Monogenic disorder, also known as single-gene disorder, is the disorder that is caused by variants of a single gene, which could be either nuclear or mitochondrial. In this chapter, we will focus on the disorders caused by nuclear genes. Most of the monogenic disorders are Mendelian diseases, the diseases for which the phenotypes follow Mendelian inheritance patterns. As the abnormal gene could be either on an autosome or on a sex chromosome, and the phenotypic expression of the abnormal allele respected to the normal allele could be dominant, co-dominant or recessive, there are several basic modes of monogenic disorder inheritance: autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive and Y-linked.

A medical pedigree is a graph presenting a family’s genetic relationships and phenotypic history. It is made up of standard symbols, lines and labels.

The Pedigree Standardization Work Group (PSWG) recommended standard symbols for the pedigree (Table 4.1). The symbols are linked with relationship lines (Table 4.2).

Table 4.1 Representative pedigree symbols

Table 4.2 Representative pedigree lines

Figure 4.1 A Pedigree Example

As shown in the example (Figure 4.1), the generations could be denoted with Roman numerals and the individuals in each generation could be denoted with Arabic numerals in an order from left to right.

Analyze a family with the pedigree to determine whether the disease is caused by genetic factor and the mode of the inheritance.

Autosomal dominant inheritance (AD) is controlled by the gene located on autosomal chromosome. The disease gene of AD is dominant, i.e., the heterozygote (Aa) expresses the same or some level of trait (phenotype) as the homozygote (AA). An individual with either Aa or AA genotype is affected, while one with aa is not affected. The AD diseases usually occur only in the heterozygous state. Based on the expression of the trait of Aa, AD could be categorized as several types.

In complete dominance inheritance, heterozygote (Aa) has the same phenotype as homozygote (AA). Normally, when an affected individual mates with an unaffected individual, their children have a risk of a half (1/2) to be affected. When an affected individual mates with an affected individual, their children have a risk of three quarters (3/4) to be affected.

Brachydactyly (“short digits”) type A3 (BDA3) is a very common and typical AD disease, featured by shortening of the middle phalanx of the little finger.

Figure 4.2 A Pedigree of Brachydactyly Type A3

Familial Adenomatous Polyposis (FAP) is an AD disease in which numerous adenomatous polyps form in the large intestine. These polyps may malignantly transform into colon cancer if they are left untreated.

Figure 4.3 A Pedigree of Familial Adenomatous Polyposis

In a typical AD inheritance, affected family members appear in multiple generations and males and females are affected with comparable chance. An affected individual is heterozygous and thus each of his or her offspring has a 50% chance of getting the mutant allele and thus being affected. Generally, one of the parents of an affected individual is affected. And the siblings of the affected individual has a 50% chance of being affected. Male-to-male transmission occurs, which is not seen in X-linked dominant inheritance. The affected individuals have affected descendants and unaffected individuals have unaffected descendants, such a phenomenon is called “vertical transmission”. New mutation may occur and thus unaffected couples may have affected offspring.

In incomplete dominance inheritance, heterozygote (Aa) has an intermediate phenotype between the dominant homozygote (AA) and recessive homozygote (aa).

Most people can taste phenylthiocarbamide (PTC) bitter, while some people cannot. The persons with the TT or Tt genotypes are taster and persons with tt genotype are non-taster. The dominant allele T was supposed to show incomplete dominance to the recessive t allele. The ones with TT genotype may be able to sense tens of folds lower concentration of PTC.

Achondroplasia is a genetic disorder caused by a dominant mutation in fibroblast growth factor receptor 3 (FGFR3) that negatively regulates bone growth. The mutant FGFR3 is constitutively active and leads to severely shortened bones. One-allele defect (Aa) is enough to cause dwarfism, while two-allele defect (AA) is fatal before or shortly after birth.

In codominance, the phenotypes of both alleles in a heterozygote are fully expressed. One typical example are the ABO blood group system, which is controlled by multiple alleles (three in this case). The IA and IB allele are codominant to i allele. A person with IAIB genotype have a blood type of AB, i.e. both A and B blood group antigen are expressed on the red blood cells.

For some reason, the dominant allele did not express the phenotype in some heterozygotes, which shows irregular transmission of phenotype in the pedigree. Expressivity and penetrance are used to describe the irregular dominance.

The clinical features can show big variation among persons, even in the same family, which is referred to as variable expressivity. For example, the number of digits of a person with polydactyly can vary. A person with several extra digits has high expressivity.

Only 80% of the persons with a pathogenic gene express a phenotype of polydactyly, which referred to as 80% penetrance. A penetrance of 100% is complete penetrance and a penetrance less than 100% is incomplete penetrance. The penetrance of an AD disorder with incomplete penetrance should be considered when estimating the recurrence risk.

