HGG Advances (Jul 2022)
Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology
- Andrew K. Sobering,
- Laura M. Bryant,
- Dong Li,
- Julie McGaughran,
- Isabelle Maystadt,
- Stephanie Moortgat,
- John M. Graham, Jr.,
- Arie van Haeringen,
- Claudia Ruivenkamp,
- Roos Cuperus,
- Julie Vogt,
- Jenny Morton,
- Charlotte Brasch-Andersen,
- Maria Steenhof,
- Lars Kjærsgaard Hansen,
- Élodie Adler,
- Stanislas Lyonnet,
- Veronique Pingault,
- Marlin Sandrine,
- Alban Ziegler,
- Tyhiesia Donald,
- Beverly Nelson,
- Brandon Holt,
- Oleksandra Petryna,
- Helen Firth,
- Kirsty McWalter,
- Jacob Zyskind,
- Aida Telegrafi,
- Jane Juusola,
- Richard Person,
- Michael J. Bamshad,
- Dawn Earl,
- Anne Chun-Hui Tsai,
- Katherine R. Yearwood,
- Elysa Marco,
- Catherine Nowak,
- Jessica Douglas,
- Hakon Hakonarson,
- Elizabeth J. Bhoj
Affiliations
- Andrew K. Sobering
- AU/UGA Medical Partnership, Department of Basic Sciences, University of Georgia Health Sciences Campus, Athens, GA 30602, USA; St. George’s University, Department of Biochemistry, St. George’s, Grenada, West Indies; Windward Islands Research and Education Foundation, True Blue, St. George’s, Grenada, West Indies; Corresponding author
- Laura M. Bryant
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Dong Li
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Julie McGaughran
- Genetic Health Queensland, RBWH, Brisbane and The University of Queensland School of Medicine, Brisbane, QLD 4029, Australia
- Isabelle Maystadt
- Centre de Génétique Humaine, Institut de Pathologie et de Génétique, 6041 Gosselies, Belgium
- Stephanie Moortgat
- Centre de Génétique Humaine, Institut de Pathologie et de Génétique, 6041 Gosselies, Belgium
- John M. Graham, Jr.
- Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA
- Arie van Haeringen
- Leiden University Medical Center, 9600, 2300 RC Leiden, the Netherlands
- Claudia Ruivenkamp
- Leiden University Medical Center, 9600, 2300 RC Leiden, the Netherlands
- Roos Cuperus
- Juliana Children’s Hospital, HAGA Medical Center, The Hague, the Netherlands
- Julie Vogt
- Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham Women’s Hospital, Birmingham B15 2TG, UK
- Jenny Morton
- West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women’s Hospital NHS Foundation Trust, Birmingham B15 2TG, UK
- Charlotte Brasch-Andersen
- Department of Clinical Genetics, Odense University Hospital, Odense 5000, Denmark; Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense 5000, Denmark
- Maria Steenhof
- Department of Clinical Genetics, Odense University Hospital, Odense 5000, Denmark
- Lars Kjærsgaard Hansen
- Department of Paediatrics, Odense University Hospital, Odense 5000, Denmark
- Élodie Adler
- Fédération de Médecine Génomique and Imagine Institute, Université de Paris, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France
- Stanislas Lyonnet
- Fédération de Médecine Génomique and Imagine Institute, Université de Paris, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France
- Veronique Pingault
- Fédération de Médecine Génomique and Imagine Institute, Université de Paris, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France
- Marlin Sandrine
- Reference Center for Genetic Deafness, Fédération de Médecine Génomique and Imagine Institute, Université de Paris, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France
- Alban Ziegler
- Reference Center for Genetic Deafness, Fédération de Médecine Génomique and Imagine Institute, Université de Paris, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France
- Tyhiesia Donald
- Clinical Teaching Unit, St. George’s University School of Medicine, St. George’s, Grenada, West Indies
- Beverly Nelson
- Clinical Teaching Unit, St. George’s University School of Medicine, St. George’s, Grenada, West Indies
- Brandon Holt
- Department of Anatomical Sciences, St. George’s University, Grenada, West Indies
- Oleksandra Petryna
- Hackensack University Ocean Medical Center, Department of Psychiatry, Hackensack, NJ 08724, USA
- Helen Firth
- Department of Clinical Genetics, Cambridge University Hospitals, Box 134, Cambridge CB2 0QQ, UK
- Kirsty McWalter
- Clinical Genomics, GeneDx, Gaithersburg, MD 20877, USA
- Jacob Zyskind
- Clinical Genomics, GeneDx, Gaithersburg, MD 20877, USA
- Aida Telegrafi
- Clinical Genomics, GeneDx, Gaithersburg, MD 20877, USA
- Jane Juusola
- Clinical Genomics, GeneDx, Gaithersburg, MD 20877, USA
- Richard Person
- Clinical Genomics, GeneDx, Gaithersburg, MD 20877, USA
- Michael J. Bamshad
- Seattle Children’s Hospital, Seattle, WA 98105, USA; Departments of Pediatrics and Genome Sciences, University of Washington, Seattle, WA 98195, USA; Brotman-Baty Institute, Seattle, WA 98195, USA
- Dawn Earl
- Seattle Children’s Hospital, Seattle, WA 98105, USA
- Anne Chun-Hui Tsai
- University of Oklahoma, Section of Genetics, 800 Stanton L Young Boulevard, Oklahoma City, OK 73117, USA
- Katherine R. Yearwood
- University Health Services, St. George’s University, Grenada, West Indies
- Elysa Marco
- Cortica Healthcare, Marin Center, 4000 Civic Center Dr, Ste 100, San Rafael, CA 94903, USA
- Catherine Nowak
- Boston Children’s Hospital, Division of Genetics and Genomics, 60 Temple Place, 2nd Floor, Boston, MA 02111, USA
- Jessica Douglas
- Boston Children’s Hospital, Division of Genetics and Genomics, 60 Temple Place, 2nd Floor, Boston, MA 02111, USA
- Hakon Hakonarson
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
- Elizabeth J. Bhoj
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Corresponding author
- Journal volume & issue
-
Vol. 3,
no. 3
p. 100102
Abstract
Summary: Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function.
