Autism, Susceptibility To, 18

A number sign (#) is used with this entry because variation in the CHD8 gene (610528) on chromosome 14q11.2 influences susceptibility to autism.

Description

Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006).

For a discussion of genetic heterogeneity of autism, see 209850.

Clinical Features

Bernier et al. (2014) clinically evaluated 15 patients with disruptive mutations in CHD8. Patients ranged in age from 4 to 41 years; 13 of 15 met strict diagnostic criteria for ASD. Of the other 2 patients, 1 was an adult suspected of having a psychotic disorder, and 1 was diagnosed with ADHD and borderline intellectual functioning. All 9 children who underwent formal ASD evaluation met criteria on both the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Instrument (ADI). Eighty percent had macrocephaly, 78% had a supraorbital ridge, 67% had downslanting palpebral fissures, and 86% were tall. Eighty-seven percent had ASD, 60% had intellectual disability, 60% had attention problems, 27% had anxiety problems, 20% had seizures, 47% showed regression, and 80% had GI problems, with 60% reporting recurrent and consistent problems with constipation. Sixty-seven percent also experienced sleep problems, with 44% having difficulty falling asleep. Two patients reported sleep challenges so profound that they would remain awake for days.

Molecular Genetics

O'Roak et al. (2012) performed whole-exome sequencing for parent-child trios exhibiting sporadic autism spectrum disorders, including 189 new trios and 20 that were previously reported (O'Roak et al., 2011). In addition, O'Roak et al. (2012) sequenced the exomes of 50 unaffected sibs corresponding to 31 of the new and 19 of the previously reported trios, for a total of 677 individual exomes from 209 families. In proband exomes, O'Roak et al. (2012) found 2 de novo disruptive mutations in CHD8, a nonsense mutation and a frameshift indel.

Sanders et al. (2012) combined all de novo events in their sample with those identified in the study of O'Roak et al. (2012) and observed from a total of 414 probands that the CHD8 gene carried 2 highly disruptive mutations.

In a study of exonic de novo mutations in autism spectrum disorders (see 209850), Neale et al. (2012) identified 3 loss-of-function mutations in the CHD8 gene among 935 cases and no mutations in CHD8 among 870 controls.

Among 2,446 probands with autism spectrum disorder, O'Roak et al. (2012) identified 9 de novo mutations in the CHD8 gene including 3 frameshift (e.g., 610528.0002), 4 nonsense (e.g., 610528.0001), an in-frame deletion (610528.0009), and a splice site mutation (610528.0003) in 9 children (2 females and 7 males). Three had average intellect. Most of the probands had macrocephaly when compared with their parents, and O'Roak et al. (2012) reported that there was significantly larger head size relative to individuals screened without CHD8 mutations (2-sample permutation test, 2-sided p = 0.0007). De novo CHD8 mutations were present in about 2% of 366 macrocephalic (head circumference z-score greater than 2.0) Simons Simplex Collection probands, which suggested a useful phenotype of patient subclassification. Probands with CHD8 mutations had nonverbal IQ scores ranging from profoundly impaired to average (mean 62.2, range 19-98).

Bernier et al. (2014) resequenced the CHD8 gene in 3,730 children with developmental delay or ASD and identified 15 independent mutations, 13 of which were truncating events. No truncating events were identified in 8,792 controls, including 2,289 unaffected sibs of the probands.

Animal Model

Bernier et al. (2014) found that disruption in zebrafish chd8 recapitulated features of the human phenotype, including increased head size as a result of forebrain/midbrain expansion and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons.