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Abstract

Two boys with Autism Spectrum Disorder (ASD) from two unrelated consanguineous families of Arabic origin were studied by Whole Genome Sequencing (WGS) together with their parents. Thugs data of the X chromosome were analyzed to identify possible predisposing, recessive and/or de novo, X-linked variants. Comparative analysis of the WGS data for X-linked de novo inheritance identified no variants, while the recessive inheritance analysis identified the following three strong candidate gene variations, in order of priority; Family 1: IL1RAPL2c.206G>C/p.S69T; Family 2: SHROOM4 c.3370C>G/p.Q1124E, and SYTL5c.1370G>A/p.R457Q. All variations found to be damaging and conserved, validated by Sanger Sequencing, co-segregate with the disease phenotype within each family and are absent in known polymorphism databases, as well as in 1800 ethnically matched control chromosomes, genotyped by TaqMan assays and Real-Time PCR. For the Comparative Analysis, the CLC Genomic Workbench Software package was used, as well as the in-house pipeline, setting the MAF cutoff at 1% and including data for pathogen city, conservation, protein effect, variants databases and so on. In Family 1: IL1RAPL2 is associated with non-syndromic X-linked ID and/or ASD and the proteinis detected at low levels in fetal and adult brain (particularly in the frontal lobe, temporal lobe and cerebellum). In Family 2: SHROOM4 plays a role in cytoskeletal architecture and it is considered an XLMR gene, as mutations have been linked to Stocco dos Santos Syndrome. Deleterious mutations might affect the morphology of the neural cells and eventually the neural development. The SYTL5 encoded protein belongs to the synaptogamin-like protein family and seems to play a role in protein transportation in specific tissues, as it is expression is restricted to placenta and liver. Maybe during embryonic development its expression is required for downstream gene control that plays a role in neural development. Genes function and suggested mechanisms, as well as the absence of the mutations from the ethnically matched control population and publically available databases, indicate that these novel rare variants identified are strong candidates for predisposition to the development of ASD. Future studies on transcriptome analysis and gene expression will enable to confirm the indications and the mechanisms might justify their involvement to ASD.

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/content/papers/10.5339/qfarc.2016.HBPP1350
2016-03-21
2019-12-15
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