H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome

Abstract

Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4‐year‐old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease‐causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4‐associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations

“…31 For one of the patients, the de novo variant was contemporaneously interpreted by UDN clinical experts to be causal. 32 Due to the findings of our analysis and the connection of UDN clinical sites through this project, the second patient’s de novo variant has now been reclassified as “pathogenic” and resulted in a new diagnosis for this participant. Two other patients with sporadic neurodevelopmental delay each harbor truncating de novo variants in ZNF865 .…”