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Biallelic USP14 variants cause a syndromic neurodevelopmental disorder Genet. Med. (IF 8.8) Pub Date : 2024-03-10 Frédéric Ebstein, Xenia Latypova, Ka Ying Sharon Hung, Miguel A. Prado, Byung-Hoon Lee, Sophie Möller, Martin Wendlandt, Barbara A. Zieba, Laëtitia Florenceau, Virginie Vignard, Léa Poirier, Bérénice Toutain, Isabella Moroni, Charlotte Dubucs, Nicolas Chassaing, Judit Horvath, Holger Prokisch, Sébastien Küry, Stéphane Bézieau, Joao A. Paulo, Daniel Finley, Elke Krüger, Daniele Ghezzi, Bertrand Isidor
Imbalances in protein homeostasis affect human brain development, with the ubiquitin-proteasome system (UPS) and autophagy playing crucial roles in neurodevelopmental disorders (NDD). This study explores the impact of biallelic variants on neurodevelopment, focusing on its role as a key hub connecting UPS and autophagy. Here, we identified biallelic variants in four individuals from three unrelated
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The Clinical Geneticist Workforce: Community Forums to Address Challenges and Opportunities Genet. Med. (IF 8.8) Pub Date : 2024-03-09 Wendy K. Chung, Shoumita Dasgupta, Debra S. Regier, Benjamin D. Solomon
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A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder Genet. Med. (IF 8.8) Pub Date : 2024-03-07 François Lecoquierre, A Mattijs Punt, Frédéric Ebstein, Ilse Wallaard, Rob Verhagen, Maja Studencka-Turski, Yannis Duffourd, Sébastien Moutton, Frédédic Tran Mau-Them, Christophe Philippe, John Dean, Stephen Tennant, Alice S. Brooks, Marjon A. van Slegtenhorst, Julie A. Jurgens, Brenda J. Barry, Wai-Man Chan, Eleina M. England, Mayra Martinez Ojeda, Elizabeth C. Engle, Caroline D. Robson, Michelle
FEM1B acts as a substrate recognition subunit for ubiquitin ligase complexes belonging to the CRL2 E3 family. Several biological functions have been proposed for FEM1B, including a structurally resolved function as a sensor for redox cell status by controlling mitochondrial activity, but its implication in human disease remains elusive. To understand the involvement of FEM1B in human disease, we made
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Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders Genet. Med. (IF 8.8) Pub Date : 2024-03-06 Camila Armirola-Ricaurte, Noortje Zonnekein, Georgios Koutsis, Silvia Amor-Barris, Ana Lara Pelayo-Negro, Derek Atkinson, Stephanie Efthymiou, Valentina Turchetti, Argyris Dinopoulos, Antonio Garcia, Mert Karakaya, German Moris, Ayşe Ipek Polat, Uluc Yis, Carmen Espinos, Liedewei Van de Vondel, Els De Vriendt, Georgia Karadima, Brunhilde Wirth, Michael Hanna, Henry Houlden, Jose Berciano, Albena Jordanova
We describe three families with Charcot-Marie-Tooth neuropathy (CMT), harboring a homozygous NM_004553.6:c.309+5G>A variant previously linked to fatal Leigh syndrome. We aimed to characterize clinically and molecularly the newly identified patients and understand the mechanism underlying their milder phenotype. The patients underwent extensive clinical examinations. Exome sequencing was done in four
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Determining priority indicators of utility for genomic testing in rare disease: a Delphi study Genet. Med. (IF 8.8) Pub Date : 2024-03-06 Zoe Fehlberg, Ilias Goranitis, Andrew J. Mallett, Zornitza Stark, Stephanie Best
Determining the value of genomic tests in rare disease necessitates a broader conceptualization of genomic utility beyond diagnostic yield. Despite widespread discussion, consensus towards which aspects of value to consider is lacking. This study aimed to use expert opinion to identify and refine priority indicators of utility in rare disease genomic testing. We used two survey rounds following Delphi
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Exome and genome sequencing in a heterogeneous population of patients with rare disease: Identifying predictors of a diagnosis Genet. Med. (IF 8.8) Pub Date : 2024-03-01 Jenna Pucel, Lauren C. Briere, Chloe Reuter, Perman Gochyyev, Kimberly LeBlanc
Exome (ES) and genome sequencing (GS) are increasingly being utilized for individuals with rare and undiagnosed diseases; however, guidelines on their use remain limited. This study aimed to identify factors associated with diagnosis by ES and/or GS in a heterogeneous population of patients with rare and undiagnosed diseases. In this case control study, we reviewed data from 400 diagnosed and 400 undiagnosed
