Mechanisms of inheritance: a more complex situation than expected
The first studies on inheritance were conducted by Gregor Mendel, the father of Genetics. He discovered that phenotypic traits (e.g. hair or eye color) where defined by the genes (DNA). Each gene has two alleles, one inherited from the mother and one inherited from the father. These alleles may be identical (homozygous alleles) or different (heterozygous alleles). In the beginning, it was thought that, in the case of heterozygous alleles, only one of the two was expressed visually (dominant), while the other remained invisible (recessive). With the advancements of science, it soon became clear that that was only the tip of the iceberg and that there are several exceptions to this mechanism of inheritance.
What is semi-dominance?
Unfortunately or fortunately, Mendel had simplified the matter far too much. In fact, alleles can interact through different mechanisms, which may escape the laws of pure dominance. For example, it may happen that neither of the two alleles is dominant over the other, as in the case of semi-dominance (also known as incomplete dominance) or even under other schemes, such as co-dominance. In human genetic pathology, the definition given by the Human Phenotype Ontology group about semi-dominance is: "A mode of inheritance that is observed for traits related to a gene encoded on chromosomes in which a trait can manifest in the heterozygotes and homozygotes, with differing phenotype severity present dependent on the number of alleles affected."
Semi-dominance and co-dominance: are they synonyms?
If you'll ever be asked whether semi-dominance (or incomplete dominance) and co-dominance are synonyms, please answer: “No!”. Both terms refer to two inheritance mechanisms that go beyond those initially proposed by Mendel and which are based on the lack of complete dominance of one allele over the other. However, there is a basic difference between semi-dominance and co-dominance. In semi-dominance, there is a blending of the two alleles that results in a third phenotype different from the ones of the parents (e.g.: the cross between a white flower and a red flower generates a pink flower) . In co-dominance, both the parental alleles are expressed together in the offspring.
Does semi-dominance exist in humans?
Yes, semi-dominance and co-dominance may be found in humans too. A co-dominance example are alleles A and B of the blood group, while semi-dominance may be at the basis of some human features such as skin color, hair shape, etc. An example of semi-dominance in rare genetic disorders is represented by type A1 brachydactyly, due to homozygous mutations in the GDF5 gene. Brachydactyly is characterized by disproportionately short fingers and toes, and forms part of the group of limb malformations characterized by bone dysostosis. Brachydactyly can occur either as an isolated malformation or as a part of a complex malformation syndrome and may also be accompanied by other hand malformations, such as syndactyly, polydactyly, or symphalangism. Byrnes et al. (2010) reported a consanguineous family in which 3 homozygous affected sibs showed significantly shortened middle phalanges of digits 2 to 5 as well as the first distal phalanx, a very short first metacarpal, similarly affected feet, and short stature. The proband's son was heterozygous for the same mutation and had a milder phenotype, consistent with a semi-dominant pattern of inheritance. Indeed, he was of average height and appeared to be unaffected; however, radiography revealed subtle shortening of the middle phalanges of the second to fifth digits.
Semi-dominance and X-linked inheritance
Females have 2 chromosomes X, whereas males have 1 chromosome X. Rare diseases associated with pathogenic mutations on the X chromosome sometimes show semi-dominance. Indeed, males (hemizygotes) show by rule a more severe phenotype than females (heterozygotes), who may be mildly affected or more simply unaffected carriers. For example, X-linked mental retardation due to mutations in the HUWE1 gene is characterized by a very severe intellectual deficit associated with dysmorphism in males and a milder cognitive deficit in females. Such type of clinical expression is evident in several other X-linked conditions, such as retinitis pigmentosa 3 (RP3), which is a severe form of inherited retinal degeneration due to mutations in the RPGR gene. Typically, males have a severe phenotype, with an early onset night blindness and loss of peripheral vision, while carrier females can show a wide spectrum of clinical features or be completely asymptomatic.
Semi-dominance: term usage in Medical Genetics
Although semi-dominance is a well known allele attribute, the usage of the term "semi-dominance" or "semi-dominant" is actually quite rare in Medical Genetics. Practically, the first point of interest of any physician is to know whether a certain genetic variant may give rise to any kind of pathologic al phenotype or not. If the phenotype is lighter or more severe is certainly extremely important, but clear terms are needed to make doctors and patients understand if any disease may ever be present. From this point of view, the classification of rare disorders in (1) autosomal dominant, (2) autosomal recessive, (3) X-linked dominant, (4) X-linked recessive, (5) mitochondrial and (6) digenic is by far the easiest and the most used one. So, the word "semi-dominant" remains seldom used, as the concept it refers to may also comprehend asymptomatic phenotypes or purely quantitative traits, alongside with more concrete examples of pathological expression.
Can whole exome sequencing or whole genome sequencing detect semi-dominant traits?
The answer is yes, of course. Whole exome sequencing and whole genome sequencing, as well as multigene panels, can look for mutations in genes of which alleles may be typically semi-dominant. However, for the abovementioned reasons, it is rare that the term semi-dominant is used in rare disorder databases and medical reports.