A clinical and genotype-phenotype analysis of MACF1 variants

Jordy Dekker¹, Rachel Schot², Kimberly A Aldinger³, David B Everman⁴, Camerun Washington⁴, Julie R Jones⁴, Jennifer A Sullivan⁵, Rebecca C Spillmann⁵, Vandana Shashi⁵, Antonio Vitobello⁶, Anne-Sophie Denommé-Pichon⁶, Anne-Laure Mosca-Boidron⁷, Laurence Perrin⁸, Stéphane Auvin⁹, Maha S Zaki¹⁰, Joseph G Gleeson¹¹, Naomi Meave¹¹, Cassidy Wallace¹¹, Sophie Nambot¹², Julian Delanne¹², Sarah M Ruggiero¹³, Ingo Helbig¹³, Mark P Fitzgerald¹³, Richard J Leventer¹⁴, Dorothy K Grange¹⁵, Emanuela Argilli¹⁶, Elliott H Sherr¹⁶, Supraja Prakash¹⁷, Derek E Neilson¹⁸, Francesco Nicita¹⁹, Antonella Sferra¹⁹, Enrico S Bertini¹⁹, Chiara Aiello²⁰, Knut Brockmann²¹, Alexander B Kuranov²², Silke Kaulfuss²², Sulman Basit²³, Majed Alluqmani²⁴, Ahmad Almatrafi²⁵, Jan M Friedman²⁶, Colleen Guimond²⁶, Faruq Mohammed²⁷, Pooja Sharma²⁷, Divya Goel²⁸, Thomas Wirth²⁹, Mathieu Anheim³⁰, Paulina Bahena³¹, Asuman Koparir³¹, Konstantinos Kolokotronis³¹, Barbara Vona³², Thomas Haaf³¹, Erdmute Kunstmann³¹, Reza Maroofian³³, Henrike L Sczakiel³⁴, Felix Boschann³⁵, Mala Misra-Isrie³⁶, Raymond J Louie⁴, Elliot S Stolerman⁴, Pedro A Sanchez-Lara³⁷, Sandra Mergler³⁸, Renske Oegema³⁹, Yuri A Zarate⁴⁰, Ariana Kariminejad⁴¹, Homa Tajsharghi⁴², Shimriet Zeidler⁴³, Anneke J A Kievit⁴³, Arjan Bouman⁴³, Gerarda Cappuccio⁴⁴, Nicola Brunetti-Pierri⁴⁵, Kyra E Stuurman⁴³, Dayna Morel Swols⁴⁶, Mustafa Tekin⁴⁶, Jariya Upadia⁴⁷, Donna M Martin⁴⁸, Daniel Craven⁴⁹, Susan M Hiatt⁵⁰, Laura A van de Pol⁵¹, Felice D'Arco⁵², Henri Margot⁵³, Martina Wilke⁴³, Soheil Yousefi⁴³, Tahsin Stefan Barakat², Monique M van Veghel-Plandsoen⁴³, Eleonora Aronica⁵⁴, Jasper Anink⁵⁵, Stephen L Rogers⁵⁶, Kevin C Slep⁵⁷, Dan Doherty⁵⁸, William B Dobyns⁵⁹, Grazia M S Mancini⁴³

Affiliations

¹ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands. Electronic address: j.dekker.1@erasmusmc.nl.
² Department 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.
³ Center 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.
⁴ Greenwood Genetic Center, Greenwood, SC 29646, USA.
⁵ Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, NC 27710, USA.
⁶ Unité 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.
⁷ UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD Génétique des Anomalies du Développement, FHU-TRANSLAD, Dijon, France.
⁸ Département de Génétique, Hôpital Robert Debré, 75019 Paris, France.
⁹ Université Paris-Cité, INSERM NeuroDiderot, APHP, Robert Debré University Hospital, Pediatric Neurology Department, CRMR Epilepsies rares, EpiCare member, Institut Universitaire de France, (IUF), Paris, France.
¹⁰ Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt.
¹¹ Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92037, USA.
¹² Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHUTRANSLAD - CHU de Dijon, Dijon, France.
¹³ Division 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.
¹⁴ Department of Neurology, Royal Children's Hospital, Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Melbourne, Parkville VIC 3052, Australia.
¹⁵ Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
¹⁶ Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁷ Phoenix Children's Hospital, Department of Genetics & Metabolism, 1919 East Thomas Road, Rosenberg Building, Suite 304, Phoenix, AZ 85016, USA.
¹⁸ Phoenix 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.
¹⁹ Unit of Neuromuscular and Neurodegenerative Disorders, IRCCS Bambino Gesù Children's Research Hospital, Rome, Italy.
²⁰ Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, IRCCS Bambino Gesù Children Hospital, Rome, Italy.
²¹ Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, Children's Hospital, University Medical Center, Göttingen, Germany.
²² Institute of Human Genetics University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany.
²³ Department of Biochemistry and Molecular Medicine, College of Medicine, Taibah University, Almadinah Almunawwarah, Saudi Arabia.
²⁴ Department of Neurology, College of Medicine, Taibah University, Almadinah Almunawwarah, Saudi Arabia.
²⁵ Department of Biology, College of Science, Taibah University, Almadinah Almunawwarah, Saudi Arabia.
²⁶ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
²⁷ Genomics and Molecular Medicine, CSIR - Institute of Genomics and Integrative Biology (IGIB), New Delhi 110007, India.
²⁸ Genomics 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.
²⁹ Service 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.
³⁰ Service 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.
³¹ Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
³² Institute 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.
³³ Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK.
³⁴ Institute 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.
³⁵ Institute 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.
³⁶ Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
³⁷ Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
³⁸ Medical 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.
³⁹ Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁴⁰ Division of Genetics and Metabolism, University of Kentucky, Lexington, KY, USA.
⁴¹ Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.
⁴² School of Health Sciences, Biomedicine Division, University of Skovde, Skovde, Sweden.
⁴³ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
⁴⁴ Department of Pediatrics -Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
⁴⁵ Department 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.
⁴⁶ Division 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.
⁴⁷ Hayward Genetics Center, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA.
⁴⁸ Departments of Pediatrics and Human Genetics, the University of Michigan Medical School, Ann Arbor, MI, USA.
⁴⁹ Department of Pediatric Pulmonology, Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
⁵⁰ HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
⁵¹ Department of Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit location, Amsterdam, the Netherlands.
⁵² Department of Neuroradiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
⁵³ Service de génétique médicale, CHU de Bordeaux, Bordeaux, France.
⁵⁴ Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Department of (Neuro)Pathology, Amsterdam, the Netherlands; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands.
⁵⁵ Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Department of (Neuro)Pathology, Amsterdam, the Netherlands.
⁵⁶ Department of Biology and Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵⁷ Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵⁸ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
⁵⁹ Department of Pediatrics, University of Washington, Seattle, WA 98105, USA; Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN 55455, USA.