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Improving access to exome sequencing in a medically underserved population through the Texome Project Genet. Med. (IF 8.8) Pub Date : 2024-02-29 Blake Vuocolo, Ryan J. German, Seema R. Lalani, Chaya N. Murali, Carlos A. Bacino, Stephanie Baskin, Rebecca Littlejohn, John D. Odom, Scott McLean, Carrie Schmid, Morgan Nutter, Melissa Stuebben, Emily Magness, Olivia Juarez, Dina El Achi, Bailey Mitchell, Kevin E. Glinton, Laurie Robak, Sandesh CS. Nagamani, Lisa Saba, Adasia Ritenour, Lilei Zhang, Haley Streff, Katie Chan, K Jordan Kemere, Kent
Genomic medicine can end diagnostic odysseys for patients with complex phenotypes; however, limitations in insurance coverage and other systemic barriers preclude individuals from accessing comprehensive genetics evaluation and testing. The Texome Project is a 4-year study that reduces barriers to genomic testing for individuals from underserved and underrepresented populations. Participants with undiagnosed
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Bi-allelic NIT1 variants cause a brain small vessel disease characterized by movement disorders, massively dilated perivascular spaces and intracerebral hemorrhage Genet. Med. (IF 8.8) Pub Date : 2024-02-27 Julie W. Rutten, Minne N. Cerfontaine, Kyra L. Dijkstra, Aat A. Mulder, Jeroen Vreijling, Mark Kruit, Roman I. Koning, Susanne T. de Bot, Koen M. van Nieuwenhuizen, Hans J. Baelde, Henk W. Berendse, Leon H. Mei, George J.G. Ruijter, Frank Baas, Carolina R. Jost, Sjoerd G. van Duinen, Esther A.R. Nibbeling, Gido Gravesteijn, Saskia A.J. Lesnik Oberstein
To describe a recessively inherited cerebral small vessel disease, caused by loss-of-function variants in (). We performed exome sequencing, brain MRI, neuropathology, electron microscopy, Western Blotting and transcriptomic and metabolic analyses in seven NIT1-small vessel disease patients from five unrelated pedigrees. The first identified patients were three siblings, compound heterozygous for the
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CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders Genet. Med. (IF 8.8) Pub Date : 2024-02-24 Clara D.M. van Karnebeek, Maja Tarailo-Graovac, René Leen, Rutger Meinsma, Solenne Correard, Judith Jansen-Meijer, Sergey V. Prykhozhij, Izabella A. Pena, Kevin Ban, Sarah Schock, Vishal Saxena, Mia L. Pras-Raves, Britt I. Drögemöller, Anita E. Grootemaat, Nicole N. van der Wel, Doreen Dobritzsch, Winfried Roseboom, Bauke V. Schomakers, Yorrick R.J. Jaspers, Lida Zoetekouw, Jeroen Roelofsen, Carlos
The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system. Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive
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Additional findings from the 100,000 Genomes Project: A qualitative study of recipient perspectives Genet. Med. (IF 8.8) Pub Date : 2024-02-24 Joshua J. Nolan, Jamie Forrest, Elizabeth Ormondroyd
Participants in the 100,000 Genomes Project, a clinical/research initiative delivered through the UK National Health Service, were offered screening for “additional findings” (AFs): pathogenic/likely pathogenic variants in genes associated with familial hypercholesterolemia or a cancer predisposition syndrome. Understanding the psychological and behavioral responses to AFs informs the clinical utility
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Section E6.7-6.12 of the American College of Medical Genetics and Genomics (ACMG) Technical Laboratory Standards: Cytogenomic studies of acquired chromosomal abnormalities in solid tumors Genet. Med. (IF 8.8) Pub Date : 2024-02-20 Alanna J. Church, Yassmine Akkari, Kristin Deeb, Ravindra Kolhe, Fumin Lin, Elizabeth Spiteri, Daynna J. Wolff, Lina Shao
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Section E6.1–6.6 of the American College of Medical Genetics and Genomics (ACMG) Technical Laboratory Standards: Cytogenomic studies of acquired chromosomal abnormalities in neoplastic blood, bone marrow, and lymph nodes Genet. Med. (IF 8.8) Pub Date : 2024-02-13 Yassmine Akkari, Linda B. Baughn, Annette Kim, Ender Karaca, Gordana Raca, Lina Shao, Fady M. Mikhail
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The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2 Genet. Med. (IF 8.8) Pub Date : 2024-02-13 Snežana Hinić, Cezary Cybulski, Rachel S. Van der Post, Janet R. Vos, Janneke Schuurs-Hoeijmakers, Fulvia Brugnoletti, Saskia Koene, Lilian Vreede, Wendy A.G. van Zelst-Stams, C. Marleen Kets, Maaike Haadsma, Liesbeth Spruijt, Marijke R. Wevers, D. Gareth Evans, Katharina Wimmer, Simon Schnaiter, Alexander E. Volk, Anna Möllring, Robin de Putter, Leila Soikkonen, Tiina Kahre, Mikk Tooming, Mirjam M
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Biallelic loss-of-function variants of SLC12A9 cause lysosome dysfunction and a syndromic neurodevelopmental disorder Genet. Med. (IF 8.8) Pub Date : 2024-02-06 Andrea Accogli, Young N. Park, Guy M. Lenk, Mariasavina Severino, Marcello Scala, Jonas Denecke, Maja Hempel, Davor Lessel, Fanny Kortüm, Vincenzo Salpietro, Patrizia de Marco, Sara Guerrisi, Annalaura Torella, Vincenzo Nigro, Myriam Srour, Ernest Turro, Veerle Labarque, Kathleen Freson, Gianluca Piatelli, Valeria Capra, Jacob O. Kitzman, Miriam H. Meisler
