Alternative titles; symbols
ORPHA: 642675;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q11.2 | Intellectual developmental disorder with autism and macrocephaly | 615032 | Autosomal dominant | 3 | CHD8 | 610528 |
A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with autism and macrocephaly (IDDAM) is caused by heterozygous mutation in the CHD8 gene (610528) on chromosome 14q11.
Intellectual developmental disorder with autism and macrocephaly (IDDAM) is characterized by impaired intellectual development, a highly penetrant autism spectrum phenotype, and macrocephaly. Other common features include tall stature, gastrointestinal symptoms, distinct facial features, sleep problems, and attention problems (summary by An et al., 2020).
Bernier et al. (2014) clinically evaluated 15 patients with mutations in the CHD8 gene. The patients ranged in age from 4 to 41 years; 10 of 15 had confirmed autism spectrum disorder (ASD) and 9 had confirmed impaired intellectual disability. One adult was suspected of having a psychotic disorder, and 1 was diagnosed with attention deficit-hyperactivity disorder (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 of patients had macrocephaly, 78% had a supraorbital ridge, 67% had downslanting palpebral fissures, and 86% were tall. Sixty percent of patients had attention problems, 27% had anxiety problems, 20% had seizures, 47% showed regression, and 80% had gastrointestinal problems, with 60% reporting recurrent and consistent problems with constipation. Sixty-seven percent experienced sleep problems, with 44% having difficulty falling asleep. Two patients reported sleep challenges so profound that they would remain awake for days.
Merner et al. (2016) reported a patient with a CHD8 mutation who had a history of developmental delay and was diagnosed with autism at 3.6 years of age. At 14 years of age, he was diagnosed with mild intellectual disability. At 17 years of age, he had macrocephaly and tall stature. His facial features included a broad nasal bridge, a long philtrum, cupid bow mouth, and posteriorly rotated ears. He also had hypotonia and clumsiness.
Douzgou et al. (2019) reviewed clinical features in 25 patients, 15 of whom had previously been reported, with mutations in the CHD8 gene. Information about intellectual function was available for 21 patients, and 17 had impaired intellectual development ranging from mild to severe, although moderate impairment was most common. All 21 patients had speech delay, and 7 patients were reported to have speech regression. Eleven patients had gross or fine motor coordination problems, 7 patients had hypotonia, and 7 patients had seizures. Brain MRI scans were available for 17 patients and showed abnormalities, including ventriculomegaly and/or delayed myelination, in 6 patients. Twenty-one of the 25 patients were diagnosed with autism spectrum disorder. Other clinical findings included sleep abnormalities in 12 patients and gastrointestinal issues, including constipation, in 10.
Ostrowski et al. (2019) reported clinical features in 27 unrelated patients, 17 of whom had previously been reported, with mutations in the CHD8 gene. The patients ranged in age from 1 to 27 years, with a male to female ratio of 21:6. All of the patients had impaired intellectual development, which was mild or moderate in most patients (1 patient was too young to be assessed). Fifteen patients had autism or impaired social interactions, 4 had attention deficits, 4 had aggressive behavior, and 2 had self-injurious behaviors. Twenty-three patients had overgrowth, defined as height and/or head circumference at least 2 standard deviations above the mean. Nine patients had neonatal hypotonia, 4 had seizures, 4 had pes planus, 2 had scoliosis, and 2 had a glabellar hemangioma.
Most of the heterozygous mutations that have been identified in patients with IDDAM have occurred de novo (see, e.g., Ostrowski et al., 2019 and An et al., 2020). In 3 patients reported by Ostrowski et al. (2019), the mutation was inherited from the mother; one of the mothers had mildly impaired intellectual development.
O'Roak et al. (2012) performed whole-exome sequencing for parent-child trios from the Simons Simplex collection of autism spectrum disorder patients, including 189 new trios and 20 that were previously reported (O'Roak et al., 2011). Some of the patients had significantly impaired intellectual development. 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) reported 2 de novo disruptive mutations in CHD8, a nonsense mutation and a frameshift indel.
In a study of exonic de novo mutations in autism spectrum disorders, Neale et al. (2012) stated that they had 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 from the Simons Simplex Collection including patients with impaired intellectual development, 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.
In a 17-year-old boy with IDDAM, Merner et al. (2016) identified a de novo heterozygous 1-bp duplication in the CHD8 gene (610528.0010).
In 10 newly identified, unrelated patients with IDDAM, Douzgou et al. (2019) identified 10 different heterozygous mutations in the CHD8 gene, including 2 splicing, 6 nonsense, and 2 frameshift. Eight of the mutations were confirmed to be de novo; in the other 2 cases, parental inheritance was unknown. None of the mutations were present in the gnomAD database. Functional studies were not performed.
