Phenotypic Variability and Paternal Inheritance of a CHD8 Variant Causing Intellectual Developmental Disorder With Autism and Macrocephaly Confirmed by Epigenetic and Structural Analyses

Abstract

Background: Intellectual developmental disorder with autism and macrocephaly (IDDAM, OMIM #615032) is an autosomal dominant neurodevelopmental disorder characterized primarily by intellectual disability, autism spectrum disorder, macrocephaly, tall stature, gastrointestinal symptoms, and variable neurological manifestations. Most cases result from de novo pathogenic variants in CHD8.

Methods: We conducted genome sequencing through the Undiagnosed Diseases Network (UDN) in a female proband harboring a CHD8 variant of uncertain significance (VUS), whose clinical presentation was consistent with IDDAM but included atypical features such as ptosis and hearing loss. Variant pathogenicity was further evaluated using EpiSign DNA methylation analysis and structural biology modeling.

Results: Genome sequencing confirmed the CHD8 variant inherited from her father, who exhibited a subtle feature, including traits consistent with attention-deficit/hyperactivity disorder. Pathogenicity was confirmed through epigenetic signature testing (EpiSign), demonstrating characteristic methylation patterns and structural biology analysis, predicting significant protein destabilization.

Conclusion: We describe the case of IDDAM caused by a paternally inherited CHD8 variant. Our findings highlight the importance of considering parental inheritance in IDDAM diagnoses and suggest epigenetic and structural biology analyses as valuable tools for reclassifying VUS when variant pathogenicity remains uncertain.

Keywords: CHD8; epigenetics; intellectual developmental disorder with autism and macrocephaly (IDDAM); phenotypic variability.

FIGURE 1

(A) Ptosis before use of pyridostigmine. (B) Improved ptosis after use of pyridostigmine.

FIGURE 2

EpiSign (DNA methylation) analysis of peripheral blood from a proband and father with a missense variant in CHD8, the causative gene for IDDAM. (A) Hierarchical clustering and (B) multidimensional scaling plots indicate the proband (red) and father (black) have a DNA methylation profile similar to subjects with a confirmed IDDAM episignature (blue) and distinct from controls (green). (C) MVP score, a multi‐class supervised classification system capable of discerning between multiple episignatures by generating a probability score for each episignature. The elevated score for IDDAM shows an episignature similar to the intellectual developmental disorder with autism and macrocephaly reference cohort.

FIGURE 3

Structural model of CHD8, Chromodomain‐Helicase‐DNA‐binding protein 8 (residues 801–1350), showing location of the R1178H mutation. Backbone is colored according to 3D colocalization of deleterious variants (Pathprox value most pathogenic, deep red, to least pathogenic, blue). Inset shows the predicted H‐bond network (cyan) stabilizing the tertiary structure of the helicase domain, which would be disrupted by the R>H substitution (Rosetta ddG score > 5 REU). Model is AF‐Q9HCK8‐F1‐v4 from AlphaFold Database.