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2) X-linked inheritance

This is a rather uneventful example meant to showcase the X-linked inheritance analysis support of the app. Additionally, it demonstrates how to set up models with incomplete dominance.

Pedigree table​

The data corresponding to the case is shown below:

 ped id fid mid sex phenotype carrier proband age
   1  1   0   0   1         .       .       .  80
   1  2   0   0   2         .       .       .  80
   1  3   1   2   1  affected     het       .  40
   1  4   0   0   1    nonaff     neg       .  60
   1  5   1   2   2    nonaff     het       .  60
   1  6   4   5   1  affected     het       1  40
   1  7   4   5   1  affected     het       .  40

There are three affected members: the proband, his brother, and the maternal uncle. All three are hemizygous for a rare variant on the X-chromosome, which the proband’s mother also carries. Ages are not really important, as they won’t be the focus of this analysis.

Recessive inheritance​

A basic model for these data would be to assume complete penetrance for hemizygous and homozygous carriers, and no phenocopies. This can be easily accomplished by switching to the Liability class mode and selecting XR on the Penetrance panel’s header. In this case, the table has two columns: neg/♀het refers to the penetrance for non-carriers and heterozygous carriers, while ♂het/hom is for the hemizygous and homozygous carriers.

After setting these values, we can proceed to Calculate the evidence for the variant’s pathogenicity.

Dominant inheritance​

Sometimes it can be interesting to assume a dominant model where hemi- and heterozygous carriers share the same penetrances. This can be easily accomplished by switching to XD, and the table will adjust accordingly.

In this particular case, however, attempting to compute cosegregation evidence with these parameters will result in an error notification from the app. This is because the proband’s mother cannot be unaffected and carrier under complete penetrance.

Incomplete dominance​

For certain analyses, it may be necessary to separate the penetrances of hemi- and heterozygous carriers from others. This can be achieved by switching to XI inheritance. Then, the penetrance table acquires three columns referring to non-carriers (neg), hemi- and heterozygous carriers (het), and homozygous carriers (hom). The penetrances of hemi- and heterozygous carriers can be further differentiated by defining sex-specific liability classes, as shown below.

Which should give the same results as the recessive model from before.