Missense variant in SRCAP with distinct DNA methylation signature associated with non-FLHS SRCAP-related neurodevelopmental disorder.
Alexandre White-BrownSanaa Choufaninull nullRosanna WeksbergDavid A DymentPublished in: American journal of medical genetics. Part A (2023)
Floating-Harbor syndrome (FLHS) is a neurodevelopmental disorder (NDD) caused by truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein gene (SRCAP). Truncating variants proximal to this location in SRCAP result in a non-FLHS SRCAP-associated NDD; an overlapping but distinct NDD characterized by developmental delay with or without intellectual disability (ID), hypotonia, normal stature, and behavioral and psychiatric issues. Here, we report a young woman who initially presented in childhood with significant delays in speech and mild ID. In young adulthood, she developed schizophrenia. On physical examination, she had facial features suggestive of 22q11 deletion syndrome. After non-diagnostic chromosomal microarray and trio exome sequencing (ES), a re-analysis of trio ES data identified a de novo missense variant in SRCAP that was proximal to the FLHS critical region. Subsequent DNA methylation studies showed the unique methylation signature associated with pathogenic sequence variants in non-FLHS SRCAP-related NDD. This clinical report describes an individual with non-FLHS SRCAP-related NDD caused by an SRCAP missense variant, and it also demonstrates the clinical utility of ES re-analysis and DNA methylation analysis for undiagnosed patients, in particular, those with variants of uncertain significance.
Keyphrases
- copy number
- dna methylation
- intellectual disability
- genome wide
- autism spectrum disorder
- gene expression
- end stage renal disease
- case report
- chronic kidney disease
- ejection fraction
- newly diagnosed
- electronic health record
- immune response
- machine learning
- inflammatory response
- patient reported outcomes
- protein protein
- artificial intelligence
- toll like receptor
- congenital heart disease