Loss-of-function variant in spermidine/spermine N1-acetyl transferase like 1 (SATL1) gene as an underlying cause of autism spectrum disorder.

Autism spectrum disorder (ASD) is a complicated, lifelong neurodevelopmental disorder affecting verbal and non-verbal communication and social interactions. ASD signs and symptoms appear early in development before the age of 3 years. It is unlikely for a person to acquire autism after a period of normal development. However, we encountered an 8-year-old child who developed ASD later in life although his developmental milestones were normal at the beginning of life. Sequencing the complete coding part of the genome identified a hemizygous nonsense mutation (NM_001367857.2):c.1803C>G; (p.Tyr601Ter) in the gene (SATL1) encoding spermidine/spermine N1-acetyl transferase like 1. Screening an ASD cohort of 28 isolated patients for the SATL1 gene identified another patient with the same variant. Although SATL1 mutations have not been associated with any human diseases, our data suggests that a mutation in SATL1 is the underlying cause of ASD in our cases. In mammals, mutations in spermine synthase (SMS), an enzyme needed for the synthesis of spermidine polyamine, have been reported in a syndromic form of the X-linked mental retardation. Moreover, SATL1 gene expression studies showed a relatively higher expression of SATL1 transcripts in ASD related parts of the brain including the cerebellum, amygdala and frontal cortex. Additionally, spermidine has been characterized in the context of learning and memory and supplementations with spermidine increase neuroprotective effects and decrease age-induced memory impairment. Furthermore, spermidine biosynthesis is required for spontaneous axonal regeneration and prevents α-synuclein neurotoxicity in invertebrate models. Thus, we report, for the first time, that a mutation in the SATL1 gene could be a contributing factor in the development of autistic symptoms in our patients.

High-resolution SNP genotyping platform identified recurrent and novel CNVs in autism multiplex families.

Single nucleotide polymorphisms (SNPs)-based genotyping using microarray platform is now frequently used to detect copy number variants (CNVs) in the human genome. Here, we report CNVs identified using Illumina Human Omni 2.5M oligonucleotide microarrays in 11 multiplex families with autism spectrum disorder (ASD) referred to Autism Research and Treatment Center (ART) and Madinah Maternity and Children Hospital (MMCH). Of the 11 families, 22 patients with ASD (all males) and their parents, were recruited for the present study. In total, 43 individuals were genotyped with high-resolution array. Abnormal microarray results were seen in all 22 patients with ASD. A total of 17 shared CNVs were selected for further analysis. Out of these 17 CNVs, we discovered one novel CNV, previously not described, and 16 recurrent CNVs that overlap with the genomic imbalances defined in the autism database, autism chromosome rearrangement database and database of genomic variants. Recurrent CNVs include 11 common and 5 rare CNVs. All rare CNVs are duplications except a 16-kb deletion on chr2q36.3. Rare gain of copy numbers includes a 2-kb duplication on chr9q21.13, overlapping duplications of 107kb and 181kb on chrXp22.33 in 2 different families and a 10-kb duplication on chr18q21.13. A novel loss of copy number on chr3q23 was found in four ASD cases. This CNV results in deletion of intron 2 of calsyntenin 2 (CLSTN2) encoding synaptic protein calsyntenin 2. CLSTN2 is expressed exclusively in the brain, with high levels occurring in cortical gamma-aminobutyric acid (GABA)ergic interneurons and in medial temporal lobe regions. These results verify the diagnostic relevance of genome-wide small common and rare CNVs and provide further evidence of the high diagnostic yield of microarray for genetic testing in children with ASD.