TY - JOUR
T1 - Phenotype delineation of ZNF462 related syndrome
AU - Kruszka, Paul
AU - Hu, Tommy
AU - Hong, Sungkook
AU - Signer, Rebecca
AU - Cogné, Benjamin
AU - Isidor, Betrand
AU - Mazzola, Sarah E.
AU - Giltay, Jacques C.
AU - van Gassen, Koen L.I.
AU - England, Eleina M.
AU - Pais, Lynn
AU - Ockeloen, Charlotte W.
AU - Sanchez-Lara, Pedro A.
AU - Kinning, Esther
AU - Adams, Darius J.
AU - Treat, Kayla
AU - Torres-Martinez, Wilfredo
AU - Bedeschi, Maria F.
AU - Iascone, Maria
AU - Blaney, Stephanie
AU - Bell, Oliver
AU - Tan, Tiong Y.
AU - Delrue, Marie Ange
AU - Jurgens, Julie
AU - Barry, Brenda J.
AU - Engle, Elizabeth C.
AU - Savage, Sarah K.
AU - Fleischer, Nicole
AU - Martinez-Agosto, Julian A.
AU - Boycott, Kym
AU - Zackai, Elaine H.
AU - Muenke, Maximilian
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
KW - ZNF462
KW - autism spectrum disorders
KW - corpus callosum
KW - craniosynostosis
KW - developmental delay
KW - ptosis
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U2 - 10.1002/ajmg.a.61306
DO - 10.1002/ajmg.a.61306
M3 - Article
C2 - 31361404
AN - SCOPUS:85071996582
VL - 179
SP - 2075
EP - 2082
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
IS - 10
ER -