ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants
Katja Kloth, Bernarda Lozić, Julia Tagoe, Mariëtte J.V. Hoffer, Amelie van der Ven, Hölger Thiele, Janine Altmüller, Christian Kubisch, Ping Yee Billie Au, Jonas Denecke, Emilia K. Bijlsma, Davor Lessel
Abstract
ANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.