Pathogenic variants of FIG4 generate enlarged lysosomes and neurological and developmental disorders. To identify additional genes regulating lysosomal volume, we carried out a genome-wide activation screen to detect suppression of enlarged lysosomes in FIG4 cells. The CRISPR-a gene activation screen utilized sgRNAs from the promoters of protein coding genes. Fluorescence-activated cell sorting separated
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Addendum: Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin Genet. Med. (IF 8.8) Pub Date : 2024-02-05 Ting Wen, C. Anwar A. Chahal, Melanie A. Manning
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Young adults with a 22q11.2 microdeletion and the cost of aging with complexity in a population-based context Genet. Med. (IF 8.8) Pub Date : 2024-02-01 Sarah L. Malecki, Tracy Heung, Walter P. Wodchis, Refik Saskin, Luis Palma, Amol A. Verma, Anne S. Bassett
Information about the impact on the adult healthcare system is limited for complex rare paediatric diseases, despite their increasing collective prevalence that has paralleled advances in clinical care of children. Within a population-based healthcare context, we examined costs and multimorbidity in adults with an exemplar of contemporary genetic diagnostics. We estimated direct healthcare costs over
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De novo variants in SP9 cause a novel form of interneuronopathy characterized by intellectual disability, autism spectrum disorder, and epilepsy with variable expressivity. Genet. Med. (IF 8.8) Pub Date : 2024-01-27 Marine Tessarech, Gaëlle Friocourt, Florent Marguet, Maryline Lecointre, Morgane Le Mao, Rodrigo Muñoz Díaz, Cyril Mignot, Boris Keren, Bénédicte Héron, Charlotte De Bie, Koen Van Gassen, Didier Loisel, Benoit Delorme, Steffen Syrbe, Annick Klabunde-Cherwon, Rami Abou Jamra, Meret Wegler, Bert Callewaert, Annelies Dheedene, Merzouka Zidannes-Marinnes, Estelle Colin
Purpose Interneuronopathies are a group of neurodevelopmental disorders characterized by deficient migration and differentiation of GABAergic interneurons resulting in a broad clinical spectrum, including autism spectrum disorders, early-onset epileptic encephalopathy, intellectual disability, and schizophrenic disorders. SP9 is a transcription factor belonging to the Krüppel-like factor and specificity
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Comparison of Literature Mining Tools for Variant Classification: Through the Lens of Fifty RYR1 Variants Genet. Med. (IF 8.8) Pub Date : 2024-01-26 Zara Wermers, Seeley Yoo, Bailey Radenbaugh, Amber Douglass, Leslie G. Biesecker, Jennifer J. Johnston
Purpose The American College of Medical Genetics and Genomics and the Association for Molecular Pathology have outlined a schema that allows for systematic classification of variant pathogenicity. While gnomAD is generally accepted as a reliable source of population frequency data and ClinGen has provided guidance on the utility of specific bioinformatic predictors, there is not a consensus source
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Variants in UBAP1L lead to autosomal recessive rod-cone and cone-rod dystrophy Genet. Med. (IF 8.8) Pub Date : 2024-01-28 Christina Zeitz, Julien Navarro, Leila Azizzadeh Pormehr, Cécile Méjécase, Luiza M. Neves, Camille Letellier, Christel Condroyer, Shahad Albadri, Andréa Amprou, Aline Antonio, Tasnim Ben-Yacoub, Juliette Wohlschlegel, Camille Andrieu, Malo Serafini, Lorenzo Bianco, Alessio Antropoli, Marco Nassisi, Said El Shamieh, Sandra Chantot-Bastaraud, Saddek Mohand-Saïd, Vasily Smirnov, José-Alain Sahel, Filippo
Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian descent with only few reports of North African descent. Genome, targeted next-generation, and Sanger sequencing was applied to cohort of ∼4000
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Chenodeoxycholic acid (CDCA) treatment during pregnancy in women with cerebrotendinous xanthomatosis (CTX): lessons learned from 19 pregnancies Genet. Med. (IF 8.8) Pub Date : 2024-01-27 Tzipora C. Falik Zaccai, Sharon Hassin-Baer, Nehama Cohen Kfir, P Barton Duell, Mark Neerhof, Ronen Sloma, Melanie Roitman, Yaz Y. Kisanuki, Aad Verrips, Andrea E. DeBarber
Purpose Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder. Biallelic pathogenic variants in CYP27A1, encoding for sterol 27-hydroxylase, impair cholic acid (CA) and chenodeoxycholic acid (CDCA) synthesis and lead to accumulation of cholestanol and C27 bile alcohols. Treatment with CDCA decreases the accumulation of these harmful metabolites and slows disease
