Clinical case report: mosaic ANK3 pathogenic variant in a patient with autism spectrum disorder and neurodevelopmental delay

• Published in: Cold Spring Harbor molecular case studies Vol. 9; no. 3; p. a006233
• Main Authors: Fang, Xiaolan, Fee, Timothy, Davis, Jessica, Stolerman, Elliot S, Caylor, Raymond C
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.06.2023
• Subjects: Actin; Ankyrins; Ankyrins - genetics; Autism; Autism Spectrum Disorder - genetics; Brain - metabolism; Case reports; Cell activation; Central nervous system; Cognitive ability; Cytoskeleton; Gene expression; Genotype & phenotype; Genotypes; Humans; Membrane proteins; Membranes; Mental disorders; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Neurodevelopmental Disorders - pathology; Next-generation sequencing; Nodes of Ranvier; Phenotypes; Polymerase chain reaction; Protein Isoforms - genetics; Proteins; Research Report; Spectrin; Synapses; mild receptive language delay; mild expressive language delay; autism; mild global developmental delay
• ISSN: 2373-2865; 2373-2873
• DOI: 10.1101/mcs.a006233

Ankyrins are a family of proteins that link integral membrane proteins to the underlying spectrin-actin cytoskeleton and play a key role in activities such as cell motility, activation, proliferation, cell-cell contact, and the maintenance of specialized membrane domains. is one of the three major subtypes of the ankyrin protein family. Ankryin genes are ubiquitously expressed, but their expression is highest in the brain. In the central nervous system, ankyrins have critical roles at the axonal initial segment, the nodes of Ranvier, and at synapses. To date, pathogenic variants in have been reported in individuals with neuropsychiatric, cognitive, and neurodevelopmental disorders. The clinical severity is variable in these individuals with both autosomal recessive and autosomal dominant patterns of inheritance observed. These findings have suggested genotype-phenotype correlations and even isoform-specific implications for individuals with pathogenic variants. Here, we report a patient with speech delay, autism spectrum disorder, and a language disorder in which a de novo nonsense alteration was discovered by exome sequencing. Interestingly, the next-generation sequencing data suggested the change was mosaic in the affected child, and it was confirmed by digital polymerase chain reaction (dPCR) at 22% allelic fraction. To our knowledge, this is the first case of an individual with a pathogenic mosaic variant. This finding expands upon the existing genotype-phenotype information available for the gene while also highlighting potential gene expression correlations with phenotype.