A Mutation in the ANK2 Gene Causing ASD and a Review of the Literature

Abstract

Objective: To investigate the clinical and genetic characteristics of patients with ANK2(HGNC:493)-associated autism spectrum disorders (ASDs) and epilepsy (EP).

Methods: We identified a novel ANK2 variant in a patient with ASD and EP and summarized the clinical and genetic characteristics of ANK2 gene variants in this patient and those in previous reports.

Results: A novel nonsense variant, ANK2 (NM_001148.6):c.3007C>T/p.R1003* in exon 27, was identified in one patient. We described the clinical features and molecular genetics of this patient and previously reported patients. This was discovered at a follow-up visit to the pediatric neurology department where genetic testing based on condition identified this rare genetic variant. He mainly presents with language delay, intellectual disability, limited learning, and communication skills, and later develops seizures, combined with common childhood neurological disorders such as hyperactivity, behavioral abnormalities, and even self-injury. The patient cohort included 16 patients with a complex array of neurological disabilities: ASD (9 patients); EP (10 patients); ASD with EP (4 patients); intellectual disability and developmental delay (5 patients); poor language communication (11 patients); language and learning impairment (11 patients); anxiety/agitation mood disorder (6 patients); attention-deficit/hyperactivity disorder (5 patients); cognitive, memory, and adaptability deficits (1 patient); tic disorder (1 patient); electrocardiogram and cardiac damage (1 patient); and abnormal electroencephalography (EEG) (9 patients).

Conclusion: For the first time, we identified a novel variant of the ANK2 gene in China, broadening the genetic spectrum of the ANK2 gene. ANK2 gene mutations can cause ASD, EP, ASD with EP, developmental delay and intellectual disability, poor language communication skills, language and learning disorders, anxiety/agitation mood disorder, and attention-deficit/hyperactivity disorder. Clinical ASD, EP, common EP should consider the ANK2 gene mutation.

Keywords: ANK2 mutation; ASD; AnkB; EP.

FIGURE 1

Video electroencephalogram of the child: Poor background rhythm, increased fast waves, and multiple focal slow waves in each period of sleep observed in the right frontal lobe.

FIGURE 2

Sanger sequencing validation for the ANK2 variant: c.3007(exon27)C>T/p.R1003*, (NM_001148) (the brother's phenotype was normal, so no preliminary genetic screening was conducted).

FIGURE 3

(A). Reported variants and the variant identified in the ANK2 gene in this study. The aqua box indicates exons, and the grey bar indicates introns (100 times shorter). Red circles indicate nonsense variants, blue hexagons indicate splice variants, and green diamonds indicate frameshift variants. (B) Canonical human ANKB structure (IBS 2.0 was used for visualization; UniProtKB Q01484, 3957 aa). The ANKB protein contains four main domains: A membrane‐binding domain (MBD), a spectrin‐binding domain (SBD), a death domain (DD) and a C‐terminal domain. The MBD contains 24 consecutive ANK repeats and can interact with membrane proteins such as ion channels and transporters. The SBD contains highly conserved ZU5‐ZU5‐UPA domains and can interact with βII‐spectrin. The function of the death domain is still unknown, but reports in the literature suggest that it plays a role in cell apoptosis and inflammation. The death domain and C‐terminal domain together constitute the regulatory domain, which can directly bind to the MBD and cause inhibition effects.