"The use of Arabic version of Social Communication Questionnaires (SCQ) in School Screening for Autism Spectrum Disorder (ASD) in Qatar"

Introduction: The prevalence rate of Autism Spectrum Disorder (ASD) in Qatar is uncertain, obtaining a reliable estimate is important in shedding the light on the magnitude of the problem, and help in better planning for providing the health care facilities needed for early detection and management of this disorder, since early intensive rehabilitation can improve the outcome of those affected tremendously. Aims of the study: To estimate the prevalence rate of ASD among children age 5-12 years residing in Qatar. Methodology: The research plan is to identify children with possible ASD among children attending ordinary primary schools as a "Low Probability Group", through using the Social Communication Questionnaires (SCQ), and those who score above the cut-off point will be further diagnosed using the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-2 (ADOS-2). Results: We worked on translating the English version of SCQ to Arabic, and we worked to validate this version through a pilot screening study that involved 35 cases of ASD and 778 controls from the schools. The pilot sample includes 813 (35 cases of ASD and 778 control children). The control children were selected in 8 schools, 3 for girls, 3 for boys and 2 mixed, between 14/6/2015 and 28/6/2015. The ASD children surveyed with the SCQ were selected from the Shafalla Center (N = 35). The boy: girl ratio was 4.0:1 (61/41; 80% male) in the ASD group. In the control group, the corresponding values were 0.59:1 (287/488; 35.9% male). The mean SCQ total score was significantly higher in cases as compared to controls (18.06 (SD = 7.2) vs 7.31 (SD = 5.2); p < .0001); as expected, the variability was larger in cases than in controls as illustrated by the standard deviations. Figure 1 shows the distribution of the SCQ scores in the total sample, and the distribution separately for cases and controls. A total of 93 children (22 cases, 71 controls) had scores equal or above the cut-off of 15; the remaining 13 cases (37.1% of the cases) had scores below the cut-off. Conclusions: The analysis to examine the overall performance of the SCQ showed excellent discrimination between cases and controls. An examination of the performance for each possible cut point on the SCQ showed that the sensitivity and specificity were optimal for the cut-offs of 10, compared to the published cut-off of the SCQ (15).qscienc

Identification of two novel autism genes, TRPC4 and SCFD2, in Qatar simplex families through exome sequencing

This study investigated the genetic underpinnings of autism spectrum disorder (ASD) in a Middle Eastern cohort in Qatar using exome sequencing. The study identified six candidate autism genes in independent simplex families, including both four known and two novel autosomal dominant and autosomal recessive genes associated with ASD. The variants consisted primarily of de novo and homozygous missense and splice variants. Multiple individuals displayed more than one candidate variant, suggesting the potential involvement of digenic or oligogenic models. These variants were absent in the Genome Aggregation Database (gnomAD) and exhibited extremely low frequencies in the local control population dataset. Two novel autism genes, TRPC4 and SCFD2, were discovered in two Qatari autism individuals. Furthermore, the D651A substitution in CLCN3 and the splice acceptor variant in DHX30 were identified as likely deleterious mutations. Protein modeling was utilized to evaluate the potential impact of three missense variants in DEAF1, CLCN3, and SCFD2 on their respective structures and functions, which strongly supported the pathogenic natures of these variants. The presence of multiple de novo mutations across trios underscored the significant contribution of de novo mutations to the genetic etiology of ASD. Functional assays and further investigations are necessary to confirm the pathogenicity of the identified genes and determine their significance in ASD. Overall, this study sheds light on the genetic factors underlying ASD in Qatar and highlights the importance of considering diverse populations in ASD research

Autism spectrum disorder in Qatar: Profiles and correlates of a large clinical sample

Autism spectrum disorder (ASD) is an increasingly prevalent disorder. Although around 15% of cases are caused by specific genetic causes, most cases involve a complex and variable combination of genetic risk and environmental factors that are not yet identified. There is a paucity of studies on ASD in Qatar, mostly in the form of case reports and genetic causes. The current study was designed to describe the clinical characteristics of ASD and its correlates in Qatar. Individuals with ASD were recruited from the Shafallah Center for Children with Special Needs which is the largest special needs center in Qatar. Within the sample of 171 individuals with ASD, 47% were ethnic Qataris, while 53% were nonethnic Qataris (Arabs and other nationalities). The analysis included the following factors: nationality, age, gender, socioeconomic status, consanguinity, prenatal/postnatal complications, and comorbidities. Eighty percent of the identified cases were males, with a 4:1 male to female ratio. Additionally, 83% of the families had one proband, 9.9% with 2 probands, and 7.1% with more than two. Comorbid conditions included: intellectual disabilities (ID) in 83% and epilepsy in 18.8%. 76.6% of subjects were nonverbal. There were 3 (1.8%) children with Rett’s syndrome, 3 (1.8%) with Fragile X, and 1 (0.6%) with tuberous sclerosis. There are currently no publications that clarify the mean age of diagnosis in Qatar, however, the present study showed that more than half of the diagnosed cases were among the ages of 7–14 years (56%). The effect of consanguinity as a risk factor was not found to be significant

