| Title: |
Phenotypic Variability and Paternal Inheritance of a CHD8 Variant Causing Intellectual Developmental Disorder With Autism and Macrocephaly Confirmed by Epigenetic and Structural Analyses |
| Authors: |
Furuta, Yutaka; Ezell, Kimberly M; Hamid, Rizwan; Cogan, Joy D; Cassini, Thomas A; Rives, Lynette; McMinn, Ashley; Shah, Shailee; Peltier, Amanda C; Layfield, Stephen; Fletcher, Robin S; Tedder, Matthew L; Louie, Raymond J; Lee, Jennifer A; Kerkhof, Jennifer; Rzasa, Jessica; Sadikovic, Bekim; Al Mamun, Abdullah; Sheehan, Jonathan H; Moth, Christopher W; Meiler, Jens; Vawter‐Lee, Marissa; Mendoza‐Sengco, Paola Maria; Holzen, Jennifer B; Pruthi, Sumit; Phillips, John A; Tinker, Rory J; Quinlan, Aaron; Elkadri, Abdul; Vanderver, Adeline; Rebelo, Adriana; Beggs, Alan H; La Spada, Albert R; Huang, Alden; Paul, Alex; Miller, Alexander; Al‐Beshri, Ali; Ward, Alistair; Bale, Allen; McConkie‐Rosell, Allyn; Tran, Alyssa A; Gropman, Andrea; Vargas, Andres; Crouse, Andrew B; Stergachis, Andrew; Hurst, Anna; Raper, Anna; Tarakad, Arjun; Andrews, Ashley; Balasubramanyam, Ashok; Swerdzewski, Barbara N Pusey; Anguiano, Beatriz; Afzali, Ben; Solomon, Ben; Martin, Beth A; Russell, Bianca E; Wilk, Brandon M; Mitchell, Breanna; Lanpher, Brendan C; Lee, Brendan H; Fogel, Brent L; Bordini, Brett; Graham, Brett H; Corner, Brian; Tucker, Brianna; Korf, Bruce; MacRae, Calum A; Toro, Camilo; Skraban, Cara; Bacino, Carlos A; Oladele, Carol; Hendry, Caroline; Smith, Carson A; Esteves, Cecilia; Xiao, Changrui; Reuter, Chloe M; Eng, Christine M; Chan, Chun‐Hung; Wahl, Colleen E; Welt, Corrine K; Tifft, Cynthia J; Kiley, Dana; Rader, Daniel J; Wegner, Daniel; Miller, Danny; Scott, Daryl A; Viskochil, Dave; Sweetser, David A; Adams, David R; Barbouth, Deborah; Rao, Deepak A; Oglesbee, Devin; Bonner, Devon; Basel, Donald; Novacic, Donna; Baldridge, Dustin; Behrens, Edward; Silverman, Edwin K; Seto, Elaine |
| Source: |
Molecular Genetics & Genomic Medicine, vol 13, iss 12 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2025 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
31 Biological Sciences (for-2020); 3102 Bioinformatics and Computational Biology (for-2020); 3105 Genetics (for-2020); Autism (rcdc); Neurosciences (rcdc); Human Genome (rcdc); Genetics (rcdc); Pediatric (rcdc); Intellectual and Developmental Disabilities (IDD) (rcdc); Mental Health (rcdc); Brain Disorders (rcdc); Biotechnology (rcdc); 2.1 Biological and endogenous factors (hrcs-rac); 4 Quality Education (sdg); Humans (mesh); Female (mesh); Megalencephaly (mesh); Intellectual Disability (mesh); Phenotype (mesh); Paternal Inheritance (mesh); DNA-Binding Proteins (mesh); Epigenesis; Genetic (mesh); Male (mesh); Autistic Disorder (mesh); Pedigree (mesh); Transcription Factors (mesh); DNA Methylation (mesh); Undiagnosed Diseases Network; CHD8 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt6sb46250; https://escholarship.org/uc/item/6sb46250; https://escholarship.org/content/qt6sb46250/qt6sb46250.pdf |
| DOI: |
10.1002/mgg3.70165 |
| Availability: |
https://escholarship.org/uc/item/6sb46250; https://escholarship.org/content/qt6sb46250/qt6sb46250.pdf; https://doi.org/10.1002/mgg3.70165 |
| Rights: |
CC-BY |
| Accession Number: |
edsbas.DB0E2221 |
| Database: |
BASE |