Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities

Elisa Cali¹, Mohnish Suri², Marcello Scala³, Matteo P Ferla⁴, Shahryar Alavi⁵, Eissa Ali Faqeih⁶, Emilia K Bijlsma⁷, Kristen M Wigby⁸, Diana Baralle⁹, Mohammad Y V Mehrjardi¹⁰, Jennifer Schwab¹¹, Konrad Platzer¹², Katharina Steindl¹³, Mais Hashem¹⁴, Marilyn Jones⁸, Dmitriy M Niyazov¹⁵, Jennifer Jacober¹⁵, Rebecca Okashah Littlejohn¹⁶, Denisa Weis¹⁷, Neda Zadeh¹⁸, Lance Rodan¹⁹, Alice Goldenberg²⁰, François Lecoquierre²⁰, Marina Dutra-Clarke²¹, Gabriella Horvath²², Dana Young²³, Naama Orenstein²⁴, Shahad Bawazeer⁶, Anneke T Vulto-van Silfhout²⁵, Yvan Herenger²⁶, Mohammadreza Dehghani¹⁰, Seyed Mohammad Seyedhassani²⁷, Amir Bahreini²⁸, Mahya E Nasab²⁷, A Gulhan Ercan-Sencicek²⁹, Zahra Firoozfar³⁰, Mojtaba Movahedinia³¹, Stephanie Efthymiou¹, Pasquale Striano³, Ehsan Ghayoor Karimiani³², Vincenzo Salpietro³³, Jenny C Taylor⁴, Melody Redman³⁴, Alexander P A Stegmann³⁵, Andreas Laner³⁶, Ghada Abdel-Salam³⁷, Megan Li³⁸, Mario Bengala³⁹, Amelie Johanna Müller⁴⁰, Maria C Digilio⁴¹, Anita Rauch¹³, Murat Gunel⁴², Hannah Titheradge⁴³, Daniela N Schweitzer²¹, Alison Kraus⁴⁴, Irene Valenzuela⁴⁵, Scott D McLean¹⁶, Chanika Phornphutkul¹⁵, Mustafa Salih⁴⁶, Amber Begtrup⁴⁷, Rhonda E Schnur⁴⁷, Erin Torti⁴⁷, Tobias B Haack⁴⁸, Carlos E Prada⁴⁹, Fowzan S Alkuraya⁵⁰, Henry Houlden¹, Reza Maroofian⁵¹

Affiliations

¹ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
² Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom.
³ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
⁴ Genomic Medicine theme, Oxford Biomedical Research Centre, NIHR, Oxford, Oxfordshire, United Kingdom; Wellcome Centre for Human Genetics, Oxford University, Oxford, Oxfordshire, United Kingdom.
⁵ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran; Palindrome, Isfahan, Iran.
⁶ Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical, City, Riyadh, Saudi Arabia.
⁷ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁸ Division of Medical Genetics, Department of Pediatrics, University of California, and Rady Children's Hospital, San Diego, CA.
⁹ Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
¹⁰ Medical Genetics Research Center, Shahid Sadoughi University of Medical Science, Yazd, Iran.
¹¹ Division of Human Genetics, Warren Alpert Medical School of Brown University, Hasbro Children's Hospital/Rhode Island Hospital, Providence, RI.
¹² Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
¹³ Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
¹⁴ Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
¹⁵ Section of Medical Genetics, Department of Pediatrics, Ochsner Health System and University of Queensland, New Orleans, LA.
¹⁶ Department of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX.
¹⁷ Department of Medical Genetics, Kepler University Hospital Med Campus IV, Johannes Kepler University, Linz, Austria.
¹⁸ Children's Hospital of Orange County, Orange, CA; Genetics Center, Orange, California.
¹⁹ Department of Neurology, Boston Children's Hospital, Boston, MA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
²⁰ Department of Genetics and Reference Center for Developmental Disorders, Normandie University, UNIROUEN, CHU Rouen, Inserm U1245, FHU G4 Génomique, Rouen, France.
²¹ Division of Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
²² BC Children's Hospital Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada; Department of Pediatrics, University of British Columbia, Vancouver, Canada.
²³ Adult Metabolic Diseases Clinic, Vancouver General Hospital, Vancouver, Canada.
²⁴ Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
²⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
²⁶ Genetica AG, Zürich, Switzerland.
²⁷ Dr. Seyedhassani Medical Genetic Center, Yazd, Iran.
²⁸ Palindrome, Isfahan, Iran; KaryoGen, Isfahan, Iran; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA.
²⁹ Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT; Masonic Medical Research Institute, Utica, NY.
³⁰ Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran; Palindrome, Isfahan, Iran.
³¹ Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
³² Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran; Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
³³ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
³⁴ Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom.
³⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
³⁶ MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.
³⁷ Human Genetics and Genome Research Division, Department of Clinical Genetics, National Research Centre, Cairo, Egypt.
³⁸ Invitae, San Francisco, CA.
³⁹ Laboratory of Medical Genetics, Tor Vergata Hospital, Rome, Italy.
⁴⁰ Autophagy Laboratory, Department of Molecular Biology, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany.
⁴¹ Medical Genetics Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁴² Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT.
⁴³ West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham, United Kingdom; Women's and Children's NHS Trust, Birmingham, United Kingdom.
⁴⁴ Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom; Castle Hill Hospital, Cottingham, Hull, United Kingdom.
⁴⁵ Department of Clinical and Molecular Genetics, University Hospital Vall d'Hebron, Barcelona, Spain; Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain.
⁴⁶ Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Pediatrics, College of Medicine, AlMughtaribeen University, Khartoum, Sudan.
⁴⁷ GeneDx, Gaithersburg, MD.
⁴⁸ Institute of Human Genetics and Applied Genomics University of Tübingen, Tübingen, Germany; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.
⁴⁹ Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH; Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL.
⁵⁰ Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Anatomy and Cell Biology College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
⁵¹ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom. Electronic address: r.maroofian@ucl.ac.uk.

