Molecular genetics & genomic medicine · 2025
Phenotypic Variability and Paternal Inheritance of a CHD8 Variant Causing Intellectual Developmental Disorder With Autism and Macrocephaly Confirmed by Epigenetic and Structural Analyses.
СтатьяКлинический случайНазвание и аннотация: Перевод в очереди
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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, Undiagnosed Diseases Network
Аннотация
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.
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.