Mode of Inheritance Predicates

There are five basic modes of inheritance for single-gene diseases: autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, and mitochondrial (See Understanding Genetics, Appendix B).

The autosomal_dominant and autosomal_recessive assigns the individual into a group based on the number of the alleles observed in the individual. GPSEA supports the following Mendelian modes of inheritance (MoI):

Mode of inheritance	Allele count	Genotype category
Autosomal dominant	0	HOM_REF
	1	HET
	\(\ge 2\)	None
Autosomal recessive	0	HOM_REF
	1	HET
	2	BIALLELIC_ALT
	\(\ge 3\)	None

Note

BIALLELIC_ALT includes both homozygous and compound heterozygous genotypes.

Clinical judgment should be used to choose the MoI for the cohort analysis. Then a predicate for the desired MoI can be created by calling one of the following methods:

• autosomal_dominant()

• autosomal_recessive()

By default, the MoI predicates will use all variants recorded in the individual. However, a VariantPredicate can be provided to select a variant subset, if necessary.

Assign individuals into genotype groups

Here we show seting up a predicate for grouping individuals for differences between genotypes of a disease with an autosomal recessive MoI.

We use autosomal_recessive to create the predicate:

>>> from gpsea.analysis.predicate.genotype import autosomal_recessive
>>> gt_predicate = autosomal_recessive()
>>> gt_predicate.display_question()
'What is the genotype group: HOM_REF, HET, BIALLELIC_ALT'

The predicate will use all recorded variants to determine if the individual belongs into homozygous reference (HOM_REF), heterozygous (HET), or biallelic alternative (BIALLELIC_ALT) category.

Use a subset of variants for choosing the genotype group

To select specific variants, a VariantPredicate can be registered with the MoI predicate. For instance, the following can be done to only consider the variants that lead to a missense change on a fictional transcript NM_1234.5 when assigning the genotype group. We set up the variant predicate:

>>> from gpsea.model import VariantEffect
>>> from gpsea.analysis.predicate.genotype import VariantPredicates
>>> tx_id = 'NM_1234.5'
>>> is_missense = VariantPredicates.variant_effect(VariantEffect.MISSENSE_VARIANT, tx_id)
>>> is_missense.get_question()
'MISSENSE_VARIANT on NM_1234.5'

and we use it to create the MoI predicate:

>>> gt_predicate = autosomal_recessive(is_missense)
>>> gt_predicate.display_question()
'What is the genotype group: HOM_REF, HET, BIALLELIC_ALT'