Send to

Choose Destination
Am J Med Genet A. 2019 Oct;179(10):2075-2082. doi: 10.1002/ajmg.a.61306. Epub 2019 Jul 30.

Phenotype delineation of ZNF462 related syndrome.

Author information

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California.
Service de génétique médicale, Hôtel-Dieu, Nantes, France.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Keck School of Medicine, University of Southern California, Los Angeles, California.
Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California.
West of Scotland Genetics Service, Queen Elizabeth Hospitals, Glasgow, Scotland.
Personalized Genomic Medicine and Pediatric Genetics, Atlantic Health System, Morristown, New Jersey.
Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Medical Genetic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy.
Genetics, Vaccine Preventable Diseases, and Sexual Health, Algoma Public Health, Sault Ste. Marie, Ontario, Canada.
Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
Victorian Clinical Genetics Services, Melbourne, Victoria, Australia.
Département de pédiatrie, Service de génétique médicale, Centre Hospitalier Universitaire Ste-Justine, Université de Montréal, Montréal, Québec, Canada.
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Howard Hughes Medical Institute, Chevy Chase, Maryland.
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
FDNA, Inc., Boston, Massachusetts.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.


Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.


ZNF462; autism spectrum disorders; corpus callosum; craniosynostosis; developmental delay; ptosis

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center