Phenotype delineation of ZNF462 related syndrome.

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.

Primary care physicians' understanding and utilization of pediatric exome sequencing results.

Optimizing exome sequencing (ES) utility requires effective communication and collaboration between primary care physicians (PCPs) and genetics healthcare providers (GHP). To explore how PCPs use ES results to coordinate multipart management plans for complex pediatric patients, we assessed result understanding and utilization. Twenty-seven PCPs of pediatric patients with ES results from a genetics clinic completed a mixed methods 45-question survey measuring perceived genetics knowledge, confidence performing genetics tasks, understanding of ES technology and results, and expectations of GHP. Quantitative and qualitative data analysis classified by ES result types generated descriptive statistics, Pearson correlation coefficients, and common themes. Forty-five-percent of PCPs interpreted variant of uncertain significance results as diagnostic (implementing management changes and recommending familial testing). Most PCPs (85%) identified positive ES results impacts, but only 65% indicated ES was beneficial to care. The majority (74%) expected GHP and patients' families to assume follow-up care responsibility and future ES results re-interpretations. Limited knowledge may be a factor, as 59% desired more patient care information from GHP. Our results suggest optimizing continuity of care and collaboration for pediatric patients with ES results requires additional communication between GHP and PCPs, along with continuing genetics education for PCPs aimed at improving genetic literacy.