Genetics in Medicine Open (Jan 2024)
Regulatory elements in SEM1-DLX5-DLX6 (7q21.3) locus contribute to genetic control of coronal nonsyndromic craniosynostosis and bone density-related traits
- Paola Nicoletti,
- Samreen Zafer,
- Lital Matok,
- Inbar Irron,
- Meidva Patrick,
- Rotem Haklai,
- John Erol Evangelista,
- Giacomo B. Marino,
- Avi Ma’ayan,
- Anshuman Sewda,
- Greg Holmes,
- Sierra R. Britton,
- Won Jun Lee,
- Meng Wu,
- Ying Ru,
- Eric Arnaud,
- Lorenzo Botto,
- Lawrence C. Brody,
- Jo C. Byren,
- Michele Caggana,
- Suzan L. Carmichael,
- Deirdre Cilliers,
- Kristin Conway,
- Karen Crawford,
- Araceli Cuellar,
- Federico Di Rocco,
- Michael Engel,
- Jeffrey Fearon,
- Marcia L. Feldkamp,
- Richard Finnell,
- Sarah Fisher,
- Christian Freudlsperger,
- Gemma Garcia-Fructuoso,
- Rhinda Hagge,
- Yann Heuzé,
- Raymond J. Harshbarger,
- Charlotte Hobbs,
- Meredith Howley,
- Mary M. Jenkins,
- David Johnson,
- Cristina M. Justice,
- Alex Kane,
- Denise Kay,
- Arun Kumar Gosain,
- Peter Langlois,
- Laurence Legal-Mallet,
- Angela E. Lin,
- James L. Mills,
- Jenny E.V. Morton,
- Peter Noons,
- Andrew Olshan,
- John Persing,
- Julie M. Phipps,
- Richard Redett,
- Jennita Reefhuis,
- Elias Rizk,
- Thomas D. Samson,
- Gary M. Shaw,
- Robert Sicko,
- Nataliya Smith,
- David Staffenberg,
- Joan Stoler,
- Elizabeth Sweeney,
- Peter J. Taub,
- Andrew T. Timberlake,
- Jolanta Topczewska,
- Steven A. Wall,
- Alexander F. Wilson,
- Louise C. Wilson,
- Simeon A. Boyadjiev,
- Andrew O.M. Wilkie,
- Joan T. Richtsmeier,
- Ethylin Wang Jabs,
- Paul A. Romitti,
- David Karasik,
- Ramon Y. Birnbaum,
- Inga Peter
Affiliations
- Paola Nicoletti
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
- Samreen Zafer
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
- Lital Matok
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- Inbar Irron
- Department of Life Sciences, Faculty of Natural Sciences and The Center for Evolutionarily Genomics and Medicine, Ben Gurion University, Beer Sheva, Israel
- Meidva Patrick
- Department of Life Sciences, Faculty of Natural Sciences and The Center for Evolutionarily Genomics and Medicine, Ben Gurion University, Beer Sheva, Israel
- Rotem Haklai
- Department of Life Sciences, Faculty of Natural Sciences and The Center for Evolutionarily Genomics and Medicine, Ben Gurion University, Beer Sheva, Israel
- John Erol Evangelista
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
- Giacomo B. Marino
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
- Avi Ma’ayan
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
- Anshuman Sewda
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY
- Greg Holmes
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
- Sierra R. Britton
- Department of Population Health Sciences, Weill Cornell Medical College of Cornell University New York, NY
- Won Jun Lee
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
- Meng Wu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
- Ying Ru
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
- Eric Arnaud
- Department of Neurosurgery, Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
- Lorenzo Botto
- Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah
- Lawrence C. Brody
- Social and Behavioral Research Branch, National Human Genome Research Institute, Bethesda, MD
- Jo C. Byren
- Craniofacial Unit, Department of Plastic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
- Michele Caggana
- Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY
- Suzan L. Carmichael
- Department of Pediatrics, Department of Obstetrics and Gynecology, Stanford University, Stanford, CA
- Deirdre Cilliers
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
- Kristin Conway
- Department of Epidemiology, University of Iowa, Iowa City, IA
- Karen Crawford
- MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
- Araceli Cuellar
- Department of Pediatrics, University of California, Davis, CA
- Federico Di Rocco
- Hôpital Femme Mère Enfant Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France
- Michael Engel
- Department of Oral and Cranio-Maxillofacial Surgery, Heidelberg University Hospital, Heidelberg, Germany
- Jeffrey Fearon
- The Craniofacial Center, Medical City Children’s Hospital Dallas, Dallas, TX
- Marcia L. Feldkamp
- Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah
- Richard Finnell
- Center for Precision Environmental Health, Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas
- Sarah Fisher
- Birth Defects Registry, New York State Department of Health, Albany, NY
- Christian Freudlsperger
- Department of Oral and Cranio-Maxillofacial Surgery, Heidelberg University Hospital, Heidelberg, Germany
- Gemma Garcia-Fructuoso
- Hospital Sant Joan de Deu, Hospital Sant Joan de Deu, Barcelona, Spain
- Rhinda Hagge
- Department of Epidemiology, University of Iowa, Iowa City, IA
- Yann Heuzé
- Université de Bordeaux, CNRS, Ministère de la Culture, PACEA, Pessac, France
- Raymond J. Harshbarger
- Department of Surgery, Division of Pediatric Plastic Surgery, UT Austin, Austin, TX
- Charlotte Hobbs
- Rady Children’s Institute for Genomic Medicine, San Diego, CA
- Meredith Howley
- Birth Defects Registry, New York State Department of Health, Albany, NY
- Mary M. Jenkins
- Division of Birth Defects and Infant Disorders, Centers for Disease Control and Prevention, Atlanta, GA
- David Johnson
- Craniofacial Unit, Department of Plastic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
- Cristina M. Justice
- Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD
- Alex Kane
- Department of Plastic Surgery, UT Southwestern Medical Center, Dallas, TX
- Denise Kay
- Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY
- Arun Kumar Gosain
- Department of Surgery, Division of Pediatric Plastic Surgery, Children’s Hospital of Chicago, Northwestern University, Chicago, IL
- Peter Langlois
- Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Austin Campus, Austin, TX
- Laurence Legal-Mallet
- Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France
- Angela E. Lin
- Medical Genetics, Mass General Hospital for Children, Harvard Medical School, Boston, MA
- James L. Mills
- Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD
- Jenny E.V. Morton
- Birmingham Health Partners, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Birmingham, United Kingdom
- Peter Noons
- Birmingham Craniofacial Unit, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Birmingham, United Kingdom
- Andrew Olshan
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC
- John Persing
- Division of Plastic and Reconstructive Surgery, Yale School of Medicine, New Haven, CT
- Julie M. Phipps
- MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
- Richard Redett
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University, Baltimore, MD
- Jennita Reefhuis
- Division of Birth Defects and Infant Disorders, Centers for Disease Control and Prevention, Atlanta, GA
- Elias Rizk
- Department of Neurosurgery, Pennsylvania State University Medical Center, Hershey, PA
- Thomas D. Samson
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Pennsylvania State University Medical Center, Hershey, PA
- Gary M. Shaw
- Department of Pediatrics, Stanford University, Stanford, CA
- Robert Sicko
- Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY
- Nataliya Smith
- Neuroscience Institute, Pennsylvania State University, College of Medicine, Hershey Medical Center, Hershey, PA
- David Staffenberg
- Hansjörg Wyss Department of Plastic Surgery, NYU Langone Medical Center, Hassenfeld Children’s Hospital, New York, NY
- Joan Stoler
- Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA
- Elizabeth Sweeney
- Department of Clinical Genetics, Liverpool Women’s Hospital NHS Trust, Liverpool, United Kingdom
- Peter J. Taub
- Division of Plastic and Reconstructive Surgery, Icahn School of Medicine at Mount Sinai, New York, NY
- Andrew T. Timberlake
- Hansjörg Wyss Department of Plastic Surgery, NYU Langone Medical Center, Hassenfeld Children’s Hospital, New York, NY
- Jolanta Topczewska
- Department of Surgery, Division of Pediatric Plastic Surgery, Children’s Hospital of Chicago, Northwestern University, Chicago, IL
- Steven A. Wall
- Craniofacial Unit, Department of Plastic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
- Alexander F. Wilson
- Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD
- Louise C. Wilson
- Clinical Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
- Simeon A. Boyadjiev
- Department of Pediatrics, University of California, Davis, CA
- Andrew O.M. Wilkie
- MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
- Joan T. Richtsmeier
- Department of Anthropology, Pennsylvania State University, University Park, PA
- Ethylin Wang Jabs
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
- Paul A. Romitti
- Department of Epidemiology, University of Iowa, Iowa City, IA
- David Karasik
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- Ramon Y. Birnbaum
- Department of Life Sciences, Faculty of Natural Sciences and The Center for Evolutionarily Genomics and Medicine, Ben Gurion University, Beer Sheva, Israel; Ramon Y. Birnbaum, Department of Life Sciences, Ben-Gurion University of the Negev, Rager Street, P.O.B 653, Beer Sheva 84105, Israel.
- Inga Peter
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; Correspondence and requests for materials should be addressed to Inga Peter, 1425 Madison Ave, New York, NY 10029.
- Journal volume & issue
-
Vol. 2
p. 101851
Abstract
Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E−12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.
