Detection of a de novo heterozygous ANK2 variant in a child with autism spectrum disorder and epilepsy: a case report

Abstract

Background The pathogenesis of autism spectrum disorder (ASD) is not fully clarified. Next-generation sequencing technologies have greatly enhanced the identification of new genes associated with ASD. Variants in ANK2 gene are known to correlate with a broad spectrum of clinical cardiac phenotypes, but, more recently, it has also been pointed out as a candidate gene for the etiology of ASD. Case presentation We report the case of a female patient with ASD and epilepsy in whom clinical exome sequencing was performed for etiological enlightenment. A heterozygous variant of uncertain significance was identified in the ANK2 gene: c.3412C > T p.(Arg1138Ter). The child was submitted to a formal cardiac evaluation, ruling out cardiovascular abnormalities. The genetic variant was searched in her parents and was negative in both, suggesting a de novo variant, which favors its pathogenicity. Conclusions We recognize the challenge of assessing variant pathogenicity in candidate genes for ASD, and ANK2 gene is currently not associated with neurodevelopmental disorders in the Online Mendelian Inheritance in Man database. Nonetheless, our case can be added to other published reports of de novo ANK2 variants in children with ASD and neurological phenotypes (including seizures), some without cardiac impairment. Hopefully, this study provides a more detailed phenotypical description that is often lacking, and it may contribute to a better understanding of the association between ANK2 and ASD.

Discovering the ANK2‐related autism phenotype

“…To our knowledge, our report is the second full clinical description of a patient with ASD caused by an ANK2 mutation. 2 Here, the patient had symptoms known to be highly prevalent in ASD such as ID, increased head circumference, 3 constipation, extensive tooth decay, 4 hyperacusis, hyperopia and astigmatism. 5 More unusual associated signs were the tall stature and testicular ectopia.…”