3.1 years ago
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,