ArticleAmerican journal of human genetics2025
A clinical and genotype-phenotype analysis of MACF1 variants.
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Article in American journal of human genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Global developmental delay and focal seizures in individuals with de novo truncating MACF1 variants.Human genomics · 2026Article
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Authors and funding
90 authors.
Jordy DekkerDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands. Electronic address: j.dekker.1@erasmusmc.nl.
Rachel SchotDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands; Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
Kimberly A AldingerCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Departments of Pediatrics and Neurology, University of Washington, Seattle, WA 98105, USA.
David B EvermanGreenwood Genetic Center, Greenwood, SC 29646, USA.
Camerun WashingtonGreenwood Genetic Center, Greenwood, SC 29646, USA.
Julie R JonesGreenwood Genetic Center, Greenwood, SC 29646, USA.
Jennifer A SullivanDepartment of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, NC 27710, USA.
Rebecca C SpillmannDepartment of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, NC 27710, USA.
Vandana ShashiDepartment of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, NC 27710, USA.
Antonio VitobelloUnité Fonctionnelle d'Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD Génétique des Anomalies du Développement, FHU-TRANSLAD, Dijon, France.
Anne-Sophie Denommé-PichonUnité Fonctionnelle d'Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD Génétique des Anomalies du Développement, FHU-TRANSLAD, Dijon, France.
Anne-Laure Mosca-BoidronUFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD Génétique des Anomalies du Développement, FHU-TRANSLAD, Dijon, France.
Laurence PerrinDépartement de Génétique, Hôpital Robert Debré, 75019 Paris, France.
Stéphane AuvinUniversité Paris-Cité, INSERM NeuroDiderot, APHP, Robert Debré University Hospital, Pediatric Neurology Department, CRMR Epilepsies rares, EpiCare member, Institut Universitaire de France, (IUF), Paris, France.
Maha S ZakiClinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt.
Joseph G GleesonRady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92037, USA.
Naomi MeaveRady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92037, USA.
Cassidy WallaceRady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92037, USA.
Sophie NambotCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHUTRANSLAD - CHU de Dijon, Dijon, France.
Julian DelanneCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHUTRANSLAD - CHU de Dijon, Dijon, France.
Sarah M RuggieroDivision of Neurology, Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Ingo HelbigDivision of Neurology, Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Mark P FitzgeraldDivision of Neurology, Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Richard J LeventerDepartment of Neurology, Royal Children's Hospital, Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Melbourne, Parkville VIC 3052, Australia.
Dorothy K GrangeDivision of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
Emanuela ArgilliDepartment of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Elliott H SherrDepartment of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Supraja PrakashPhoenix Children's Hospital, Department of Genetics & Metabolism, 1919 East Thomas Road, Rosenberg Building, Suite 304, Phoenix, AZ 85016, USA.
Derek E NeilsonPhoenix Children's Hospital, Department of Genetics & Metabolism, 1919 East Thomas Road, Rosenberg Building, Suite 304, Phoenix, AZ 85016, USA; University of Arizona College of Medicine-Phoenix, Department of Child Health, 475 N. 5th Street, Phoenix, AZ 85004, USA.
Francesco NicitaUnit of Neuromuscular and Neurodegenerative Disorders, IRCCS Bambino Gesù Children's Research Hospital, Rome, Italy.
Antonella SferraUnit of Neuromuscular and Neurodegenerative Disorders, IRCCS Bambino Gesù Children's Research Hospital, Rome, Italy.
Enrico S BertiniUnit of Neuromuscular and Neurodegenerative Disorders, IRCCS Bambino Gesù Children's Research Hospital, Rome, Italy.
Chiara AielloLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, IRCCS Bambino Gesù Children Hospital, Rome, Italy.
Knut BrockmannInterdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, Children's Hospital, University Medical Center, Göttingen, Germany.
Alexander B KuranovInstitute of Human Genetics University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany.
Silke KaulfussInstitute of Human Genetics University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany.
