Monogenic inheritance PDF

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Summary of the genetics discipline on monogenic inheritance, its main characteristics and mechanisms....

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UNICESUMAR MEDICINE – MEDICAL GENETICS / BIMESTER 2: CLASS 3

monogenic inheritance MONOGENIC DISORDERS the disturbances

monogenic

they are

those ones

THE Huntington's disease it is an autosomal dominant disease with a dominant phenotype. Normally,

determined by the alleles of a gene, which are on a pair of homologous chromosomes. Furthermore, they are characterized by a transmission pattern, Mendelian patterns, where there are fixed proportions depending on the specific type of mating, for example, in Mendel's experiments, 3:1,

people have less than 40 repeats in this gene in both alleles, to be normal, however, as soon as there is nucleotide expansion, a transmuted protein will be produced, triggering the disease. It will only take one mutation for Huntington's

9:3:1:1.

disease to express itself. Therefore, the genotype of an individual affected by Huntington's disease can be either “AA” or “Aa”. In relation to a genetic disease, the normal population is “aa” and these mutations are rare events, thus,

Most monogenic disorders are pediatric. About 1 in 300 newborns have a monogenic disorder, accounting for 7% of pediatric hospitalizations. Less than 10% of these disorders will occur after puberty and only about 1% after the end of the reproductive period. Monogenic inheritance can be autosomal or sex-linked depending on the chromosome on which it is located.

BASIC CONCEPTS - Homozygous: It has two homologous chromosomes, the same type of allele at the same locus (“AA” (dominant) or “aa” (recessive)). It only forms one type of gamete and hence, a type of zygote. - Heterozygous: It has two different alleles, however one is wild. For example, “Aa”, if we consider “A” to be the wild allele, therefore, “a” is the mutant allele, however, the opposite can occur. - Compound heterozygote: Has two mutated alleles different, that is, there is no wild allele. Through SNIPS, a gene can have multiple alleles. In cases where the "aa" is two different alleles (two mutated alleles and there is no wild-type allele (A), one "a" can be the true one and the other can be an "a'" or "a*", which vary between them, ie different mutated alleles, this is called compound heterozygotes.

it is more likely that the individual with the disease has only one mutation (“Aa”). Diseases in which there are both mutated alleles ("AA"), the manifestations are more severe and in most cases do not evolve, not surviving for a long time. That way, the vast majority of times it will be “Aa”. - Disease is autosomal recessive: the genotype of the affected one is “aa” and the normal one is “AA”, considering that the mutation is something rare. However, with “Aa” individuals it can also happen, but in general, it is more likely thinking genetic diseases and rare conditions will be a normal individual with the “AA” genotype. Conditions considered rare can be frequent in a given population, due to the many mutant alleles present. NORMAL VARIABILITY Many characteristics are of normal variability, determined by a single gene, such as dimples in the cheeks, ability to roll the tongue (tong-roller), earlobe being loosened or stuck. The loose ear lobe is dominant, but it is differentiated into “AA” or “Aa” because it is no longer part of the issue of rarity. Thus, in common characteristics, it is not possible to say the genotype.

Often, there is no way to discover the phenotypically compound heterozygote, only with gene sequencing. Let's assume that “a” does not produce any proteins, “a'” and “a*” neither, so phenotypically it is not possible to differentiate these alleles. However, there may be mutant alleles that affect

HEREDOGRAM OR GENEALOGY

enzyme activity differently. For example, "a" no longer produces the enzyme, however, there may be "a" that produces an enzyme with 5% activity, while "a*" has an enzyme with 10% activity, thus changing the phenotype according to the combination of mutated alleles.

collected from family members.

The more alleles of a gene described, the greater the chance of individuals being compound heterozygotes than homozygous themselves. Depending on location.

arrow on the heredogram.

method used for the study of the inheritance of a characteristic from the information Generally, the person (proving) what you're looking for

an advice genetic, is indicated by an

The doctor collects information and assembles the

- Dominant: Phenotype that expresses itself in a heterozygote.

genealogy. Generations are marked with Roman numerals (I,

- Recessive: It will only express itself when it has two mutations

II, III...), and in each generation, individuals are marked with normal numbers (1, 2, 3...).

in both alleles.