PMID: 36399134
PMCID: PMC10620944
DOI: 10.1016/j.gim.2022.09.016

Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities

Elisa Cali et al. Genet Med. 2023 Jan.

. 2023 Jan;25(1):135-142.

doi: 10.1016/j.gim.2022.09.016. Epub 2022 Nov 18.

Authors

Affiliations

¹ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
² Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom.
³ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
⁴ Genomic Medicine theme, Oxford Biomedical Research Centre, NIHR, Oxford, Oxfordshire, United Kingdom; Wellcome Centre for Human Genetics, Oxford University, Oxford, Oxfordshire, United Kingdom.
⁵ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran; Palindrome, Isfahan, Iran.
⁶ Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical, City, Riyadh, Saudi Arabia.
⁷ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁸ Division of Medical Genetics, Department of Pediatrics, University of California, and Rady Children's Hospital, San Diego, CA.
⁹ Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
¹⁰ Medical Genetics Research Center, Shahid Sadoughi University of Medical Science, Yazd, Iran.
¹¹ Division of Human Genetics, Warren Alpert Medical School of Brown University, Hasbro Children's Hospital/Rhode Island Hospital, Providence, RI.
¹² Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
¹³ Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
¹⁴ Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
¹⁵ Section of Medical Genetics, Department of Pediatrics, Ochsner Health System and University of Queensland, New Orleans, LA.
¹⁶ Department of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX.
¹⁷ Department of Medical Genetics, Kepler University Hospital Med Campus IV, Johannes Kepler University, Linz, Austria.
¹⁸ Children's Hospital of Orange County, Orange, CA; Genetics Center, Orange, California.
¹⁹ Department of Neurology, Boston Children's Hospital, Boston, MA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
²⁰ Department of Genetics and Reference Center for Developmental Disorders, Normandie University, UNIROUEN, CHU Rouen, Inserm U1245, FHU G4 Génomique, Rouen, France.
²¹ Division of Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
²² BC Children's Hospital Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada; Department of Pediatrics, University of British Columbia, Vancouver, Canada.
²³ Adult Metabolic Diseases Clinic, Vancouver General Hospital, Vancouver, Canada.
²⁴ Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
²⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
²⁶ Genetica AG, Zürich, Switzerland.
²⁷ Dr. Seyedhassani Medical Genetic Center, Yazd, Iran.
²⁸ Palindrome, Isfahan, Iran; KaryoGen, Isfahan, Iran; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA.
²⁹ Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT; Masonic Medical Research Institute, Utica, NY.
³⁰ Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran; Palindrome, Isfahan, Iran.
³¹ Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
³² Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran; Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
³³ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
³⁴ Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom.
³⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
³⁶ MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.
³⁷ Human Genetics and Genome Research Division, Department of Clinical Genetics, National Research Centre, Cairo, Egypt.
³⁸ Invitae, San Francisco, CA.
³⁹ Laboratory of Medical Genetics, Tor Vergata Hospital, Rome, Italy.
⁴⁰ Autophagy Laboratory, Department of Molecular Biology, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany.
⁴¹ Medical Genetics Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁴² Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT.
⁴³ West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham, United Kingdom; Women's and Children's NHS Trust, Birmingham, United Kingdom.
⁴⁴ Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom; Castle Hill Hospital, Cottingham, Hull, United Kingdom.
⁴⁵ Department of Clinical and Molecular Genetics, University Hospital Vall d'Hebron, Barcelona, Spain; Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain.
⁴⁶ Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Pediatrics, College of Medicine, AlMughtaribeen University, Khartoum, Sudan.
⁴⁷ GeneDx, Gaithersburg, MD.
⁴⁸ Institute of Human Genetics and Applied Genomics University of Tübingen, Tübingen, Germany; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.
⁴⁹ Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH; Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL.
⁵⁰ Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Anatomy and Cell Biology College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
⁵¹ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom. Electronic address: r.maroofian@ucl.ac.uk.