Sulman BasitDepartment of Biochemistry and Molecular Medicine, College of Medicine, Taibah University, Almadinah Almunawwarah, Saudi Arabia.
Majed AlluqmaniDepartment of Neurology, College of Medicine, Taibah University, Almadinah Almunawwarah, Saudi Arabia.
Ahmad AlmatrafiDepartment of Biology, College of Science, Taibah University, Almadinah Almunawwarah, Saudi Arabia.
Jan M FriedmanDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Colleen GuimondDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Faruq MohammedGenomics and Molecular Medicine, CSIR - Institute of Genomics and Integrative Biology (IGIB), New Delhi 110007, India.
Pooja SharmaGenomics and Molecular Medicine, CSIR - Institute of Genomics and Integrative Biology (IGIB), New Delhi 110007, India.
Divya GoelGenomics and Molecular Medicine, CSIR - Institute of Genomics and Integrative Biology (IGIB), New Delhi 110007, India; Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi 110062, India.
Thomas WirthService de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
Mathieu AnheimService de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; Centre de Référence des Maladies Neurogénétiques Rares, Strasbourg, France.
Paulina BahenaInstitute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
Asuman KoparirInstitute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
Konstantinos KolokotronisInstitute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
Barbara VonaInstitute of Human Genetics University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany; Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany; Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Thomas HaafInstitute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
Erdmute KunstmannInstitute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
Reza MaroofianDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK.
Henrike L SczakielInstitute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; BIH Biomedical Innovation Academy, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany; RG Development and Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Felix BoschannInstitute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; BIH Biomedical Innovation Academy, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
Mala Misra-IsrieDepartment of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Raymond J LouieGreenwood Genetic Center, Greenwood, SC 29646, USA.
Elliot S StolermanGreenwood Genetic Center, Greenwood, SC 29646, USA.
Pedro A Sanchez-LaraDepartment of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Sandra MerglerMedical Department ASVZ, Care and Service Center for People with Intellectual Disabilities, Sliedrecht, the Netherlands; Department of General Practice and Intellectual Disability Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Renske OegemaDepartment of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Yuri A ZarateDivision of Genetics and Metabolism, University of Kentucky, Lexington, KY, USA.
Ariana KariminejadKariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.
Homa TajsharghiSchool of Health Sciences, Biomedicine Division, University of Skovde, Skovde, Sweden.
Shimriet ZeidlerDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
Anneke J A KievitDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
Arjan BoumanDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
Gerarda CappuccioDepartment of Pediatrics -Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
Nicola Brunetti-PierriDepartment of Translational Medicine, Federico II University, Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, University of Naples Federico II, Naples, Italy.
Kyra E StuurmanDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
Dayna Morel SwolsDivision of Clinical and Translational Genetics, Dr. John T Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.
Mustafa TekinDivision of Clinical and Translational Genetics, Dr. John T Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.
Jariya UpadiaHayward Genetics Center, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA.
Donna M MartinDepartments of Pediatrics and Human Genetics, the University of Michigan Medical School, Ann Arbor, MI, USA.
Daniel CravenDepartment of Pediatric Pulmonology, Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
Susan M HiattHudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
Laura A van de PolDepartment of Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit location, Amsterdam, the Netherlands.
Felice D'ArcoDepartment of Neuroradiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
Henri MargotService de génétique médicale, CHU de Bordeaux, Bordeaux, France.
Martina WilkeDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
Soheil YousefiDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
Tahsin Stefan BarakatDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands; Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
Monique M van Veghel-PlandsoenDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
Eleonora AronicaAmsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Department of (Neuro)Pathology, Amsterdam, the Netherlands; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands.
Jasper AninkAmsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Department of (Neuro)Pathology, Amsterdam, the Netherlands.
Stephen L RogersDepartment of Biology and Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA.
Kevin C SlepDepartment of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
Dan DohertyCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
William B DobynsDepartment of Pediatrics, University of Washington, Seattle, WA 98105, USA; Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN 55455, USA.
