SV/CNV

Similar to the automated SNV analysis, Moon generates a list of potential provisional diagnoses by sequentially filtering and ranking the structural variants (INS, INV, BND) and copy number variants (DEL, DUP) in the uploaded SV/CNV file. Results of this automated analysis are presented in the SV/CNV tab in the Shortlist.

Common deletions and duplications in the general population are filtered out, as these are unlikely to contribute to a disease phenotype. CNVs are excluded if they are completely comprised by a common (>1%) population CNV or have the same gene content. For this filter step, Moon checks overlap with DGV Gold standard variants and with the gnomAD structural variant (SV) data set. An exception is made for SVs completely encompassing LP/P events in dbVar.

Only those SVs impacting exonic regions of known disease genes, which are based on Moon's disorder model Apollo, are retained. For deletions and duplications, Moon requires exonic regions of Apollo genes to be located between the start and end positions of the events. InsertionsInsertionsInsertions are only retained if the insertion site is exonic or immediately near an intron-exon border of an Apollo gene. Inversions are only retained if the start or end of the event disrupts a disease-associated gene and the inversion at least impacts an exonic part of a disrupted Apollo gene, irrespective of whether the breakpoint itself is exonic or intronic. BNDs are retained if disrupting an Apollo gene irrespective of whether the location is exonic or intronic.

If a family analysis is performed, segregation of the variants is taken into account, requiring that candidate SVs are shared among affected members (80% reciprocal overlap required). In addition, if only impacting genes associated with dominant conditions, heterozygous SVs are also filtered out if present in healthy family members.

For SVs that affect a single gene and are expected to cause loss of function (including BND, INV breakpoints, INS, exonic DELs, DUPs with at least 1 exonic breakpoint), Moon will check whether the zygosity matches the inheritance pattern of associated disease(s). If only annotated with recessive conditions, heterozygous calls will only be retained for the Shortlist if they are in compound heterozygous state with another SV or SNV. Homozygous calls will be excluded if only annotated with dominant disorders.

Finally, Moon performs a final filtering step based on phenotype overlap between the input HPO terms and known disease presentations. At least 1 matching HPO term between known diseases and the input phenotype is required.