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Assessment of Mendelian and risk factor genes in Alzheimer disease: a prospective nationwide clinical utility study and recommendations for genetic screening Genet. Med. (IF 8.8) Pub Date : 2024-01-24 Gaël Nicolas, Aline Zaréa, Morgane Lacour, Olivier Quenez, Stéphane Rousseau, Anne-Claire Richard, Antoine Bonnevalle, Catherine Schramm, Robert Olaso, Florian Sandron, Anne Boland, Jean-François Deleuze, Daniela Andriuta, Pierre Anthony, Sophie Auriacombe, Anna-Chloé Balageas, Guillaume Ballan, Mélanie Barbay, Yannick Bejot, Serge Belliard, David Wallon
Purpose To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD). Methods We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant
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Gene selection for genomic newborn screening: Moving toward consensus? Genet. Med. (IF 8.8) Pub Date : 2024-01-23 Lilian Downie, Sophie E. Bouffler, David J. Amor, John Christodoulou, Alison Yeung, Ari E. Horton, Ivan Macciocca, Alison D. Archibald, Meghan Wall, Jade Caruana, Sebastian Lunke, Zornitza Stark
Gene selection for genomic newborn screening (gNBS) underpins the validity, acceptability, and ethical application of this technology. Existing gNBS gene lists are highly variable despite being based on shared principles of gene-disease validity, treatability, and age of onset. This study aimed to curate a gNBS gene list that builds upon existing efforts and provide a core consensus list of gene-disease
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Diagnostic utility and reporting recommendations for clinical DNA methylation episignature testing in genetically undiagnosed rare diseases Genet. Med. (IF 8.8) Pub Date : 2024-01-18 Jennifer Kerkhof, Cassandra Rastin, Michael A. Levy, Raissa Relator, Haley McConkey, Leigh Demain, Elena Dominguez-Garrido, Laura Donker Kaat, Sofia Douzgou Houge, Barbara R. DuPont, Timothy Fee, Robin S. Fletcher, David Gokhale, Bjørn Ivar Haukanes, Peter Henneman, Sarah Hilton, Benjamin A. Hilton, Sarah Jenkinson, Jennifer A. Lee, Raymond J. Louie, Bekim Sadikovic
Purpose This study aims to assess the diagnostic utility and provide reporting recommendations for clinical DNA methylation episignature testing based on the cohort of patients tested through the EpiSignTM Clinical Testing Network (ECTN). Methods The EpiSignTM assay utilized unsupervised clustering techniques and a support vector machine-based classification algorithm to compare each patient's genome-wide
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A gene pathogenicity tool ‘GenePy’ identifies missed biallelic diagnoses in the 100,000 Genomes Project Genet. Med. (IF 8.8) Pub Date : 2024-01-18 Eleanor G. Seaby, Gary Leggatt, Guo Cheng, N. Simon Thomas, James J. Ashton, Imogen Stafford
Purpose The 100,000 Genomes Project (100KGP) diagnosed a quarter of affected participants, but 26% of diagnoses were not on the applied gene panel(s); with many being de novo variants. Assessing biallelic variants without a gene panel is more challenging. Methods We sought to identify missed biallelic diagnoses using GenePy, which incorporates allele frequency, zygosity, and a user-defined deleterious
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Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing, and health economic analyses in an exome-negative intellectual disability cohort Genet. Med. (IF 8.8) Pub Date : 2024-01-19 Kerith-Rae Dias, Rupendra Shrestha, Deborah Schofield, Carey-Anne Evans, Emily O’Heir, Ying Zhu, Futao Zhang, Krystle Standen, Ben Weisburd, Sarah L. Stenton, Alba Sanchis-Juan, Harrison Brand, Michael E. Talkowski, Alan Ma, Sondy Ghedia, Meredith Wilson, Sarah A. Sandaradura, Janine Smith, Benjamin Kamien, Anne Turner, Madhura Bakshi, Lesley C. Adès, David Mowat, Matthew Regan, George McGillivray
Genome sequencing (GS)–specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)–negative intellectual disability (ID) cohorts have not been reported extensively. ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID. The ES diagnostic yield was 42 of 74 (57%). GS diagnoses were made in 9 of 32 (28%) ES-unresolved
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Diagnostic delay in monogenic disease: a scoping review Genet. Med. (IF 8.8) Pub Date : 2024-01-17 Rory J. Tinker, Miles Fisher, Alex F. Gimeno, Kayce Gill, Camille Ivey, Josh F. Peterson, Lisa Bastarache
Purpose Diagnostic delay in monogenic disease is reportedly common. We conducted a scoping review investigating variability in study design, results, and conclusions. Methods We searched the academic literature on January 17, 2023, for original peer reviewed journals and conference papers that quantified diagnostic delay in monogenic disease. We abstracted the reported diagnostic delay, relevant study
