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 2026-04-02)
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 Oct 2;112(10):2363-2380.

doi: 10.1016/j.ajhg.2025.08.010. Epub 2025 Sep 8.

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 2026-04-02)
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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

1. Stanley J.R., Hawley-Nelson P., Yuspa S.H., Shevach E.M., Katz S.I. Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia. Cell. 1981;24:897–903. - PubMed
1. Byers T.J., Beggs A.H., McNally E.M., Kunkel L.M. Novel actin crosslinker superfamily member identified by a two step degenerate PCR procedure. FEBS Lett. 1995;368:500–504. - PubMed
1. Yang Y., Dowling J., Yu Q.C., Kouklis P., Cleveland D.W., Fuchs E. An essential cytoskeletal linker protein connecting actin microfilaments to intermediate filaments. Cell. 1996;86:655–665. - PubMed
1. Leung C.L., Sun D., Zheng M., Knowles D.R., Liem R.K. Microtubule actin cross-linking factor (MACF): a hybrid of dystonin and dystrophin that can interact with the actin and microtubule cytoskeletons. J. Cell Biol. 1999;147:1275–1286. - PMC - PubMed
1. Feng Y., Walsh C.A. Protein-protein interactions, cytoskeletal regulation and neuronal migration. Nat. Rev. Neurosci. 2001;2:408–416. - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources