gain-of-function versus loss-of-function variants. We hypothesized that incorporating disease-specific

    更新日期:2020-10-13
  • A model-based cost-effectiveness analysis of pharmacogenomic panel testing in cardiovascular disease management: preemptive, reactive, or none?
    Genet. Med. (IF 8.904) Pub Date : 2020-10-12
    Ye Zhu; James P. Moriarty; Kristi M. Swanson; Paul Y. Takahashi; Suzette J. Bielinski; Richard Weinshilboum; Liewei Wang; Bijan J. Borah

    Purpose Pharmacogenomics (PGx) studies how inherited genetic variations in individuals affect drug absorption, distribution, and metabolism. PGx panel testing can potentially help improve efficiency and accuracy in individualizing therapy. This study compared the cost-effectiveness between preemptive PGx panel testing, reactive PGx panel testing and usual care (no testing) in cardiovascular disease

    更新日期:2020-10-12
  • CMAP changes upon symptom onset and during treatment in spinal muscular atrophy patients: lessons learned from newborn screening
    Genet. Med. (IF 8.904) Pub Date : 2020-10-09
    Wen-Chin Weng; Yu-Kan Hsu; Fu-Man Chang; Chun-Yen Lin; Wuh-Liang Hwu; Wang-Tso Lee; Ni-Chung Lee; Yin-Hsiu Chien

    Purpose Early identification and treatment of spinal muscular atrophy (SMA) are crucial but difficult. In this study, we aimed to assess the significance of compound motor action potential (CMAP) amplitude in patients identified through a newborn screening program. Methods We initiated a large-scale population newborn screening program for SMA in Taiwan in 2014. Patients had access to treatment through

    更新日期:2020-10-11
  • Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy
    Genet. Med. (IF 8.904) Pub Date : 2020-10-09
    David A. Parry; Carol-Anne Martin; Philip Greene; Joseph A. Marsh; Moira Blyth; Helen Cox; Deirdre Donnelly; Lynn Greenhalgh; Stephanie Greville-Heygate; Victoria Harrison; Katherine Lachlan; Caoimhe McKenna; Alan J. Quigley; Gillian Rea; Lisa Robertson; Mohnish Suri; Andrew P. Jackson

    Purpose Lamins are the major component of nuclear lamina, maintaining structural integrity of the nucleus. Lamin A/C variants are well established to cause a spectrum of disorders ranging from myopathies to progeria, termed laminopathies. Phenotypes resulting from variants in LMNB1 and LMNB2 have been much less clearly defined. Methods We investigated exome and genome sequencing from the Deciphering

    更新日期:2020-10-11
  • Return of results in a global survey of psychiatric genetics researchers: practices, attitudes, and knowledge
    Genet. Med. (IF 8.904) Pub Date : 2020-10-09
    Gabriel Lázaro-Muñoz; Laura Torgerson; Stacey Pereira

    Purpose Patient-participants in psychiatric genetics research may be at an increased risk for negative psychosocial impacts related to the return of genetic research results. Examining psychiatric genetics researchers’ return of results practices and perspectives can aid the development of empirically informed and ethically sound guidelines. Methods A survey of 407 psychiatric genetics researchers

    更新日期:2020-10-11
  • Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia
    Genet. Med. (IF 8.904) Pub Date : 2020-10-07
    Simone Schröder; Yun Li; Gökhan Yigit; Janine Altmüller; Ingrid Bader; Andrea Bevot; Saskia Biskup; Steffi Dreha-Kulaczewski; G. Christoph Korenke; Raimund Kottke; Johannes A. Mayr; Martin Preisel; Sandra P. Toelle; Sarah Wente-Schulz; Saskia B. Wortmann; Heidi Hahn; Eugen Boltshauser; Anja Uhmann; Bernd Wollnik; Knut Brockmann

    Purpose This study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable. Methods We compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We

    更新日期:2020-10-07
  • Correction: Initial experience from a renal genetics clinic demonstrates a distinct role in patient management
    Genet. Med. (IF 8.904) Pub Date : 2020-10-06
    Christie P. Thomas; Margaret E. Freese; Agnes Ounda; Jennifer G. Jetton; Myrl Holida; Lama Noureddine; Richard J. Smith

    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:2020-10-07
  • Ethical and public health implications of genetic testing for suicide risk: family and survivor perspectives
    Genet. Med. (IF 8.904) Pub Date : 2020-10-06
    Brent M. Kious; Anna R. Docherty; Jeffrey R. Botkin; Teneille R. Brown; Leslie P. Francis; Douglas D. Gray; Brooks R. Keeshin; Louisa A. Stark; Brieanne Witte; Hilary Coon

    Purpose Death from suicide has an estimated heritability of ~50%. Research may soon allow calculation of polygenic risk scores (PRS) for suicide death, which could be marketed directly to consumers. This raises ethical concerns. Understanding how consumers will utilize this information is urgent. Methods We conducted three focus groups involving suicide attempt survivors (“survivors”) and family members