Grazia M S ManciniDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
Funding
De novo copy number variation and gene discovery in human brain malformationsR01NS058721 · NINDS · UNIVERSITY OF CHICAGO · PI ARGILLI, EMANUELA · 2008 to 2025
$10.9MTranscriptional Atlas of Human Brain DevelopmentRC2MH089929 · NIMH · YALE UNIVERSITY · PI SESTAN, NENAD · 2009 to 2010
$9.9MTranscriptional Atlas of Human Brain DevelopmentRC2MH090047 · NIMH · UNIVERSITY OF SOUTHERN CALIFORNIA · PI KNOWLES, JAMES A, LEVITT, PAT · 2009 to 2010
$8.9MGenomic Diagnosis in Children with Developmental DelayUM1HG007301 · NHGRI · HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY · PI COOPER, GREGORY MICHAEL, MYERS, RICHARD M · 2013 to 2016
$7.5MDevelopment and Organization of the Human Frontal CortexU01MH081896 · NIMH · YALE UNIVERSITY · PI SESTAN, NENAD · 2009 to 2013
$5.7MMolecular Characterization of Pontocerebellar HypoplasiaR01NS098004 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI JOSEPH G GLEESON · 2016 to 2026
$4.6MLong-read genome sequencing for the discovery of highly penetrant variation in rare diseasesR01HD112437 · NICHD · HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY · PI Gregory Michael Cooper, Jane Grimwood · 2024 to 2026
$1.8MNHGRI NIH HHS UM1 HG007301NICHD NIH HHS R01 HD112437NIMH NIH HHS RC2 MH089929NIMH NIH HHS RC2 MH090047NIMH NIH HHS U01 MH081896NINDS NIH HHS R01 NS058721NINDS NIH HHS R01 NS098004
Abstract
Microtubule-actin cross-linking factor 1 (MACF1) is a large protein of the spectraplakin family, which is essential for brain development. MACF1 interacts with microtubules through the growth arrest-specific 2 (Gas2)-related (GAR) domain. Heterozygous MACF1 missense variants affecting the zinc-binding residues in this domain result in a distinctive cortical and brain stem malformation. Evidence for other MACF1-associated disorders is still limited. Here, we present a cohort of 45 individuals with heterozygous or bi-allelic MACF1 variants to explore the phenotypic spectrum and assess possible pathogenic relevance. We observe that de novo heterozygous missense variants in the EF-hand domains also result in distinctive brain malformation and provide experimental evidence that variants in the EF-hand/GAR module increase microtubule binding, suggestive of a toxic gain of function. Notably, no phenotype-genotype correlation was possible for the remaining heterozygous variants in other domains. A clinical review of eight families with bi-allelic variants reveals a possible complex neurodevelopmental syndrome of the central and peripheral nervous systems. In these individuals, bi-allelic variants mostly affect the Plakin domain. Furthermore, RNA sequencing and chromatin immunoprecipitation (ChIP) analyses of human fetal brain tissue reveal five MACF1 isoforms with region-specific expression, differing in their exon 1 transcription start sites but splicing to a common exon 2. This differential expression explains the frontal-predominant lissencephaly in an individual with a homozygous stop-gain in exon 1 (MACF1-204: c.70C>T [p.Arg24∗]), as this isoform is preferentially expressed in the frontal cortex. We conclude that MACF1-related disorders are strictly linked to domain function and the level of transcript expression, explaining the observed wide clinical heterogeneity.
Indexed as
Genetic Association StudiesMicrofilament ProteinsTrans-ActivatorsAdolescentAdultAllelesBrainChildChild, PreschoolFemaleGenotypeHeterozygoteHumansInfantMaleMicrotubulesMACF1 protein, humanMicrofilament ProteinsProtein IsoformsTrans-ActivatorsACF7axonal pathfindingbrainstem hypoplasialissencephalyMACF1microtubules
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