Abstract
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders, usually diagnosed in early childhood, that are characterized by adaptive deficits in social interaction, communication skills, and restricted or stereotyped repetitive patterns of behavior. There had been limited success to define ASD subtypes on the behavioral basis. Genetically categorized ASD subtypes may provide basis to determine the course, prognosis, and individualized mechanism based treatment. Mutations in chromodomain helicase DNA-binding protein 8 (CHD8) gene, have been associated with autism, macrocephaly, speech delay, distinct facial features, sleep and gastrointestinal disturbances. There are few cases in the literature reporting de novo mutations of CHD8 exhibiting sporadic ASD. Here we describe a Saudi boy with developmental delay, intellectual disability, macrocephaly, craniofacial abnormalities, speech delay, but without any history of seizures, gastrointestinal problems or sleep disturbance. Whole exome sequencing for parent-child trio revealed a de novo heterozygous loss-of-function mutation (c.4984C>T, p.Arg1662Ter) in CHD8 gene. Our findings elaborate the genotype-phenotype correlation and confirm that the CHD8 disruptions represent a clinical ASD subtype and further highlight the significance of implementing genomic medicine in clinical practice for an early intervention and necessary support for the families.
Highlights
Autism spectrum disorder (ASD) encompasses a group of clinically heterogeneous neurodevelopmental disorders, that are characterized by impaired social communication, language deficits, restrictive interests or stereotyped repetitive behaviors[1,2]
We report a case of a Saudi child with intellectual disability and autistic behaviour, diagnosed by the clinical examinations and confirmed by genetic testing, together with whole exome sequencing (WES), which led us to the identification of a de novo mutation of chromodomain helicase DNA-binding protein 8 (CHD8) gene
The CHD8 gene located on 14q11.2 encodes the CHD8 protein, which has been associated with ASD by independent studies
Summary
Autism spectrum disorder (ASD) encompasses a group of clinically heterogeneous neurodevelopmental disorders, that are characterized by impaired social communication, language deficits, restrictive interests or stereotyped repetitive behaviors[1,2]. We report a case of a Saudi child with intellectual disability and autistic behaviour, diagnosed by the clinical examinations and confirmed by genetic testing, together with whole exome sequencing (WES), which led us to the identification of a de novo mutation of CHD8 gene. A 7-years-old Saudi boy was referred to the genetic clinic with the history of developmental delay. He sat at the age of one year and walked after two and a half years. The affected boy had significant speech delay He was not interested in his surroundings and had an abnormal social interaction with an aggressive behaviour. WES for the parents was unremarkable, which indicated the de novo status of the identified CHD8 variant in the affected boy. The variant creates a premature stop codon (p.Arg1662Ter) leading to the loss of 919 amino acids of the protein and was determined to be pathogenic according to ACMG guidelines
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