PMID: 40925378
PMCID: PMC12431674 (available on 2026-09-03)
DOI: 10.1016/j.ajhg.2025.08.010

A clinical and genotype-phenotype analysis of MACF1 variants

Jordy Dekker et al. Am J Hum Genet. 2025.

. 2025 Sep 3:S0002-9297(25)00320-9.

doi: 10.1016/j.ajhg.2025.08.010. Online ahead of print.

Authors

Affiliations

¹ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands. Electronic address: j.dekker.1@erasmusmc.nl.
² Department 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.
³ Center 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.
⁴ Greenwood Genetic Center, Greenwood, SC 29646, USA.
⁵ Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, NC 27710, USA.
⁶ Unité 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.
⁷ UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD Génétique des Anomalies du Développement, FHU-TRANSLAD, Dijon, France.
⁸ Département de Génétique, Hôpital Robert Debré, 75019 Paris, France.
⁹ Université Paris-Cité, INSERM NeuroDiderot, APHP, Robert Debré University Hospital, Pediatric Neurology Department, CRMR Epilepsies rares, EpiCare member, Institut Universitaire de France, (IUF), Paris, France.
¹⁰ Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt.
¹¹ Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92037, USA.
¹² Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHUTRANSLAD - CHU de Dijon, Dijon, France.
¹³ Division 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.
¹⁴ Department of Neurology, Royal Children's Hospital, Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Melbourne, Parkville VIC 3052, Australia.
¹⁵ Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
¹⁶ Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁷ Phoenix Children's Hospital, Department of Genetics & Metabolism, 1919 East Thomas Road, Rosenberg Building, Suite 304, Phoenix, AZ 85016, USA.
¹⁸ Phoenix 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.
¹⁹ Unit of Neuromuscular and Neurodegenerative Disorders, IRCCS Bambino Gesù Children's Research Hospital, Rome, Italy.
²⁰ Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, IRCCS Bambino Gesù Children Hospital, Rome, Italy.
²¹ Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, Children's Hospital, University Medical Center, Göttingen, Germany.
²² Institute of Human Genetics University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany.
²³ Department of Biochemistry and Molecular Medicine, College of Medicine, Taibah University, Almadinah Almunawwarah, Saudi Arabia.
²⁴ Department of Neurology, College of Medicine, Taibah University, Almadinah Almunawwarah, Saudi Arabia.
²⁵ Department of Biology, College of Science, Taibah University, Almadinah Almunawwarah, Saudi Arabia.
²⁶ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
²⁷ Genomics and Molecular Medicine, CSIR - Institute of Genomics and Integrative Biology (IGIB), New Delhi 110007, India.
²⁸ Genomics 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.
²⁹ Service 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.
³⁰ Service 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.
³¹ Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
³² Institute 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.
³³ Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK.
³⁴ Institute 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.
³⁵ Institute 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.
³⁶ Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
³⁷ Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
³⁸ Medical 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.
³⁹ Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁴⁰ Division of Genetics and Metabolism, University of Kentucky, Lexington, KY, USA.
⁴¹ Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.
⁴² School of Health Sciences, Biomedicine Division, University of Skovde, Skovde, Sweden.
⁴³ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, the Netherlands.
⁴⁴ Department of Pediatrics -Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
⁴⁵ Department 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.
⁴⁶ Division 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.
⁴⁷ Hayward Genetics Center, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA.
⁴⁸ Departments of Pediatrics and Human Genetics, the University of Michigan Medical School, Ann Arbor, MI, USA.
⁴⁹ Department of Pediatric Pulmonology, Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
⁵⁰ HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
⁵¹ Department of Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit location, Amsterdam, the Netherlands.
⁵² Department of Neuroradiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
⁵³ Service de génétique médicale, CHU de Bordeaux, Bordeaux, France.
⁵⁴ Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Department of (Neuro)Pathology, Amsterdam, the Netherlands; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands.
⁵⁵ Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Department of (Neuro)Pathology, Amsterdam, the Netherlands.
⁵⁶ Department of Biology and Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵⁷ Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵⁸ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
⁵⁹ Department of Pediatrics, University of Washington, Seattle, WA 98105, USA; Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN 55455, USA.

PMID: 40925378
PMCID: PMC12431674 (available on 2026-09-03)
DOI: 10.1016/j.ajhg.2025.08.010

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.

Keywords: ACF7; MACF1; axonal pathfinding; brainstem hypoplasia; lissencephaly; microtubules.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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A clinical and genotype-phenotype analysis of MACF1 variants

Affiliations

A clinical and genotype-phenotype analysis of MACF1 variants

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources