Novel homozygous AP3B2 mutations in four individuals with developmental and epileptic encephalopathy: A rare clinical entity

Abstract

Objectives: Developmental and epileptic encephalopathies (DEEs) are heterogeneous severe neurodevelopmental disorders characterized by recurrent clinical seizures that begin in the neonatal period and early childhood and regression or delay in cognitive, sensory and motor skills in the context of accompanying epileptiform abnormalities. Adaptor-related protein complex 3 beta-2 subunit (AP3B2) gene variants are thought to cause disruption of neuron-specific neurotransmitter release.

Methods: In this case report, whole exome sequencing (WES) was performed on two of the four pediatric patients who came from two unrelated families and were affected by DEE. As a result of WES, previously unreported variants, that is, p.Ala149Serfs* 34 and p.Pro993Argfs* 5, were detected in the AP3B2 gene. These variants were studied using Sanger sequencing in the siblings affected by DEE of the said pediatric patients and in their healthy parents.

Results: Autosomal recessive variants of the AP3B2 are associated with the development of DEE. To date, only 14 cases of AP3B2 mutations have been reported in the literature. Consequentially, DEE phenotype involving severe global developmental delay emerged, which is characterized by early-onset infantile epileptic encephalopathy, severe hypotonia, postnatal microcephaly, poor eye contact, speech retardation, abnormal involuntary movements, stereotypical hand movements, progressive intellectual disability, and behavioral and neuropsychiatric findings.

Conclusion: Given the limited number of patients reported in the literature, detailed studies of the specific clinical and molecular features of AP3B2 gene variants, will shed light on the genotype-phenotype correlation.

Keywords: AP3B2; Children; Developmental and epileptic encephalopathy; Developmental delay; Phenotypic variation.