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Response to Kulseth Genet. Med. (IF 8.8) Pub Date : 2024-01-16 Georg F. Vogel, René G. Feichtinger, Johannes A. Mayr, Saskia B. Wortmann
Abstract not available
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Correspondence on “Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants” by Vogel et al Genet. Med. (IF 8.8) Pub Date : 2024-01-16 Mari Ann Kulseth
Abstract not available
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Improving care for rare genetic neurodevelopmental disorders: a systematic review and critical appraisal of clinical practice guidelines using AGREE II Genet. Med. (IF 8.8) Pub Date : 2024-01-12 Mirthe J. Klein Haneveld, Iméze J. Hieltjes, Miranda W. Langendam, Martina C. Cornel, Charlotte M.W. Gaasterland, Agnies M. Van Eeghen
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Real-world diagnostic outcomes and cost-effectiveness of genome-wide sequencing for developmental and seizure disorders: evidence from Canada Genet. Med. (IF 8.8) Pub Date : 2024-01-08 Dean A. Regier, Rosalie Loewen, Brandon Chan, Morgan Ehman, Samantha Pollard, Jan M. Friedman, Sylvia Stockler-Ipsiroglu, Clara van Karnebeek, Simone Race, Alison M. Elliott, Nick Dragojlovic, Larry D. Lynd, Deirdre Weymann
Purpose To determine real-world diagnostic rates, cost trajectories, and cost-effectiveness of exome sequencing (ES) and genome sequencing (GS) for children with developmental and/or seizure disorders in British Columbia, Canada. Methods Based on medical records review, we estimated real-world costs and outcomes for 491 patients who underwent standard of care (SOC) diagnostic testing at BC Children’s
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Unbiased phenotype and genotype matching maximizes gene discovery and diagnostic yield Genet. Med. (IF 8.8) Pub Date : 2024-01-06 Jonathan Rips, Orli Halstuk, Adina Fuchs, Ziv Lang, Tal Sido, Shiri Gershon-Naamat, Bassam Abu-Libdeh, Simon Edvardson, Somaya Salah, Oded Breuer, Mohamad Hadhud, Sharon Eden, Itamar Simon, Mordechai Slae, Nadirah S. Damseh, Abdulsalam Abu-Libdeh, Marina Eskin-Schwartz, Ohad S. Birk, Julia Varga, Ora Schueler-Furman, Tamar Harel
Purpose Widespread application of next-generation sequencing, combined with data exchange platforms, has provided molecular diagnoses for countless families. To maximize diagnostic yield, we implemented an unbiased semi-automated genematching algorithm based on genotype and phenotype matching. Methods Rare homozygous variants identified in 2 or more affected individuals, but not in healthy individuals
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The cost of proband and trio exome and genome analysis in rare disease: a micro-costing study Genet. Med. (IF 8.8) Pub Date : 2023-12-30 Dylan A. Mordaunt, Francisco Santos Gonzalez, Sebastian Lunke, Stefanie Eggers, Simon Sadedin, Belinda Chong, Kim Dalziel, Zornitza Stark, Ilias Goranitis
Introduction Rare disease genomic testing is a complex process involving various resources. Accurate resource estimation is required for informed prioritization and reimbursement decisions. This study aims to analyze the costs and cost drivers of clinical genomic testing. Methods Based on genomic sequencing workflows we microcosted limited virtual panel analysis on exome sequencing (ES) backbone, proband
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Response to Stern Genet. Med. (IF 8.8) Pub Date : 2023-12-29 Helen Hanson, Esteban Astiazaran-Symonds, Laura M. Amendola, Judith Balmaña, William D. Foulkes, Paul James, Susan Klugman, Joanne Ngeow, Rita Schmutzler, Nicoleta Voian, Myra J. Wick, Tuya Pal, Marc Tischkowitz, Douglas R. Stewart
Abstract not available
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Correspondence on “Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)” by Hanson et al Genet. Med. (IF 8.8) Pub Date : 2023-12-29 Ralph H. Stern
Abstract not available
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Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome Genet. Med. (IF 8.8) Pub Date : 2023-12-27 Laurens Hannes, Marta Atzori, Alice Goldenberg, Jesús Argente, Tania Attie-Bitach, Jeanne Amiel, Catia Attanasio, Débora G. Braslavsky, Ange-Line Bruel, Mireille Castanet, Christèle Dubourg, An Jacobs, Stanislas Lyonnet, Julian Martinez-Mayer, María Inés Pérez Millán, Nunziana Pezzella, Elise Pelgrims, Mio Aerden, Marijke Bauters, Anne Rochtus, Jeroen Breckpot
Purpose Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families. Methods Exome sequencing of affected probands was supplemented
