ClinVar Genomic variation as it relates to human health

This CNV is a 5.9 Mb deletion of 15q25.3-q26.2 on chromosome 15 (seq[GRCh37]del(15)(q25.3q26.2); chr15:g.88465861_94411846del), found in a de novo state. This CNV constitutes a loss encompassing 103 genes, of which, at least 50 are protein coding and include the CHD2 and ACAN genes. Haploinsufficiency of the CHD2 gene has been associated with CHD2-related neurodevelopmental disorders, which are characterized by an early-onset epileptic encephalopathy with refractory seizures and regression associated with frequent epileptiform activity. Seizure onset is typically between the ages of six months and four years. Other common features include developmental delay, intellectual disability, autism spectrum disorders and behavioral issues including anxiety. attention-deficit / hyperactivity disorder and aggressive or self-injurious behavior. Variants associated with CHD2-related neurodevelopmental disorders are typically caused by de novo variants (Carvil et al. 2021). Heterozygous loss of function variants in the ACAN gene have been associated with short stature and advanced bone age with or without early-onset osteoarthritis and/or osteochondritis dissecans, an autosomal dominant disorder characterized by disproportionate short stature, low birth weight and length, early growth cessation, and advanced bone age. Additional features include mild facial dysmorphism (mild midface hypoplasia, flat nasal bridge and frontal bossing), brachydactyly, bone deformities, joint problems and early-onset osteoarthritis (Gkourogianni et al. 2017; van der Steen et al. 2017; Stavber et al. 2020). Similar CNVs have not been reported in the peer-reviewed literature. However, a similar overlapping loss of 5.9 Mb, classified as pathogenic, has been reported in one individual with a phenotype including developmental delay in ClinVar. This CNV has not been reported in controls. Based on the available evidence, this CNV is classified as pathogenic.