Insights From a Novel Splicing Variant and Recurrent Arginine Variants in the CHD3 Gene Causing Snijders Blok–Campeau Syndrome

ABSTRACT Snijders Blok–Campeau syndrome (SNIBCPS, OMIM#618205) is an autosomal dominant neurodevelopmental disorder attributed to pathogenic variants in the chromodomain helicase DNA binding protein 3 ( CHD3 ) gene. To date, more than 100 individuals have been diagnosed with SNIBCPS. The syndrome is characterized by intellectual disability, global developmental delay, speech or language impediments, and dysmorphic features associated with macrocephaly. Additionally, affected individuals may exhibit behavioral issues, hypotonia, and autistic traits. A novel splicing variant (c.5590+1G > T) in the C‐terminal 2 region of the CHD3 gene was identified in a patient predominantly exhibiting autistic characteristics. In vitro minigene splicing experiments conducted in HEK293 cells revealed that aberrant splicing resulted in the formation of a cryptic site 46 nucleotides downstream of the 5′ splice site. This alteration was predicted to disrupt the reading frame by eliminating the physiological stop codon, consequently causing an extension in protein translation. Furthermore, an additional patient presenting with hypotonia, dysmorphic features, and global developmental delay was documented. This patient harbored a missense variant in the helicase C‐terminal domain, c.3505C > T (p. Arg1169Trp). The pathogenic variant was anticipated to impact chromatin remodeling capacity and enzyme activity. Given the high prevalence of arginine residue pathogenic variants in the CHD3 protein and its notable propensity for binding and storing ATP molecules, intriguing insights into the potential effects of arginine residue pathogenic variants on phenotypes are provided. These findings contribute to a more comprehensive understanding of the genetic landscape of SNIBCPS while elucidating potential molecular mechanisms underlying the syndrome.