ClinVar Genomic variation as it relates to human health

The 1p36.33 deletion is an approximately 39kb deletion on the short arm of chromosome 1. The region in which this deletion is found contains several highly homologous sequences which makes mapping the exact breakpoints difficult with genome sequencing. The centromeric breakpoint of this deletion is in the ATAD3B gene, 5’ to exon 6, and the telomeric breakpoint of the deletion is between exons 3 and 5 of ATAD3A. The deletion identified here is absent from gnomAD(SVs v2.1) as well as the Database of Genomic Variants (DGV), suggesting it is not a common benign variant in the populations represented in those databases. Deletions similar to the one identified here have been identified as homozygous or compound heterozygous copy number variants in affected individuals in the literature [PMID:28549128, 27640307]. One of these studies suggests that deletions in this region to lead to a fusion between the ATAD3B and ATAD3A genes [PMID:28549128]. Expression studies in fibroblasts of individuals with similar deletions in homozygous state (specifically individuals S2 and S3; Desai, 2017[PMID:28549128]) suggest significantly reduced expression of ATAD3A at the mRNA and protein level, most likely due to the ATAD3B-ATAD3A fusion gene being under control of the ATAD3B promoter [PMID:28549128], although functional consequences of the deletions or fusion proteins were not interrogated. Mitochondrial defects were observed in affected patients with similar deletions in homozygous state [PMID:28549128]. Given its absence in population databases, observation as a homozygous variant in affected individuals in the literature, and functional studies demonstrating reduced expression, the 1p36.33 deletion identified in this individual is reported here as Likely Pathogenic.