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

[mvelinder]

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]

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]

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.