Hi all,

I’m looking for input on how to interpret a large structural variant call from Manta, particularly in the context of additional SV signals inside the duplicated region.

The primary call is:

chr6  7441879  MantaDUP:TANDEM:14063:1:2:0:0:0  C  <DUP:TANDEM>  228  PASS
END=48984647;SVTYPE=DUP;SVLEN=41542768;CIPOS=0,3;CIEND=0,3;HOMLEN=3;HOMSEQ=TAA
GT:FT:GQ:PL:PR:SR
0/1:PASS:228:278,0,710:28,1:42,11

arr[GRCh38] 6p25.1p12.3(7441879_48984647)x3 6p25.1–p12.3

then in the later parts has this call appears:

6   32491883    MantaDUP:TANDEM:56477:0:2:0:0:0 A   <DUP:TANDEM>    57  Ploidy  END=32538107;SVTYPE=DUP;SVLEN=46224;IMPRECISE;CIPOS=-148,149;CIEND=-89,89   GT:FT:GQ:PL:PR  0/1:PASS:57:107,0,62:5,6
6   32492169    MantaDEL:45263:1:2:0:0:0    T   <DEL>   207 PASS    END=32492941;SVTYPE=DEL;SVLEN=-772;IMPRECISE;CIPOS=-132,133;CIEND=-100,100  GT:FT:GQ:PL:PR  1/1:PASS:29:260,32,0:0,11
6   32522076    MantaDEL:56501:0:1:0:0:0    A   <DEL>   58  Ploidy  END=32584140;SVTYPE=DEL;SVLEN=-62064;IMPRECISE;CIPOS=-133,134;CIEND=-87,88  GT:FT:GQ:PL:PR  0/1:PASS:58:108,0,89:7,7
6   32522864    MantaDUP:TANDEM:56490:4:5:0:0:0 G   <DUP:TANDEM>    202 Ploidy  END=32558889;SVTYPE=DUP;SVLEN=36025;IMPRECISE;CIPOS=-102,103;CIEND=-223,224 GT:FT:GQ:PL:PR  0/1:PASS:202:252,0,303:22,15
6   32523158    MantaDEL:56490:5:6:0:0:0    A   <DEL>   88  Ploidy  END=32559115;SVTYPE=DEL;SVLEN=-35957;IMPRECISE;CIPOS=-108,108;CIEND=-151,151    GT:FT:GQ:PL:PR  0/1:PASS:88:138,0,111:9,10
6   32524850    MantaDEL:56490:1:2:0:0:0    A   <DEL>   62  Ploidy  END=32585017;SVTYPE=DEL;SVLEN=-60167;IMPRECISE;CIPOS=-175,176;CIEND=-252,252    GT:FT:GQ:PL:PR  0/1:PASS:45:112,0,43:4,7
6   32528193    MantaDUP:TANDEM:56479:1:2:0:0:0 T   <DUP:TANDEM>    248 Ploidy  END=32571238;SVTYPE=DUP;SVLE**N=43045;IMPRECISE;CIPOS=-156,157;CIEND=-203,203   GT:FT:GQ:PL:PR  1/1:PASS:38:301,41,0:0,14**

Key word Ploidy.

Within the boundaries of the larger duplication, person also have additional SV calls, including:

-smaller deletions

-BND (breakend) calls

-inversions -insertions

all within the largest duplicated segment.

Suspect a change in TNXB especially as person has an unspecified connective tissue that resembles EDS syndromes and stickler syndromes due to eye, skin laxity, and joint hypermobility, early age gum recession, nerve issues. Person has history with neurodivergence or/and adhd but no sub intelligence suspected or likely. Person has polyneuropathy and myofascial pain with giant feet and , but other than that is Normocephalic / normotypic. I think more genes may have been effected as person has eye issues, gastrointestinal, recurring immunity issues ( person has a pathogenic indel changes on an unrelated chromosome for Gilbert, and c6 defiency that can also explain this caused this), and has high body inflammation markers on blood test not related to sequncing.

My questions are:

How should this type of call be interpreted — does this most likely represent a true large tandem duplication with internal rearrangements, or could this be a collapsed/complex or fusion region producing compound signals? Is this mosaic as I understand this person doesn't strongly fit strong 6p duplication but fits its the categories across mildly to slight expression in most areas . or is this non classic partial 6p syndrome. Or am I just looking at possible noise with noncritical meaning. Canvas tool agrees an changes has happened in this region and I used annovar says its a 1.8 likely pathogenic score.

Highly suspecting a mild case of 6p partial syndrome with haploinsufficiency of many genes especially withing the Rccx module and HLA module. Notch 1 also has some early peptide snp changes in sequence with no RSID but high DAMN and CADD score . In your experience, how reliable are very large Manta tandem DUP calls when accompanied by multiple nested SV types and extra copy calls?

Would you treat this as a single complex SV event, or any other interpretations)?

Are there recommended validation or visualization approaches (e.g., IGV patterns, split-read signatures, long-read confirmation) that work best for SVs of this scale?

For context, this is from WGS 30X data, and the call passed quality filters with strong PR/SR support only a few deletion fails with a mapping score of 2 occurred within duplication.

Any insight into interpretation strategies, common pitfalls, or similar cases would be much appreciated.

Thanks in advance!