Multiple de novo copy number variant (MdnCNV) driven mirror traits and blended phenotype

Purpose: To determine the genetic variation underlying phenotypic trait manifestation in a Multiple de novo copy number variant (MdnCNV) case. Method: Clinical microarray identified a previously unreported MdnCNV proband. Short and long-read genomic sequencing, SV analyses, and visualization tools for merged datasets were implemented to characterize MdnCNV mutagenesis. Human phenotype ontology based quantitative analyses identified gene(s) driving proband phenotype.Results: Eight dnCNVs of average length ~1 Mb were mapped in the MdnCNV proband. Sequence microhomology/microhomeology was present at 6/8 breakpoint junctions. dnSNVs (6/79) and de novo indels (1/12) are enriched within 4 Mb of the dnCNV regions. Of the duplication encompassed genes, NSD1 and SMARCC2 had the highest phenotypic match to the proband. Conclusion: Biparental origin of constitutive dnCNVs (4:4) supports an early perizygotic mutagenesis event as the cause of genome-wide hypermutation. Microhomology/microhomeology and regional hypermutation supports microhomology-mediated break-induced replication as the process underlying MdnCNV formation. The family reported here, together with published NSD1 variation associated cases further define NSD1 as a triplosensitivity locus that exhibits mirror quantitative traits from those associated with its haploinsufficiency. Quantitative phenotype analysis identified NSD1 and SMARCC2 as contributors to a blended phenotype. The goal of this experiment was to determine the size, genomic extent and gene content of a family with a proband carrying the multiple de novo CNV phenotype.