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Biallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities Genet. Med. (IF 8.8) Pub Date : 2023-12-27 Marcello Scala, Kamal Khan, Claire Beneteau, Rachel G. Fox, Sandra von Hardenberg, Ayaz Khan, Madeleine Joubert, Lorraine Fievet, Marie Musquer, Claudine Le Vaillant, Julie Korda Holsclaw, Derek Lim, Ann-Cathrine Berking, Andrea Accogli, Thea Giacomini, Lino Nobili, Pasquale Striano, Federico Zara, Annalaura Torella, Vincenzo Nigro, Michael F. Wells
Purpose We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. Methods We performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate
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Documentation of results and medication prescribing after combinatorial psychiatric pharmacogenetic testing: A case for discrete results Genet. Med. (IF 8.8) Pub Date : 2023-12-25 John Loftus, Howard P. Levy, James M. Stevenson
Purpose Combinatorial pharmacogenetic (PGx) panels intended to aid psychiatric prescribing are available to clinicians. Here, we evaluated the documentation of PGx panel results and subsequent prescribing patterns within a tertiary health care system. Methods We performed a query of psychiatry service note text in our electronic health record using 71 predefined PGx terms. Patients who underwent combinatorial
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Molecular Testing in Newborn Screening: VUS Burden Among True Positives and Secondary Reproductive Limitations via Expanded Carrier Screening Panels Genet. Med. (IF 8.8) Pub Date : 2023-12-23 Sabina Cook, Emily Dunn, Jenna Kornish, Laurel Calderwood, MaryAnn Campion, Kristina P. Cusmano-Ozog, Christina G. Tise
Purpose Expanded carrier screening (ECS) gene panels have several limitations including variable content, current knowledge of disease-causing variants, and differing reporting policies. This study evaluated if the disease-associated variants identified in affected neonates who screened positive by California newborn screening (NBS) for an inherited metabolic disorder (IMD) by tandem mass spectrometry
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Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure Genet. Med. (IF 8.8) Pub Date : 2023-12-19 Joshua Nolan, James Buchanan, John Taylor, Joao Almeida, Tina Bedenham, Edward Blair, Suzanne Broadgate, Samantha Butler, Angela Cazeaux, Judith Craft, Treena Cranston, Gillian Crawford, Jamie Forrest, Jessica Gabriel, Elaine George, Donna Gillen, Ash Haeger, Jillian Hastings Ward, Lara Hawkes, Claire Hodgkiss, Elizabeth Ormondroyd
Purpose The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation
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Characterization of central manifestations in patients with Niemann-Pick disease type C Genet. Med. (IF 8.8) Pub Date : 2023-12-19 Raquel van Gool, Emma Golden, Benjamin Goodlett, Fan Zhang, Adam P. Vogel, Jason A. Tourville, Kylie Yao, Mariesa Cay, Sneham Tiwari, Edward Yang, Leo R. Zekelman, Nick Todd, Lauren J. O’Donnell, Boyu Ren, Olaf A. Bodamer, Walla Al-Hertani, Jaymin Upadhyay
Purpose Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease characterized by progressive neurodegeneration and neuropsychiatric symptoms. This study investigated pathophysiological mechanisms underlying motor deficits, particularly speech production, and cognitive impairment. Methods We prospectively phenotyped 8 adults with NPC and age-sex-matched healthy controls using a comprehensive
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DNA methylation episignature, extension of the clinical features, and comparative epigenomic profiling of Hao-Fountain syndrome caused by variants in USP7 Genet. Med. (IF 8.8) Pub Date : 2023-12-18 Liselot van der Laan, Karim Karimi, Kathleen Rooney, Peter Lauffer, Haley McConkey, Pilar Caro, Raissa Relator, Michael A. Levy, Pratibha Bhai, Cyril Mignot, Boris Keren, Silvana Briuglia, Andrew K. Sobering, Dong Li, Lisenka E.L.M. Vissers, Alexander J.M. Dingemans, Irene Valenzuela, Eline A. Verberne, Mala Misra-Isrie, Petra J.G. Zwijnenburg, Peter Henneman
Purpose Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder caused by pathogenic variants in USP7. HAFOUS is characterized by developmental delay, intellectual disability, speech delay, behavioral abnormalities, autism spectrum disorder, seizures, hypogonadism, and mild dysmorphic features. We investigated the phenotype of 18 participants with HAFOUS and performed DNA methylation (DNAm)
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Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort Genet. Med. (IF 8.8) Pub Date : 2023-12-11 Lisa M. van den Bersselaar, Judith M.A. Verhagen, Jos A. Bekkers, Marlies Kempers, Arjan C. Houweling, Marieke Baars, Eline Overwater, Yvonne Hilhorst-Hofstee, Daniela Q.C.M. Barge-Schaapveld, Eline Rompen, Ingrid P.C. Krapels, Eelco Dulfer, Marja W. Wessels, Bart L. Loeys, Hence J.M. Verhagen, Alessandra Maugeri, Jolien W. Roos-Hesselink, Hennie T. Brüggenwirth, Ingrid M.B.H. van de Laar
