De Novo Complex Genomic Rearrangement Spanning 2q31.1 in a Proband With Congenital Malformations: Genotype-Phenotype...

The 2q31 region is commonly associated with pathogenic alleles of the HOXD cluster leading to various clinical phenotypes related to skeletal development. We present a proband with tetralogy of Fallot and multiple congenital anomalies. Genomic variant screening including an in-house CGR detection pipeline pairing genome sequencing (GS) structural variant calls with read-depth data revealed a de novo complex genomic rearrangement (CGR) spanning 2.7 Mb across 2q31 characterized by a series of duplications and triplications including the HOXD gene cluster. The genomic structure was assembled by applying combined methodologies including short-read and long-read GS, and optical genome mapping (OGM). This in-house CGR pipeline detected five additional rearrangements throughout the genome confirmed by orthogonal methodologies as inherited and unlikely to impact this individual's phenotype. Importantly, these catastrophic genomic events, chromoanasynthesis-like, are surprisingly commonly observed in the genome, inherited and involve large regions of the genome. Moreover, such inherited CGRs often include copy-number gains that partially affect disease-causing genes which complicate clinical interpretation. Overall, we show the utility of short-read sequencing to uncover de novo and inherited chromoanasynthesis events and established genotype-phenotype correlation in a proband with multiple congenital malformations.