The symptoms of some genetic disorders tend to appear at an earlier age and/or be more severe as the disorder is passed to the successive generations. This phenomenon is called genetic anticipation. Some subtypes of autosomal dominant cerebellar ataxias (ADCAs) are caused by expansion of CAG trinucleotide repeats. As the repeat times of the CAG of the pathogenic allele may increase during passing from parent to child, in some cases of these subtypes, the onset of the symptom of the child is earlier than the parent.

For some autosomal dominant disorders, a single gene may give rose to more than one apparently unrelated effects. A good example of pleiotropy is Marfan syndrome, an AD disorder that affects eye, skeleton and cardiovascular system.

Although the pathogenic genes of AD disorders are located on autosome, in some cases, their expression may be different in male and female individuals, and thus the phenotype types of male and female individuals with the same genotype may be different.

In the case of hereditary baldness, affected males become bald while affected females only suffer hair thinning.

In some cases, the phenotypic expression of the pathogenic genes are limited to one gender, referred as sex-limited. This is caused by anatomical or endocrinological difference.

In the case of uterine or testicular defects, as males do not have uterine and thus cannot be affected by uterine defects.

Some of genes are expressed only when it comes from the father or the mother. These genes are called to be imprinted.

In the case of Huntington's disease, when the pathogenic allele comes from the father, the age of onset get advanced, and while the pathogenic allele came from the mother, the age of onset is same to the mother.

In autosomal recessive (AR) inheritance, the pathogenic gene is located on autosome and an individual need both two alleles mutant to be effected. A heterozygote is called carrier.

When a normal individual (AA) mates with a carrier (Aa), their offspring have a 50% chance to be carrier (Aa). When a normal individual mates with an affected individual, their offspring have a 50% chance to be carrier (Aa). When a carrier (Aa) mated with a carrier (Aa), their offspring have a 25% chance to be normal (AA), a 50% chance to be carrier (Aa) and a 25% chance to be affected. When a carrier (Aa) mated with an affected (aa), their offspring have a 50% chance to be carrier (Aa) and a 50% chance to be affected (aa).

Typical example

Albinism is an AR disorder that the skin, hair and eye of an affected individual lost pigment completely or partially. The affected individuals are more susceptible to sunburn and skin cancers.

Figure 4.4 An Idealized Pedigree of Albinism

Sickle cell anemia is another example. The red blood cells of affected person is sickle-shaped, which may block the blood capillaries and eventually results in lots of health problems including pain, anemia and stroke. The normal hemoglobin (HbA) and mutated hemoglobin (HbS) can be distinguished by protein electrophoresis. The person with a single pathogenic allele is said to have sickle-cell trait, i.e., with HbS detected. Obviously, the sickle-cell trait inherit in an AD pattern.

In a typical AD inheritance, males and females are affected with comparable chance. If both of the parents of an affected individual is not affected, both of them should be carriers. In such a cases, the siblings of the affected individual has a 25% chance of being affected and a 75% chance of being carrier. The offspring of an affected are likely unaffected but has a 100% chance of being carrier. The affected individuals are sporadic and sometimes there is only the proband is affected. Parental consanguinity is likely to result in higher occurrence of AR conditions, because each offspring is more likely to get the same pathogenic allele from their common ancestor.

Consanguineous marriage is the marriage between closely related individuals, i.e., who are related as second cousins or closer. The coefficient of relationship (R) is used to measure the degree of consanguinity and defined as the probability that two individuals get the same allele from the shared ancestor(s).

One’s parents, siblings and offsprings are first degree relatives that share an R of 1/2 with him/her. One’s half-siblings, grandparents, grandchildren, aunts/uncles and nephews/nieces are second degree relatives that share an R of 1/4 with him/her. The great grandparents, great grandchildren, and the first cousins are third degree relatives that share an R of 1/8 with him/her.

The coefficient of relationship of any two individuals could be calculated from the pedigree by summing up all the coefficient values of the paths that link these two individuals through the common ancestors. And the coefficient of each path is calculated by multiplying all the coefficient values of descent lines on the path. As shown by Figure 4.5, IV1 and IV4 (second cousins) share two common ancestors, I1 and I2. There are two paths linking IV1 and IV4, one through I1 and the other one through I2. Thus the coefficient of relationship between IV1 and IV4 are calculated as 1/32.

Figure 4.5 Calculation of Coefficient of Relationship

The coefficient of relationship could be employed in calculation of recurrence risk. For example, to calculate the recurrence risk of the offspring of male carrier and his cousin, the coefficient of relationship should be considered. The carrier’s cousin has a chance of 1/8 to be carrier as well and thus the risk of their offspring is affected is calculated as 1×1/8 × 1/4 = 1/32. If the man mates with a random female, given the frequency of heterozygotes (Aa) in the population is 1/1000, the risk is calculated as 1×1/1000 × 1/4 = 1/4000, which is 125 fold lower than the consanguineous marriage with his cousin.

A condition could be caused by two or more alleles or genes. Allelic heterogeneity when a similar phenotype can be caused by different mutation of the same gene and locus heterogeneity occurs when a similar phenotype can be caused by mutations of different genes. In the case of congenital deafness, an AR disorder could be caused by the mutation of any of two different gene (A and B), an affected male (aaBB) mating with an affected female (AAbb) could give rise to unaffected children, as all of their children has a genotype of AaBb.