Abstract not available
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Most Fanconi anemia heterozygotes are not at increased cancer risk: A genome-first DiscovEHR cohort population study Genet. Med. (IF 8.8) Pub Date : 2023-12-05 Joseph Deng, Burak Altintas, Jeremy S. Haley, Jung Kim, Mark Ramos, David J. Carey, Douglas R. Stewart, Lisa J. McReynolds
Purpose Fanconi anemia (FA) is a bone marrow failure and cancer predisposition syndrome caused primarily by biallelic pathogenic variants in 1 of 22 genes involved in DNA interstrand cross-link repair. An enduring question concerns cancer risk of those with a single pathogenic FA gene variant. To investigate all FA genes, this study utilized the DiscovEHR cohort of 170,503 individuals with exome sequencing
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Severity-adjusted evaluation of liver transplantation on health outcomes in Urea Cycle Disorders Genet. Med. (IF 8.8) Pub Date : 2023-12-03 Roland Posset, Sven F. Garbade, Florian Gleich, Svenja Scharre, Jürgen G. Okun, Andrea L. Gropman, Sandesh C.S. Nagamani, Ann-Catrin Druck, Friederike Epp, Georg F. Hoffmann, Stefan Kölker, Matthias Zielonka
Purpose Liver transplantation (LTx) is performed in individuals with urea cycle disorders (UCDs) when medical management insufficiently prevents the occurrence of hyperammonemic events (HAEs). However, there is a paucity of systematic analysis on the effects of LTx on health-related outcome parameters as compared to individuals with comparable severity who are medically managed. Methods We investigated
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Clinical variants paired with phenotype: A rich resource for brain gene curation Genet. Med. (IF 8.8) Pub Date : 2023-12-04 Maya Chopra, Juliann M. Savatt, Taylor I. Bingaman, Molly E. Good, Alexis Morgan, Caitlin Cooney, Allison M. Rossel, Bryanna VanHoute, Ineke Cordova, Sonal Mahida, Virginia Lanzotti, Dustin Baldridge, Christina A. Gurnett, Joseph Piven, Heather Hazlett, Scott L. Pomeroy, Mustafa Sahin, Philip R.O. Payne, Erin Rooney Riggs, John N. Constantino, Rachel Hauck
Purpose Clinically ascertained variants are under-utilized in neurodevelopmental disorder research. We established the Brain Gene Registry (BGR) to coregister clinically identified variants in putative brain genes with participant phenotypes. Here, we report 179 genetic variants in the first 179 BGR registrants and analyze the proportion that were novel to ClinVar at the time of entry and those that
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Sequential tumor molecular profiling identifies likely germline variants Genet. Med. (IF 8.8) Pub Date : 2023-12-03 Ira L. Kraft, Hatice Basdag, Ashwin Koppayi, Courtnee V. Rodgers, Caner Saygin, Yogameenakshi Haribabu, Pankhuri Wanjari, Nifang Niu, Soma Das, Jill L.O. de Jong, Jeremy Segal, Lucy A. Godley
Purpose To identify likely germline DNA variants from sequential tumor profiling data from hematopoietic malignancies (HMs). Methods The coefficient of variance was calculated from variant allele frequency of next-generation sequencing assays. Variants’ likelihood of being germline was ranked on a 1 to 5 scale. Outcomes were examined in patients with such variants. Results In a pilot set of 33 genes
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Biallelic variants in SLC4A10 encoding a sodium-dependent bicarbonate transporter lead to a neurodevelopmental disorder Genet. Med. (IF 8.8) Pub Date : 2023-12-03 Reza Maroofian, Mina Zamani, Rauan Kaiyrzhanov, Lutz Liebmann, Ehsan Ghayoor Karimiani, Barbara Vona, Antje K. Huebner, Daniel G. Calame, Vinod K. Misra, Saeid Sadeghian, Reza Azizimalamiri, Mohammad Hasan Mohammadi, Jawaher Zeighami, Sogand Heydaran, Mehran Beiraghi Toosi, Javad Akhondian, Meisam Babaei, Narges Hashemi, Rhonda E. Schnur, Mohnish Suri, Christian A. Hübner
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Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group Genet. Med. (IF 8.8) Pub Date : 2023-12-03 Ryan J. Schmidt, Marcie Steeves, Pinar Bayrak-Toydemir, Katherine A. Benson, Bradley P. Coe, Laura K. Conlin, Mythily Ganapathi, John Garcia, Michael H. Gollob, Vaidehi Jobanputra, Minjie Luo, Deqiong Ma, Glenn Maston, Kelly McGoldrick, T. Blake Palculict, Tina Pesaran, Toni I. Pollin, Emily Qian, Heidi L. Rehm, Erin R. Riggs, Yuxin Fan
Purpose Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework
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Identification of DNA methylation episignature for the intellectual developmental disorder, autosomal dominant 21 syndrome, caused by variants in the CTCF gene Genet. Med. (IF 8.8) Pub Date : 2023-12-03 Karim Karimi, Merel O. Mol, Sadegheh Haghshenas, Raissa Relator, Michael A. Levy, Jennifer Kerkhof, Haley McConkey, Alice Brooks, Evelien Zonneveld-Huijssoon, Erica H. Gerkes, Matthew L. Tedder, Lisenka Vissers, Emanuela Salzano, Maria Piccione, Sebastian Dorin Asaftei, Diana Carli, Alessandro Mussa, Elena Shukarova-Angelovska, Slavica Trajkova, Alfredo Brusco, Bekim Sadikovic