PMID: 36399134
PMCID: PMC10620944
DOI: 10.1016/j.gim.2022.09.016

Abstract

Purpose: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder.

Methods: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature.

Results: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss.

Conclusion: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities.

Keywords: Chromatinopathy; Mendelian disorders of the epigenetic machinery; PRMT7; Syndromic neurodevelopmental disorder; Syndromic obesity.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Megan Li is an employee of Invitae. Erin Torti, Amber Begtrup, and Rhonda E Schnur are employees of GeneDx, Inc. All other authors declare no conflicts of interest.

Figures

**Figure 1**
**Phenotypic presentation of individuals with *PRMT7*-related syndrome.** From I to XVI: craniofacial features of affected individuals, front view. From XVII^a to XXIV^d: evolution of facial features among different ages. From XXV to XL: craniofacial features of affected individuals, sagittal view. From XLI to LIII: digital abnormalities. From LIV to LIX: stature of affected individuals. From LX to LXVIII: foot abnormalities.

**Figure 2**
**Overview of the main clinical features of *PRMT7*-related disorder.** A. Occurrence of the main phenotypic features in the cohort. Green: Phenotype present. Blue: Phenotype not present. Yellow: Information not available. B. Degree of intellectual disability. C. Prevalence of obesity by age group and sex. D. Distribution of height percentile throughout the cohort. E. Prevalence of short stature among different ages. F. Deep characterization of the main dysmorphological features of the craniofacial (blue), periorbital (green), nasal (yellow), and perioral (light blue) areas.

See this image and copyright information in PMC

References

1. Guccione E., Richard S. The regulation, functions and clinical relevance of arginine methylation. Nat Rev Mol Cell Biol. 2019;20(10):642–657. Published correction appears in Nat Rev Mol Cell Biol. 2019;20(9):567. - PubMed
1. Lorton B.M., Shechter D. Cellular consequences of arginine methylation. Cell Mol Life Sci. 2019;76(15):2933–2956. doi: 10.1007/s00018-019-03140-2. - DOI - PMC - PubMed
1. Halabelian L., Barsyte-Lovejoy D. Structure and function of protein arginine methyltransferase PRMT7. Life (Basel) 2021;11(8):768. doi: 10.3390/life11080768. - DOI - PMC - PubMed
1. Akawi N., McRae J., Ansari M., et al. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat Genet. 2015;47(11):1363–1369. doi: 10.1038/ng.3410. - DOI - PMC - PubMed
1. Agolini E., Dentici M.L., Bellacchio E., et al. Expanding the clinical and molecular spectrum of PRMT7 mutations: 3 additional patients and review. Clin Genet. 2018;93(3):675–681. doi: 10.1111/cge.13137. - DOI - PubMed

Publication types

Actions
Actions

MeSH terms

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

Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities

Affiliations

Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases