Abstract
Autism spectrum disorder (ASD) is characterized by ritualistic-repetitive behaviors and impaired verbal/non-verbal communication. Many ASD susceptibility genes implicated in neuronal pathways/brain development have been identified. The Lebanese population is ideal for uncovering recessive genes because of shared ancestry and a high rate of consanguineous marriages. Aims here are to analyze for published ASD genes and uncover novel inherited ASD susceptibility genes specific to the Lebanese. We recruited 36 ASD families (ASD: 37, unaffected parents: 36, unaffected siblings: 33) and 100 unaffected Lebanese controls. Cytogenetics 2.7 M Microarrays/CytoScan™ HD arrays allowed mapping of homozygous regions of the genome. The CNTNAP2 gene was screened by Sanger sequencing. Homozygosity mapping uncovered DPP4, TRHR, and MLF1 as novel candidate susceptibility genes for ASD in the Lebanese. Sequencing of hot spot exons in CNTNAP2 led to discovery of a 5 bp insertion in 23/37 ASD patients. This mutation was present in unaffected family members and unaffected Lebanese controls. Although a slight increase in number was observed in ASD patients and family members compared to controls, there were no significant differences in allele frequencies between affecteds and controls (C/TTCTG: γ2 value = 0.014; p = 0.904). The CNTNAP2 polymorphism identified in this population, hence, is not linked to the ASD phenotype.
Highlights
IntroductionSequencing of hot spot exons in CNTNAP2 led to discovery of a 5 bp insertion in 23/37 Autism spectrum disorder (ASD) patients
We found one stretch of runs of homozygosity (ROH) common to 5 children with Autism spectrum disorder (ASD), located on chromosome 8q23.1, two ROH common to 6 children with ASD, one located on chromosome 2p22.1 and the other located on chromosome 3q25.32, and one ROH common to 7 children with ASD located on chromosome 18q11.2
ASD-associated copy number variations spanning these ROH regions in part, or whole, of all 4 ROH regions listed below have been reported in individuals with autism in the Simons Foundation Autism Research Initiative (SFARI) gene database
Summary
Sequencing of hot spot exons in CNTNAP2 led to discovery of a 5 bp insertion in 23/37 ASD patients This mutation was present in unaffected family members and unaffected Lebanese controls. More recent whole exome sequencing studies, identified de novo mutations in up to 15% of ASD case[12,13] Both CNVs and point mutations in genes such as CNTNAP2, SHANK3, NLGN3, NLGN4, and NRXN1 have been reported in cases of ASD14–16. The distinctive genetic fingerprint of the Lebanese population is well suited for comparative genomic hybridization (CGH) microarray analysis, homozygosity mapping, and CNV analysis for discovery of novel as well as previously described recessive disease-causing genes in ASD. We screened CNTNAP2 for mutations in our cohort of ASD patients, their family members, and unaffected controls, and identified a novel polymorphism in the Lebanese population
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