Case Report

Akt3 Partial Deletion in a Child with Microcephaly and Autism: A Case Report and Literature Review

Rose M Joy, Joseph W Ray, Allison D Britt, Christine RC Murphy, Pamela Lupo, Fangling Xu, Jianli Dong

1School of Medicine, University of Texas Medical Branch, Galveston, TX, USA

2Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA

3Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

*Corresponding author: Jianli Dong, Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0743, USA, Phone: +1 409 772 4866, Fax: +1 409 772 5683, E-mail: jidong@utmb.edu

Received: 11 December 2018; Accepted: 01 March 2019; Published: 09 March 2019

Citation: Joy RM, Xu F, Ray JW, et al. AKT3 partial deletion in a child with microcephaly and autism: A case report and literature review. Scimaze Pediatr 2019;1:101.

V-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma) (AKT3) is a component of the phosphoinositide-3-kinase (PI3K)-AKT-mechanistic target of rapamycin (MTOR) signaling pathway. Gain of function mutations of AKT3, which lead to activation of PI3K-AKT-MTOR pathway, have been identified in patients with macrocephaly and autism spectrum disorder (ASD), whereas deletions of AKT3 gene have been reported in patients with microcephaly. To our knowledge, only one patient with AKT3 deletion was reported to present with microcephaly and autistic behavior (DECIPHER Patient 317423). We present another patient with a heterozygous deletion of AKT3 with microcephaly and a clinical diagnosis of ASD. These cases support the idea that while AKT3 gain and loss of function mutations are associated with macro- and micro-cephaly, respectively, patients with both changes can develop autism.

Keywords: AKT; Chromosome 1q44; Microdeletion, Chromosome microarray; Microcephaly; Autism 

Patient History and Chromosome Microarray Result

The patient is a 9-year-old female who was diagnosed with autism spectrum disorder (ASD) [1]. She presents with behavioral problems including poor social interaction, hyperactivity, anxiety, and strict adherence to routine. Her other symptoms include microcephaly (MIC) but no intellectual disabilities (ID). She is nondysmorphic and has above average intelligence. She was adopted by a couple when she was 6 months old. Therefore, there is limited information about her parents or other family members. However, there is reported family history of psychiatric illnesses of her biological relatives (Figure 1). Her three biological siblings were all diagnosed with ASD and attention-deficit/hyperactivity disorder (ADHD). Her biological mother has been diagnosed with obsessive compulsive disorder, bipolar disorder and schizophrenia. Her mother’s parents have also been diagnosed with unspecified psychiatric illnesses and/or intellectual disabilities. The patient’s paternal history of psychiatric illness is unknown. In 2016 clinical visits, her parents described her ASD symptoms as mild. To identify potential genetic cause of her ASD diagnosis, blood samples were collected for chromosomal microarray (CMA) and fragile X syndrome testing. Her result for fragile X syndrome was negative.

Chromosomal microarray was performed using peripheral blood and examined with Cytoscan HD microarray (Affymetrix, Santa Clara, CA, USA). This array consists of 2,696,550 oligonucleotide probes, including 1,953,246 distinctive nonpolymorphic oligonucleotide probes, and 743,304 single nucleotide polymorphism (SNP) probes. Genomic DNA (gDNA) was extracted and purified from whole blood sample using Gentra Puregene Blood Kit (Qiagen Inc., Valencia, CA, USA). Procedures for DNA digestion, adapter ligation, polymerase chain reaction (PCR), amplicon DNA fragmentation, labeling and hybridization of the arrays were performed according to manufacturer’s instructions (Affymetrix, Santa Clara, CA, USA). Results were investigated using the Chromosome Analysis Suite (ChAS) made by Affymetrix (Santa Clara, CA, USA). The settings for smallest copy number variation (CNV) regions in ChAS were 25 Kb and 25 markers for losses, and 50 Kb and 50 markers for gains. CMA identified a 239 Kb deletion in 1q44 (Figure 2). This deletion included the 5’ part of v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma) (AKT3).

From March 2013 to March 2018, 1,200 germline CMA results were generated in the Molecular Diagnostics Laboratory at the University of Texas Medical Branch (UTMB) in Galveston, Texas, and our patient was the only case carrying 1q44 microdeletion affecting AKT3 gene. We performed chart review of this patient using UTMB’s electronic medical record. The study was approved by UTMB institutional review board (IRB).

To facilitate the assignment of the clinical significance of this deletion, we performed a literature review and database search for individuals carrying a pure AKT3 deletion involving at least one exon of this gene and identified 14 patients (Table 1). Of these 14 patients, 12 displayed microcephaly, and two patients (our patient and DECIPHER Patient 317423) presented with autistic behavior.

From March 2013 to March 2018, 1,200 germline CMA results were generated in the Molecular Diagnostics Laboratory at the University of Texas Medical Branch (UTMB) in Galveston, Texas, and our patient was the only case carrying 1q44 microdeletion affecting AKT3 gene. We performed chart review of this patient using UTMB’s electronic medical record. The study was approved by UTMB institutional review board (IRB).

To facilitate the assignment of the clinical significance of this deletion, we performed a literature review and database search for individuals carrying a pure AKT3 deletion involving at least one exon of this gene and identified 14 patients (Table 1). Of these 14 patients, 12 displayed microcephaly, and two patients (our patient and DECIPHER Patient 317423) presented with autistic behavior.

