search

brentp / slivar

genetic variant expressions, annotation, and filtering for great good.
MIT License
247 stars 23 forks source link

Compound het allele segregation in multi-generational pedigree with multiple affecteds #123

Open mvelinder opened 2 years ago

mvelinder commented 2 years ago

Hey Brent,

Here's the pedigree I'm working with:

#Kindred_ID Sample_ID   Paternal_ID Maternal_ID Sex Affection_Status    Project
K01 UDN019315   0   0   2   1   A1247-211214-VAR-Botto-UFAGSFAA
K01 UDN032463   UDN901989   UDN019315   2   2   A1247-211214-VAR-Botto-UFAGSFAA
K01 UDN301487   0   UDN032463   1   2   A1247-211214-VAR-Botto-UFAGSFAA
K01 UDN722550   0   UDN032463   2   2   A1247-211214-VAR-Botto-UFAGSFAA
K01 UDN774226   0   UDN032463   2   2   A1247-211214-VAR-Botto-UFAGSFAA
K01 UDN901989   0   0   1   1   A1247-211214-VAR-Botto-UFAGSFAA

A mother (proband) with her parents and her 3 affected children

I did my usual slivar filtering and had TRPM4 compound het variants prioritized. But in checking the allele segregation and genotypes for all individuals it seems not all affecteds have both variants. UDN301487 lacks the chr19:49182889 variant. And UDN774226 lacks the chr19:49190460 variant.

#CHROM  POS ID  REF ALT QUAL    FILTER  INFO    FORMAT  UDN019315   UDN032463   UDN301487   UDN722550   UDN774226   UDN901989
chr19   49182889    .   G   A   3558.62 PASS    [...]gnomad_popmax_af=0.00224907;gnomad_n_hets=248;gnomad_n_homalt=2;impactful;genic;highest_impact_order=3;comphet_side=UDN032463;slivar_comphet=UDN032463/TRPM4/48968/chr19/49190460/AGGGAGTGCTGT/A   GT:AD:DP:GQ:PL:SAC  0/0:44,0:44:99:0,105,1800:. 0/1:43,51:94:99:1549,0,1447:24,19,22,29 0/0:55,0:55:99:0,120,1800:. 0/1:18,21:39:99:694,0,611:10,8,9,12 0/1:18,11:29:99:360,0,641:8,10,8,3  0/1:26,32:58:99:1062,0,912:10,16,14,18
chr19   49190460    .   AGGGAGTGCTGT    A   4286.19 PASS    [...]gnomad_popmax_af=6.57289e-05;gnomad_n_hets=6;gnomad_n_homalt=0;highest_impact_order=46;comphet_side=UDN032463;slivar_comphet=UDN032463/TRPM4/48968/chr19/49182889/G/A  GT:AD:DP:GQ:PL:SAC  0/1:24,32:56:99:1270,0,3032:17,7,18,14  0/1:59,51:110:99:1960,0,7113:38,21,28,23    0/1:34,30:64:99:1153,0,4188:16,18,13,17 0/0:43,0:43:99:0,109,1800:. 0/0:51,0:51:64:0,64,1627:.  0/0:52,0:52:99:0,105,1800:.

Does compound-het only work on proband? Not all affecteds in the pedigree? Would it be easy to extend to all affecteds?

Thanks pal!

mvelinder commented 2 years ago

If it's not feasible to extend slivar to this compound-het functionality, I was thinking of running slivar twice, once on mother and her parents as a trio. And then take the mother's variants from the first run and merge with the children's variants and run slivar again on mother and her affected children. Thoughts?

brentp commented 2 years ago

Hi Matt, Yes, right now, comphet must be run only on trios (or duos, but that doesn't work as well). So what you describe--intersecting after running on each trio would be the best current option. You actually only need to run slivar expr once and then slivar compound-hets once, and the merge/filter the output of slivar compoun-hets.