Purpose The main objective of this study was to assess clinical features and genome-wide DNA methylation profiles in individuals affected by intellectual developmental disorder, autosomal dominant 21 (IDD21) syndrome, caused by variants in the CCCTC-binding factor (CTCF) gene. Methods DNA samples were extracted from peripheral blood of 16 individuals with clinical features and genetic findings consistent
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Should secondary pharmacogenomic variants be actively screened and reported when diagnostic genome-wide sequencing is performed in a child? Genet. Med. (IF 8.8) Pub Date : 2023-11-23 Jan M. Friedman, Yvonne Bombard, Bruce Carleton, Amalia M. Issa, Bartha Knoppers, Sharon E. Plon, Vasiliki Rahimzadeh, Mary V. Relling, Marc S. Williams, Clara van Karnebeek, Danya Vears, Martina C. Cornel
This white paper was prepared by the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream’s Pediatric Task Team to review and provide perspective with respect to ethical, legal, and social issues regarding the return of secondary pharmacogenomic variants in children who have a serious disease or developmental disorder and are undergoing exome or genome sequencing to identify a
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Impact of genetic counseling strategy on diagnostic yield and workload for genome-sequencing-based tumor diagnostics Genet. Med. (IF 8.8) Pub Date : 2023-11-22 Roelof Koster, Luuk J. Schipper, Noor A.A. Giesbertz, Daphne van Beek, Matías Mendeville, Kris G. Samsom, Efraim H. Rosenberg, Frans B.L. Hogervorst, Paul Roepman, Mirjam C. Boelens, Linda J.W. Bosch, Jose G. van den Berg, Gerrit A. Meijer, Emile E. Voest, Edwin Cuppen, Marielle W.G. Ruijs, Tom van Wezel, Lizet van der Kolk, Kim Monkhorst
Purpose Genome sequencing (GS) enables comprehensive molecular analysis of tumors and identification of hereditary cancer predisposition. According to guidelines, directly determining pathogenic germline variants (PGVs) requires pretest genetic counseling, which is cost-ineffective. Referral for genetic counseling based on tumor variants alone could miss relevant PGVs and/or result in unnecessary referrals
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Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships—allelic requirement, inheritance modes, and disease mechanisms Genet. Med. (IF 8.8) Pub Date : 2023-11-17 Angharad M. Roberts, Marina T. DiStefano, Erin Rooney Riggs, Katherine S. Josephs, Fowzan S. Alkuraya, Joanna Amberger, Mutaz Amin, Jonathan S. Berg, Fiona Cunningham, Karen Eilbeck, Helen V. Firth, Julia Foreman, Ada Hamosh, Eleanor Hay, Sarah Leigh, Christa L. Martin, Ellen M. McDonagh, Daniel Perrett, Erin M. Ramos, Peter N. Robinson, James S. Ware
Purpose The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here, we standardize the terminology for the characterization
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Monogenic etiologies of persistent human papillomavirus infections: A comprehensive systematic review Genet. Med. (IF 8.8) Pub Date : 2023-11-14 Sajjad Biglari, Atefeh Sohanforooshan Moghaddam, Mohammad Amin Tabatabaiefar, Roya Sherkat, Leila Youssefian, Amir Hossein Saeidian, Fatemeh Vahidnezhad, Lam C. Tsoi, Johann E. Gudjonsson, Hakon Hakonarson, Jean-Laurent Casanova, Vivien Béziat, Emmanuelle Jouanguy, Hassan Vahidnezhad
Purpose Persistent human papillomavirus infection (PHPVI) causes cutaneous, anogenital, and mucosal warts. Cutaneous warts include common warts, Treeman syndrome, and epidermodysplasia verruciformis, among others. Although more reports of monogenic predisposition to PHPVI have been published with the development of genomic technologies, genetic testing is rarely incorporated into clinical assessments
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Neurological manifestations in PMM2-congenital disorders of glycosylation (PMM2-CDG): Insights into clinico-radiological characteristics, recommendations for follow-up, and future directions Genet. Med. (IF 8.8) Pub Date : 2023-11-10 Karthik Muthusamy, Judit M. Perez-Ortiz, Anna N. Ligezka, Ruqaiah Altassan, Christin Johnsen, Matthew J. Schultz, Marc C. Patterson, Eva Morava
Purpose In the absence of prospective data on neurological symptoms, disease outcome, or guidelines for system specific management in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG), we aimed to collect and review natural history data. Methods Fifty-one molecularly confirmed individuals with PMM2-CDG enrolled in the Frontiers of Congenital Disorders of Glycosylation natural history