Phenotype delineation of ZNF462 related syndrome

Abstract

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.

Keywords: ZNF462; autism spectrum disorders; corpus callosum; craniosynostosis; developmental delay; ptosis.

Figure 1.

ZNF462 variant locations. Variants from the present study are in blue and variants from previous publications are shown in black. Thirteen of the seventeen variants are on exon 3 which makes up 54% of ZNF462. Note that there are two unrelated individuals with the p.(His2072Tyrfs*8) variant (patients 4 and 11 in Table 1).

Figure 2.

A. Patient 1; B. Patient 2; C. Patient 3; D. Patient 4; E. Patient 5 at 8 years; F. Patient 6 at two and 7 months; G. Patient 7; H. Patient 8 at 3 months and 2.5 years; I. Patient 9 at ages 8 and 15 years; J. Patient 12; K. Patient 13; L. Patient 14; M. Patient 15; N. Patient 16; O. Patient 17; P. Patient 18; Q. Patient 19; R. Patient 20; S. Patient 21; T. Patient 22; U. Patient 24; (Figures M-T are from Weiss et al., 2017 and Figure U is from Cosemans et al., 2018)