MG-126 A <i>de novo</i> truncating mutation in the chromatin remodeler chd8 in a patient with autism, macrocephaly and overgrowth
Bibliographic record
Abstract
Background CHD8 is one of a few genes in which de novo loss of function mutations have been identified in multiple cases across multiple autism cohorts in recent extensive exome sequencing studies. CHD8 is an ATP-dependent chromodomain helicase involved in chromatin remodelling and regulation of Wnt/beta-catenin and p53 pathways, which are pathways that have been implicated in non-syndromic and syndromic autism and intellectual disability. Objectives We will describe a patient with autism and intellectual disability with a novel CHD8 mutation. We also review the phenotype of previously reported patients with CHD8 loss of function mutations. Methods Exome sequencing of the proband and parents was used to identify de novo variants using the trio approach. A PubMed-based literature search identified other reported patients. Results Our patient has a de novo truncating CHD8 mutation (c.4342C >T, NM_020920). He is macrocephalic (>+3SD), and has extremely tall stature with proportionate weight (>+7SD), suggestive of an overgrowth phenotype. Other patients with CHD8 mutations that have been reported in the literature also have macrocephaly and a tendency to taller stature. Conclusions CHD8 mutations may cause syndromic autism. Further delineation of this phenotype will be helpful for diagnostic and prognostic guidance in the future. The association of a truncating CHD8 mutation with macrocephaly and overgrowth is particularly interesting since other disorders of chromatin remodelling implicated in the Wnt/beta-catenin pathway, such as Coffin-Siris and Weaver syndromes, also have abnormal neurodevelopment associated with altered head size and in some instances generalised overgrowth.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".