4.8 years ago by
It depends first of all on the mode of inheritance :
If your trait is inherited as AD:
I would advise you to remove all variants that have a MAF > 0.01% in the general population (e.g: 1KG and EVS), than go and prioritise the variants... give a high priority for stop, frameshift, splice site mutations. once you have a list of candidate variants, go for co-segregation in other family members. If you have a healthy brother/sister then your patient and his brother/sister should not share any candidate variants. If you have the parents and if your mutation is not de novo, then your patient and one of his parent should share the mutation.
If your trait is inherited as AR:
set the threshold MAF to >0.5% (1KG and EVS).. prioritise you variants. and then go for co-segregation: Lets say you found an interesting HMZ (M1:M1) variant in your patient : If you have the parents, then they should each carry one M1 allele (father: M1:WT mother : M1:WT).. If also you have a brother/sister unaffected, this sibling can be HTZ for M1 or WT for M1 but not M1:M1. If you have two affected members in the same family, so they both should be M1:M1.
-> the pathogenic variant should be : M1:M1 in your patient and his affected brother/sister and M1:WT in each of the parents..
Idem for compound HTZ (M1:M2). same MAF and co-segregation rules.
Hope this would help,