Discussion

In this report, we present a case with a clinical diagnosis of ASD and microcephaly and heterozygous deletion of the 5’ part of AKT3 gene. AKT3 deletion is frequently involved in 1q43q44 deletion syndrome (OMIM 612337). Microdeletions of 1q43q44 have been associated with a variety of developmental abnormalities of brain, including microcephaly (MIC), agenesis of the corpus callosum (ACC), and seizures (SZR) [2-4]. Genotype-phenotype correlation studies of 1q43q44 microdeletions have associated heterozygous deletions of AKT3 with MIC phenotypes [2-4] supporting haploinsufficiency of this gene in the development of MIC [2,3]. To date, there have been at least 14 patients with pure AKT3 deletions, and 12 of the patients have microcephaly (Table 1). Interestingly, our patient and patient #7 (DECIPHER Patient 317423) presented with autistic behaviors.

Autism spectrum disorder (ASD) causes social and behavioral abnormalities in about one in every 68 children in the United States [5]. ASDs occur either sporadically or as familial cases and have been categorized into 2 groups: syndromic ASD and nonsyndromatic/idiopathic ASD [6,7]. Examples of ASD related syndromes include fragile X syndrome, RASopathies, Rett’s syndrome, tuberous sclerosis complex, and phosphatase and tensin homolog (PTEN) hamartoma-tumor syndrome. On the other hand, nonsyndromic ASDs don’t have identifiable symptom association [6,7]. The pathophysiology of ASD is not fully understood and believed to associate with variety of genetic mutations and/ or environmental contributions. Proposed causes include brain malformations, dysregulation of cell signaling pathways and gene alterations. Genome wide segmental aneuploidy profiling has revealed numerous submicroscopic copy number variations (CNVs), either inherited or emerged de novo in 7% to 27% of ASD patients [6,8].

AKT3 is a component of the phosphoinositide-3-kinase (PI3K)- AKT-mechanistic target of rapamycin (MTOR) pathway. PI3KAKT-MTOR signaling cascade contributes to multiple intracellular and extracellular signals and cellular processes including cell proliferation, growth, survival, and nutrient uptake. Dysregulation of this pathway has been attributed to several neurodevelopmental diseases, such as megalencephaly, microcephaly, autism spectrum disorders, intellectual disability, schizophrenia, and epilepsy. Dysregulation of this pathway has been indicated in the development of ASD [7]. ASD has been associated with both upregulation [9,10] and downregulation [11,12] of PI3K-AKT-MTOR pathway, which is consistent with pleiotropic activity of the pathway and multiple factors that contribute to the development of ASD. Although sample from our patient was not available to examine PI3K-AKT-MTOR pathway activity, the microcephaly presentation is consistent with a downregulation of the pathway.

Because of the important regulatory role of AKT3 in the PI3KAKT-MTOR pathway, changes in AKT3 have the potential to induce pathological changes to the brain. Deletion of AKT3 may lead to ASD but this genotype to phenotype correlation has rarely described. AKT3 deletion has been associated with other neurological and psychiatric problems in patients, including global developmental delay, ID, and cognitive impairment (Table 1). This is the second reported case, to our knowledge, of a diagnosed ASD patient with microcephaly presenting with a partial AKT3 deletion. More cases of pure AKT3 deletion with detailed clinical information will need to be analyzed to improve our understanding of the phenotypes of a pure AKT3 deletion. To our knowledge no confirmed de novo deletions of AKT3 have been reported. Patients were reported to inherit the deletions from normal or affected parents (Table 1) supporting incomplete penetrance of the deletions.

Figure 1: Pedigree of the patient’s pertinent biological family members with psychiatric history.

 

Figure 2: Chromosomal microarray detected a 239 Kb loss in 1q44; ARR[GRCh37] 1q44(243,810,929_244,050,033)x1. The heterozygous deletion includes 5’ untranslated region (5’ UTR) and exons 1-3 of AKT3 gene (RefSeq NM_181690).

1. Diagnostic and Statistical Manual of Mental Disorders. (5th ed.). Washington, DC: Am Psychiatr Assoc Publ 2013.

2. Gai D, Haan E, Scholar M, et al. Phenotypes of AKT3 deletion: A case report and literature review. Am J Med Genet A 2015;167: 174-179.

3. Ballif BC. High-resolution array CGH defines critical regions and candidate genes for microcephaly, abnormalities of the corpus callosum, and seizure phenotypes in patients with microdeletions of 1q43q44. Hum Genet 2012; 131:145-156.

4. Nagamani SC, Erez A, Bay C, et al. Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43-q44. Eur J Hum Genet 2012; 20: 176-179.

5. Christensen DL. Prevalence and characteristics of autism spectrum disorder among children aged 8 years--autism and developmental disabilities monitoring network, 11 Sites, United States, 2012. MMWR Surveill Summ 2016; 65:1-23.

6. Lord C, Bishop SL. Recent advances in autism research as reflected in DSM-5 criteria for autism spectrum disorder. Annu Rev Clin Psychol 2015; 11:53-70.

7. Winden KD, Ebrahimi-Fakhari D, Sahin M, et al. Abnormal mtor activation in autism. Annu Rev Neurosci 2018; 41:1-23.

8. Poot M. Towards identification of individual etiologies by resolving genomic and biological conundrums in patients with autism spectrum disorders. Mol Syndromol 2013; 4:213-226.

9. Tang G. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 2014; 83:1131-1143.

10.Onore C, Yang H, Van de Water J, et al. Dynamic Akt/mTOR signaling in children with autism spectrum disorder. Front Pediatr 2107; 5: 43.

11.Nicolini C, Ahn Y, Michalski B, et al. Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid. Acta Neuropathol Commun 2015; 3:3.

12.Tylee DS. Blood transcriptomic comparison of individuals with and without autism spectrum disorder: A combined-samples mega-analysis. Am J Med Genet B Neuropsychiatr Genet 2017; 174:181-201.