In 27 patients with IDDAM, 10 of whom had previously been reported, Ostrowski et al. (2019) identified heterozygous mutations in the CHD8 gene, including 2 missense and 24 null mutations. The null mutations were distributed throughout the gene. One mutation (R564X) was identified in 2 unrelated patients. Twenty-four mutations were determined to be de novo and 3 were maternally inherited. One of these mothers had mildly impaired intellectual development.
An et al. (2020) screened a cohort of 96 patients with autism spectrum disorder by next-generation sequencing of a gene panel including the CHD8 gene. Three patients were identified with de novo heterozygous mutations in the CHD8 gene (R1188X, 610528.0011; c.4818-1G-A, 610528.0013; Y1168N, 610528.0014). An et al. (2020) identified an additional patient with autism spectrum disorder and a de novo heterozygous mutation (E689X; 610528.0012) in the CHD8 gene by trio whole-exome sequencing. Functional studies were not performed.
In a review of the clinical and molecular findings of 24 individuals with IDDAM, An et al. (2020) identified a tendency for a more severe phenotype in patients who had mutations in the HELIC domain of CHD8, including greater weight gain, lower verbal IQ, and an overall greater number of phenotypic features.
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.
An, Y., Zhang, L., Liu, W., Jiang, Y., Chen, X., Lan, X., Li, G., Hang, Q., Wang, J., Gusella, J. F., Du, Y., Shen, Y. De novo variants in the helicase-C domain of CHD8 are associated with severe phenotypes including autism, language disability and overgrowth. Hum. Genet. 139: 499-512, 2020. [PubMed: 31980904] [Full Text: https://doi.org/10.1007/s00439-020-02115-9]
Bernier, R., Golzio, C., Xiong, B., Stessman, H. A., Coe, B. P., Penn, O., Witherspoon, K., Gerdts, J., Baker, C., Vulto-van Silfhout, A. T., Schuurs-Hoeijmakers, J. H., Fichera, M., and 22 others. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158: 263-276, 2014. [PubMed: 24998929] [Full Text: https://doi.org/10.1016/j.cell.2014.06.017]
Douzgou, S., Liang, H. W., Metcalfe, K., Somarathi, S., Tischkowitz, M., Mohamed, W., Kini, U., McKee, S., Yates, L., Bertoli, M., Lynch, S. A., Holder, S., the Deciphering Developmental Disorders Study, Banka, S. The clinical presentation caused by truncating CHD8 variants. Clin. Genet. 96: 72-84, 2019. [PubMed: 31001818] [Full Text: https://doi.org/10.1111/cge.13554]
Merner, N., Forgeot d'Arc, B., Bell, S. C., Maussion, G., Peng, H., Gauthier, J., Crapper, L., Hamdan, F. F., Michaud, J. L., Mottron, L., Rouleau, G. A., Ernst, C. A de novo frameshift mutation in chromodomain helicase DNA-binding domain 8 (CHD8): a case report and literature review. Am. J. Med. Genet. 170A: 1225-1235, 2016. [PubMed: 26789910] [Full Text: https://doi.org/10.1002/ajmg.a.37566]
Neale, B. M., Kou, Y., Liu, L., Ma'ayan, A., Samocha, K. E., Sabo, A., Lin, C.-F., Stevens, C., Wang, L.-S., Makarov, V., Polak, P., Yoon, S., and 47 others. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485: 242-245, 2012. [PubMed: 22495311] [Full Text: https://doi.org/10.1038/nature11011]
O'Roak, B. J., Deriziotis, P., Lee, C., Vives, L., Schwartz, J. J., Girirajan, S., Karakoc, E., Mackenzie, A. P., Ng, S. B., Baker, C., Rieder, M. J., Nickerson, D. A., Bernier, R., Fisher, S. E., Shendure, J., Eichler, E. E. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genet. 43: 585-589, 2011. Note: Erratum: Nature Genet. 44: 471 only, 2012. [PubMed: 21572417] [Full Text: https://doi.org/10.1038/ng.835]
O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338: 1619-1622, 2012. [PubMed: 23160955] [Full Text: https://doi.org/10.1126/science.1227764]
O'Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., Turner, E. H., Stanaway, I. B., and 11 others. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485: 246-250, 2012. [PubMed: 22495309] [Full Text: https://doi.org/10.1038/nature10989]
Ostrowski, P. J., Zachariou, A., Loveday, C., Beleza-Meireles, A., Bertoli, M., Dean, J., Douglas, A. G. L., Ellis, I., Foster, A., Graham, J. M., Hague, J., Hilhorst-Hofstee, Y., and 23 others. The CHD8 overgrowth syndrome: a detailed evaluation of an emerging overgrowth phenotype in 27 patients. Am. J. Med. Genet. 181C: 557-564, 2019. [PubMed: 31721432] [Full Text: https://doi.org/10.1002/ajmg.c.31749]