Phenotype delineation of ZNF462 related syndrome

作者：Paul Kruszka, Tommy Hu, Sung‐Kook Hong, Rebecca Signer, Benjamin Cogné, Betrand Isidor, Sarah Mazzola, Jacques C. Giltay, Koen L.I. van Gassen, Eleina England, Lynn Pais, Charlotte W. Ockeloen, Pedro A. Sanchez‐Lara, Esther Kinning, Darius J. Adams, Kayla Treat, Wilfredo Torres‐Martinez, Maria Francesca Bedeschi, Maria Iascone, Stephanie Blaney, Oliver Bell, Tiong Yang Tan, Marie‐Ange Delrue, Julie A. Jurgens, Brenda J. Barry, Elizabeth C. Engle, Sarah Savage, Nicole Fleischer, Julián A. Martínez-Agosto, Kym M. Boycott, Elaine H. Zackai, Maximilian Muenke · 发表于：American Journal of Medical Genetics Part A · 年份：2019 · DOI：10.1002/ajmg.a.61306 · 被引用次数：40 · 研究领域：RNA modifications and cancer、RNA regulation and disease、Genomic variations and chromosomal abnormalities

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.