Image_1_Characterization of a loss-of-function NSF attachment protein beta mutation in monozygotic triplets affected with epilepsy and autism using cortical neurons from proband-derived and CRISPR-corrected induced pluripotent stem cell lines.JPEG

We investigated whether a homozygous recessive genetic variant of NSF attachment protein beta (NAPB) gene inherited by monozygotic triplets contributed to their phenotype of early-onset epilepsy and autism. Induced pluripotent stem cell (iPSC) lines were generated from all three probands and both parents. The NAPB genetic variation was corrected in iPSC lines from two probands by CRISPR/Cas9 gene editing. Cortical neurons were produced by directed, in vitro differentiation from all iPSC lines. These cell line-derived neurons enabled us to determine that the genetic variation in the probands causes exon skipping and complete absence of NAPB protein. Electrophysiological and transcriptomic comparisons of cortical neurons derived from parents and probands cell lines indicate that loss of NAPB function contributes to alterations in neuronal functions and likely contributed to the impaired neurodevelopment of the triplets.</p

Image_3_Characterization of a loss-of-function NSF attachment protein beta mutation in monozygotic triplets affected with epilepsy and autism using cortical neurons from proband-derived and CRISPR-corrected induced pluripotent stem cell lines.TIF

We investigated whether a homozygous recessive genetic variant of NSF attachment protein beta (NAPB) gene inherited by monozygotic triplets contributed to their phenotype of early-onset epilepsy and autism. Induced pluripotent stem cell (iPSC) lines were generated from all three probands and both parents. The NAPB genetic variation was corrected in iPSC lines from two probands by CRISPR/Cas9 gene editing. Cortical neurons were produced by directed, in vitro differentiation from all iPSC lines. These cell line-derived neurons enabled us to determine that the genetic variation in the probands causes exon skipping and complete absence of NAPB protein. Electrophysiological and transcriptomic comparisons of cortical neurons derived from parents and probands cell lines indicate that loss of NAPB function contributes to alterations in neuronal functions and likely contributed to the impaired neurodevelopment of the triplets.</p

Image_2_Characterization of a loss-of-function NSF attachment protein beta mutation in monozygotic triplets affected with epilepsy and autism using cortical neurons from proband-derived and CRISPR-corrected induced pluripotent stem cell lines.TIF

We investigated whether a homozygous recessive genetic variant of NSF attachment protein beta (NAPB) gene inherited by monozygotic triplets contributed to their phenotype of early-onset epilepsy and autism. Induced pluripotent stem cell (iPSC) lines were generated from all three probands and both parents. The NAPB genetic variation was corrected in iPSC lines from two probands by CRISPR/Cas9 gene editing. Cortical neurons were produced by directed, in vitro differentiation from all iPSC lines. These cell line-derived neurons enabled us to determine that the genetic variation in the probands causes exon skipping and complete absence of NAPB protein. Electrophysiological and transcriptomic comparisons of cortical neurons derived from parents and probands cell lines indicate that loss of NAPB function contributes to alterations in neuronal functions and likely contributed to the impaired neurodevelopment of the triplets.</p

Table_1_Characterization of a loss-of-function NSF attachment protein beta mutation in monozygotic triplets affected with epilepsy and autism using cortical neurons from proband-derived and CRISPR-corrected induced pluripotent stem cell lines.DOCX

We investigated whether a homozygous recessive genetic variant of NSF attachment protein beta (NAPB) gene inherited by monozygotic triplets contributed to their phenotype of early-onset epilepsy and autism. Induced pluripotent stem cell (iPSC) lines were generated from all three probands and both parents. The NAPB genetic variation was corrected in iPSC lines from two probands by CRISPR/Cas9 gene editing. Cortical neurons were produced by directed, in vitro differentiation from all iPSC lines. These cell line-derived neurons enabled us to determine that the genetic variation in the probands causes exon skipping and complete absence of NAPB protein. Electrophysiological and transcriptomic comparisons of cortical neurons derived from parents and probands cell lines indicate that loss of NAPB function contributes to alterations in neuronal functions and likely contributed to the impaired neurodevelopment of the triplets.</p