    更新日期:2020-10-06
  • Prospective clinical investigations of children with periodontal Ehlers–Danlos syndrome identify generalized lack of attached gingiva as a pathognomonic feature
    Genet. Med. (IF 8.904) Pub Date : 2020-10-02
    Ines Kapferer-Seebacher; Elizabeth Oakley-Hannibal; Ulrike Lepperdinger; Diana Johnson; Neeti Ghali; Angela F. Brady; Glenda Sobey; Johannes Zschocke; Fleur S. van Dijk

    Purpose We report prospective clinical investigations of children affected with periodontal Ehlers–Danlos syndrome (pEDS). The main clinical features of pEDS in adults are early severe periodontitis, generalized lack of attached gingiva, and pretibial hemosiderin plaques due to dominant pathogenic variants in the C1R or C1S genes. Methods Nineteen children with a parent diagnosed with molecularly confirmed

    更新日期:2020-10-02
  • Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)
    Genet. Med. (IF 8.904) Pub Date : 2020-10-02
    Carlos R. Ferreira; Mary E. Hackbarth; Shira G. Ziegler; Kristen S. Pan; Mary S. Roberts; Douglas R. Rosing; Margaret S. Whelpley; Joy C. Bryant; Ellen F. Macnamara; Sisi Wang; Kerstin Müller; Iris R. Hartley; Emily Y. Chew; Timothy E. Corden; Christina M. Jacobsen; Ingrid A. Holm; Frank Rutsch; Esra Dikoglu; Marcus Y. Chen; M. Zulf Mughal; Michael A. Levine; Rachel I. Gafni; William A. Gahl

    Purpose Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. Methods We performed deep phenotyping

    更新日期:2020-10-02
  • Assessment of plasma lyso-Gb 3 for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease
    Genet. Med. (IF 8.904) Pub Date : 2020-09-30
    Daniel G. Bichet; Johannes M. Aerts; Christiane Auray-Blais; Hiroki Maruyama; Atul B. Mehta; Nina Skuban; Eva Krusinska; Raphael Schiffmann

    Purpose To assess the utility of globotriaosylsphingosine (lyso-Gb3) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat. Methods A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)–experienced patients with migalastat-amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label

    更新日期:2020-09-30
  • (Un)standardized testing: the diagnostic odyssey of children with rare genetic disorders in Alberta, Canada
    Genet. Med. (IF 8.904) Pub Date : 2020-09-29
    Christine Michaels-Igbokwe; Brenda McInnes; Karen V. MacDonald; Gillian R. Currie; Fadya Omar; Brittany Shewchuk; Francois P. Bernier; Deborah A. Marshall

    Purpose We provide a description of the diagnostic odyssey for a cohort of children seeking diagnosis of a rare genetic disorder in terms of the time from initial consultation to most recent visit or receipt of diagnosis, the number of tests per patient, and the types of tests received. Methods Retrospective chart review of 299 children seen at the Alberta Children’s Hospital (ACH) Genetics Clinic

    更新日期:2020-09-29
  • A genotype-first approach to exploring Mendelian cardiovascular traits with clear external manifestations
    Genet. Med. (IF 8.904) Pub Date : 2020-09-29
    Brittany M. Wenger; Nihir Patel; Madeline Lui; Arden Moscati; Ron Do; Douglas R. Stewart; Marco Tartaglia; Laura Muiño-Mosquera; Julie De Backer; Amy R. Kontorovich; Bruce D. Gelb

    Purpose The purpose of this study is to use a genotype-first approach to explore highly penetrant, autosomal dominant cardiovascular diseases with external features, the RASopathies and Marfan syndrome (MFS), using biobank data. Methods This study uses exome sequencing and corresponding phenotypic data from Mount Sinai’s BioMe (n = 32,344) and the United Kingdom Biobank (UKBB; n = 49,960). Variant

    更新日期:2020-09-29
  • Identifying rare, medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls
    Genet. Med. (IF 8.904) Pub Date : 2020-09-29
    Kevin M. Bowling; Michelle L. Thompson; David E. Gray; James M. J. Lawlor; Kelly Williams; Kelly M. East; Whitley V. Kelley; Irene P. Moss; Devin M. Absher; E. Christopher Partridge; Anna C. E. Hurst; Jeffrey C. Edberg; Gregory S. Barsh; Bruce R. Korf; Gregory M. Cooper

    Purpose To evaluate the effectiveness and specificity of population-based genomic screening in Alabama. Methods The Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory

    更新日期:2020-09-29
  • Impact of newborn screening and quality of therapy on the neurological outcome in glutaric aciduria type 1: a meta-analysis.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-28
    Nikolas Boy,Katharina Mengler,Jana Heringer-Seifert,Georg F Hoffmann,Sven F Garbade,Stefan Kölker

    Purpose Glutaric aciduria type 1 (GA1), a rare inherited neurometabolic disorder, results in a complex movement disorder (MD) with predominant dystonia if untreated. Implementation into newborn screening (NBS) programs and adherence to recommended therapy are thought to improve the neurological outcome. Methods Systematic literature search for articles published from 2000 to 2019 was performed using

    更新日期:2020-09-28
  • Response to Thibodeau and Langlois.
    Genet. Med. (IF 8.904) Pub Date : 2020-09-27
    Amber E L van Nisselrooij,Emmelien Aten,Gijs W E Santen,Monique C Haak

    更新日期:2020-09-27