When the pathogenic gene is located on X chromosome and the pathogenic allele is dominant to the normal allele, the disorder is under X-linked dominant inheritance (XD). The pathogenic allele of a male only comes from his mother, and will and only will be transmitted to his daughter. The pathogenic gene will never be transmitted from father to son, which shows criss-cross inheritance. For A gene, a female with X^aX^a genotype are unaffected while both with X^AX^A and X^AX^a are affected. An X^aY male are normal while an X^AY male are affected. The male is called hemizygote as he have only one X-chromosone and thus only one allele of X-linke genes. As the affected female may have one normal allele, the condition may be less severe.

When a normal female (X^aX^a) mated with an affected male (X^AY), each of their daughters has a 100% chance to be affected (X^AX^a) and the all of their sons (X^aY) are normal. When an affected female (more likely to be X^AX^a) mated with a normal male (X^aY), both the daughters and sons have a 50% chance of being affected (X^AX^a:X^aX^a:X^AY:X^aY=1:1:1:1). All of a homozygote affected female (X^AX^A) are affected.

X-linked hypophosphataemic rickets (XLHR) is commonest form of hypophosphataemic rickets, which is featured by defects of re-absorption of phosphate in the renal. The symptom of XLHR patients are growth failure, short stature, bow leg, bone deformity, bone pain and walking difficulties.

Figure 4.6 An Idealized Pedigree of X-linked hypophosphataemic rickets

Oral-facial-digital syndromes (OFDS) type I and type VII are XD disorders. OFDS is developmental disorders characterized by abnormalities of the mouth, the face and the digits. Almost all OFDS type I affected individuals are female, as it is prenatally lethal to affected male, usually during the first or second trimester of pregnancy. The oral features include gingival frenulae and lingual hamartomas cleft or lobulated tongue cleft palate. The facial features include hypertelorism, cleft lip and pseudocleft of the upper lip. The hands anomalies include brachydactyly, clinodactyly and polydactyly. The feet anomalies include preaxial polydactyly.

In a typical XD pedigree, more females are expected to be affected than males and the condition of affected females is likely to be less severe than that of the affected males. At least one of the affected individual’s parents should be affected. All the daughter of an affected male is affected while all the sons of an affected male mating with a normal female is unaffected. Both daughter(s) and son(s) of an affected female have a 50% chance to be affected. Continuous transmission could be seen in the pedigree.

When the pathogenic gene is located on X chromosome and the pathogenic allele is recessive to the normal allele, the disorder is under X-linked recessive inheritance (XR). The pathogenic allele of a male can be transmitted to his granddaughter via his daughter and, which shows criss-cross inheritance. For A gene, a female with X^aX^a genotype are affected while both with X^AX^A and X^AX^a (carrier) are unaffected. The males are hemizygotes. An X^aY male are affected while an X^AY male are normal.

When a normal female (X^AX^A) mates with an affected male (X^aY), each of their daughters has a 100% chance to be carrier (X^AX^a) and the all of their sons (X^AY) are normal. When a female carrier (X^AX^a) mates with a normal male (X^AY), each of their daughters has a chance of 50% to be carrier and each of their sons have a 50% chance of being affected (X^AX^a:X^aX^a:X^AY:X^aY=1:1:1:1).

Red-green colour blindness is the most common types of hereditary color blindness. The affected individuals have no or abnormal sensitivity to red or green light. The inability to perceive green and red is termed deuteranopia and protanopia respectively, both of which are dichromatic. The abnormal perception of green and res are termed deuteranomalous and protanomalous respectively. More males are affected than females.

Figure 4.7 An Idealized Pedigree of Red-green colour blindness

Duchenne muscular dystrophy (DMD), inherited in XR manner, is a severe and most common type of muscular dystrophy. All the affected are boys. The symptom of muscle weakness begins around the age of 4 and worsens quickly. Most of the affected are unable to walk around the age of 12 and die from respiratory or cardiac failure around the age of 20. The female carriers may show mild symptoms.

In a typical XR pedigree, much more males are expected to be affected than females. An affected male’s mother must be carrier if not affected. An affected female’s mother must be carrier if not affected and father must be affected. Criss-cross inheritance is seen on a pedigree that the brothers, maternal male cousins, maternal uncles, nephews and daughter's sons of an affected male have a high chance of being affected.

When the pathogenic gene is located on Y chromosome, the trait can only be transmitted from father to son (Figure 4.8), the disorder is under Y-linked inheritance, also referred as holandric.

Y-Linked disorder is very rare. Y-Linked Hearing Impairment is the only documented and verified Y-linked disorder with only two cases are reported in China. The hairy ears condition, once widely cited as Y-linked, has been shown not Y-linked.

Figure 4.8 An Idealized Pedigree of Y-linked inheritance