X‐linked recessive condition, due to skewed X‐inactivation. For example, in Duchenne muscular dystrophy, approximately 25% of female carriers will exhibit some symptoms of the condition, ranging from muscle weakness to features as severe as seen in males (Hoogerwaard et al. 1999). This has led many researchers to argue that conditions with loci on the X‐chromosome should simply be termed, “X‐linked.”
Mitochondrial Inheritance
Mitochondrial inheritance is a non‐classical pattern of single gene inheritance that is observed in conditions in which the causative allele is located in the mitochondrial DNA (mtDNA). In humans, each mitochondrion has approximately 2–10 copies of the mtDNA, which contains 37 genes. A mutation in one of these genes may be present in all copies of the mtDNA in a cell (known as homoplasmy). Alternately, a cell may contain some mtDNA with the mutation and other mtDNA without the mutation, known as heteroplasmy. The degree of heteroplasmy may vary by tissue and can influence the severity of the disease and the risk to future offspring. Mitochondria are inherited from the mother and, therefore, are referred to as having “maternal inheritance.” The risk for an affected mother to pass on the genetic defect in the mtDNA can approach 100%.
Y‐linked
Alleles located on the Y chromosome are transmitted from affected males to all sons, and in each case, the son’s Y‐linked phenotype will be identical to that of the father; daughters of males with a Y‐linked trait will not inherit the trait, since they receive their father’s X chromosome. Very few expressed genes have been localized to the Y chromosome.
Genetic Changes Associated with Disease/ Trait Phenotypes
Mutations Versus Polymorphisms
Alterations in the genetic code can be neutral, beneficial, or deleterious. Neutral and beneficial changes contribute to the natural variation among individuals and are not considered to have a negative effect on the organism. Rare changes in the genetic code that lead to an abnormal trait or disease phenotype are typically termed a mutation (or a pathogenic variant). The pathology of a mutation can be the result of either a loss or gain of function of the gene product. Such changes can occur in a number of different ways as highlighted below. A polymorphism, on the other hand, is used to describe a genetic variation in which there are two or more possible alleles at a particular locus. A genetic variation is typically termed a polymorphism if it is found in >1% of the population. A polymorphism may be a change in a single nucleotide, known as a single nucleotide polymorphism, an insertion or deletion (indel), or a duplication or deletion of a large segment of DNA, sometimes referred to as a copy number variant (CNV). Much research is currently underway to evaluate the effects of such polymorphisms on common and complex diseases, such as multiple sclerosis, cancer, and heart disease.
Point Mutations
A point mutation is defined as an alteration in a single bp in a stretch of DNA, thereby changing the 3‐bp codon. Since the genetic code is degenerate, many such changes do not necessarily alter the resulting amino acid. However, if the single bp change leads to the substitution of one amino acid for another, the result can significantly affect the final protein product. Point mutations can be classified as transition mutations (purine → purine or pyrimidine → pyrimidine) or as the less common transversion mutations (purine → pyrimidine or pyrimidine → purine). In general, transitions are less likely than transversion mutations to change the resulting amino acid. Five effects of point mutations have been described:
Synonymous or silent mutations are single bp changes in the DNA that do not affect the resultant amino acid
Nonsense mutations result in a premature stop codon, leading to a polypeptide of reduced length
Missense mutations lead to the substitution of one amino acid for another
Splice site mutations affect the correct processing of the mRNA strand by eliminating a signal for the excision of an intron
Mutations in regulatory genes alter the amount of material produced
Several examples of point mutations in human diseases are illustrated below.
Sickle Cell Anemia
Sickle cell anemia, an autosomal recessive disorder with a carrier frequency in African Americans of approximately 1/12, is a classic example of a point mutation leading to disease. Sickle cell anemia results from a single nucleotide substitution in the HBB gene of an adenine to a thymine, which changes the resultant amino acid from glutamine to valine at codon 6. The pathogenic variant (mutation) leads to the formation of an abnormal form of hemoglobin, hemoglobin S, which causes the red blood cell to take on an abnormal form that resembles a sickle. This causes red blood cells to break down prematurely, leading to anemia. In addition, the sickled red blood cells may accumulate in blood vessels and lead to episodes of severe pain. Interestingly, the carrier state for sickle cell trait may lead to a selective advantage in certain environments: carriers have a resistance to malaria that is useful in tropical climates, which explains the high carrier rate in certain populations.
Achondroplasia
Achondroplasia, the most common type of short‐limbed dwarfism, is an autosomal dominant disorder. About 85% of cases are the result of a new mutation. It has been observed that the rate of new dominant mutations increases with advancing paternal age (Penrose 1955; Stoll et al. 1982). Achondroplasia is now known to result from mutations in the fibroblast growth receptor 3 gene (FGFR3), located on chromosome 4p16.3. Interestingly, over 95% of the mutations are the identical G‐to‐A transition at nucleotide 1138 on the paternal allele (Rousseau et al. 1994; Shiang et al. 1994; Bellus et al. 1995). This single change causes a gain of function mutation which results in constitutive activation of the receptor, thereby inhibiting the proliferation of cartilage cells, or chondrocytes, and significantly restricting growth in individuals with this condition. Other pathogenic variants in FGFR3 are also responsible for hypochondroplasia and thanatophoric dysplasia, types of dwarfism that are clinically distinct from achondroplasia.
Deletion/Insertion Mutations
Another class of mutations involves the deletion or insertion of DNA into an existing sequence. Deletions or insertions may be as small as 1 bp, or they may involve one or many exons or even the entire gene. Even single bp deletions or insertions can have devastating effects, frequently by altering the reading frame of the DNA strand. A specific type of deletion/insertion mutation is a CNV. A CNV is structural variation in which kilobases to several megabases of DNA have been deleted or added and may encompass numerous genes. It is hypothesized that CNVs may account for 5–13% of the genome (Stankiewicz and Lupski 2010; Zarrei et al. 2015). Most CNVs are expected to be benign, while some are directly tied to a particular disease. Other CNVs may confer an increased risk for a particular condition, and much research is currently taking place about the role of CNVs in complex diseases.
Duchenne and Becker Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a severe, childhood‐onset X‐linked muscular dystrophy. Becker muscular dystrophy (BMD) is allelic with DMD but typically has a later age of onset and a milder presentation. Boys with DMD typically have normal development for the first few years of life, after which rapidly progressive muscle deterioration becomes obvious. Affected
