Table 3.

Inheritance qualifier terms- these optional terms can be combined with either inheritance terms or allelic requirement terms to provide additional information about the relationship of a disease-gene pair. Penetrance describes the proportion of genotype-positive individuals that develop disease given a lifespan of 80 years. Expressivity describes the severity and scope of phenotypic manifestation

Inheritance Qualifier HP:0034335 (Parent and Child Terms)	Definition (Parent Term)
Typified by somatic mosaicism HP:0001442	Description of conditions in which affected individuals typically display somatic mosaicism, ie, genetically distinct populations of somatic cells in a given organism caused by DNA variants, epigenetic alterations of DNA, chromosomal abnormalities, or the spontaneous reversion of inherited variants. In many conditions typified by somatic mosaicism, constitutive variants are lethal, and cases are exclusively or predominantly mosaic.
Typically de novo HP:0025352	Description of conditions that are exclusively or predominantly observed because of de novo variants. In some cases, this may be due to the limited reproductive fitness of affected individuals.
Typified by incomplete penetrance HP:0003829 - Typified by moderate penetrance HP:4000159 - Typified by high penetrance HP:4000158	Description of conditions in which not all individuals with a given genotype exhibit the disease. Penetrance is the proportion that develop disease given a lifespan of 80 years. Examples include, CYP1B1 glaucoma, which has approximately 90% penetrance; Van der Woude syndrome due to IRF6 causes cleft lip and/or palate with penetrance estimated at 80%; C9orf72 causes frontotemporal dementia and/or amyotrophic lateral sclerosis with approximately 50% penetrance. Typified by moderate penetrance HP:4000159 Description of conditions in which only a moderate proportion of individuals with a given genotype exhibit the disease regardless of age assuming a full lifespan of 80 years. There is no commonly accepted definition for moderate penetrance, but we suggest that this term be applied if at least 20 percent, but less than 80 percent of individuals with the given genotype would manifest the disease with a full lifespan. Typified by high-penetrance HP:4000158 Description of conditions in which only an incomplete but relatively high proportion of individuals with a given genotype exhibit the disease regardless of age assuming a full lifespan of 80 years. There is no commonly accepted definition for incomplete but high penetrance, but we suggest that this term be applied if at least 80 percent but less than 100 percent of individuals with the given genotype would manifest the disease with a full lifespan.
Typified by complete penetrance HP:0034950	Description of conditions in which all individuals with a given genotype exhibit the disease within a lifespan of 80 years. For example, penetrance of Neurofibromatosis type 1 due to NF1 is close to 100%. Penetrance describes the proportion of genotype positive individuals that develop disease given a lifespan of 80 years.
Typified by highly variable age of onset HP:0034857	Description of conditions in which age of onset is highly variable even in family members who share the same disease-associated variant or variants.
Typified by age-related onset HP:0003831	Description of conditions in which age of onset is typically later in life and in which penetrance is dependent on the age of the subject Additional terms to capture details of age of onset at an individual level are available within HPO as child terms of Onset HP:0003674.
Imprinted HP:0034338 - With maternal imprinting HP:0012275 - With paternal imprinting - HP:0012274	Requires that the abnormal allele be paternal or maternal in origin, depending on the disease-gene relationship. Imprinting refers to a normal developmental process in which either the paternal or maternal allele is inactivated, depending on the specific locus, thus leading to expression from only one copy of the gene. Disease typically manifests when a deleterious variant is inherited from a parent whose copy of the gene would normally be expressed, but not when a deleterious variant is inherited from a parent whose copy of the gene would normally be inactivated.
Displays anticipation HP:0003743	A phenomenon in which the severity of a disorder increases, or the age of onset decreases, as the disorder is passed from one generation to the next, typically due to expansion of a repeat sequence. For example, myotonic dystrophy is caused by triplet repeat expansion in the DMPK gene.
Requires heterozygosity HP:0034343	Covers rare instances of a condition that is most severe in the heterozygous state. Such disorders are rare and currently all are X-linked. Most X-linked recessive conditions manifest if hemizygous in males, or biallelic in females, though may have a mild phenotype in the heterozygous state in females. However, Craniofrontonasal dysplasia due to EFNB1, and PCDH19-related epilepsy, are both X-linked dominant and paradoxically more severe in females. Hemizygous males may be mildly affected but seldom manifest the full phenotype. Importantly the mutant allele can be inherited from a normal or very mildly affected father. The mechanism is currently accepted to be due to cellular interference whereby the 2 distinct cell populations (those with and without the variant) exhibit abnormal cellular interactions in the mosaic state—in women, who are functionally mosaic due to random X inactivation, or mosaic males. The same mechanism could theoretically be observed in autosomal genes with a mosaic variant.
Sex-limited expression HP:0001470 - Male-limited expression HP:0001475 - Female- limited expression - HP:0034344	Condition in which the phenotype only manifests in 1 sex, ie, either manifests in males or females but not both. Example: autosomal recessive sex reversal due to DHH on chr12 manifests only in XY males causing gonadal dysgenesis, whereas XX females are phenotypically normal.
Contiguous gene syndrome HP:0001466	Syndrome caused by the effects of abnormality (typically a deletion or duplication) of 2 or more adjacent genes.

HPO, human phenotype ontology.