A flower is pink being “AA”, but when there is an “Aa” the flower remains pink, as there will still be the dominant “A”. The recessive (“aa”) is the one that needs both mutations, thus changing its phenotype to white rose.

CONSTRUCTION OF HEREDOGRAMS

Symbols:

they can form normal or affected individuals, however, those affected have a more severe phenotype. The risk and severity of offspring receiving the mutation will depend on whether one or both of the parents are affected, and whether the character is pure dominant or incomplete dominant. However, no matter if the person is an “AA” homozygote or an “Aa” heterozygote, the individual will be equally affected.

The most common are incomplete dominant/semidominant diseases, where the heterozygote has a milder and less severe phenotype than the homozygote or compound heterozygote. AUTOSOMIC RECESSIVE INHERITANCE

At first it is not possible to think about the pattern of transmission, because the parents, in most cases, are normal in recessive diseases, if it is recessive, the affected individuals are “aa”, so obviously both parents need to have a mutated allele. What will increase the chance of autosomal recessive inheritance is consanguineous marriage.

NOTE: There is a question in the test that has numbers inside the symbols, but they are only to identify individuals, they do not mean that in number 10, for example, there are 10 children.

HERITAGE PATTERNS: AUTOSOMIC DOMINANT INHERITANCE

Representing more than half of all Mendelian disorders, will be seen in both homozygous (“AA”) and heterozygous (“Aa”). When studying a pedigree, one must first look at the generations and prevalence of the disease. If almost all generations are affected, it must be related to a dominant inheritance with a dominant phenotype. Another point to note is if men and women are equally affected (same proportion), the number may not be exactly the same, as it depends on the number of individuals in the same family. When reaching men and women equally, we must think of an autosomal characteristic, as it is not related to the sex chromosome. It should also be noted the types of transmission (who passes to whom). If an affected woman passes on to a male child, who in turn passes on to a female daughter, there are signs that there is no specificity of any kind. In this bias, these factors indicate that it is an autosomal dominant disease. Normally, in autosomal dominant inheritance we have the phenotype in all generations. Any child of an affected parent has an average risk of 50% of inheriting the phenotype. In addition, phenotypically normal family members do not transmit the phenotype to their children, because as this is an autosomal dominant inheritance, for the individual to be normal, it has to be “aa”. Homozygosis can happen, above all, due to the union of families in search of knowledge, government help, association of parents and friends, causing individuals with the same disease to approach and get involved. As there is the possibility of being heterozygous,

General features: parents almost never have an anomaly because they are heterozygous. It affects both sexes equally. The parents of an affected child have a 25% chance of bearing another affected child. From an affected couple, only affected children are born (both the man and the woman are “aa”), while from couples consisting of one affected and another normal, normal individuals are usually born. The proportion of consanguineous couples among the parents of those affected is higher than that of the population. There is a predominance of compound heterozygotes when there are diseases with many alleles (eg, cystic fibrosis; beta-thalessemia), with a greater chance that different alleles are found by chance. It is estimated that each person has between 50 and 200 deleterious alleles in each individual genome, that is, it is these alleles that, when homozygous, result in recessive inheritance. Assuming we have 20,000 genes, of these, 50 are deleterious alleles, your spouse also has 50 deleterious alleles, but the chance of your allele and his being the same is very low, so it is very difficult to find recessive mutations. In a population where a gene has many mutations, it is possible that we have recessive alleles in the same gene, not necessarily these alleles will be the same, but thus compound heterozygosity occurs. Normally, autosomal recessive diseases are associated with the impossibility of reproduction by the affected individuals.

ASSOCIATED FACTORS

- Consanguinity: Have a common ancestor, thus having a consanguine relationship. increasing the chance of mutations in the mutated allele in the same gene. When you have consanguinity, you think of the true recessive homozygote, not compound heterozygosity, as it is the same mutation that came from the common ancestor. Often when you see a consanguineous marriage, you think of autosomal recessive inheritance, but it is not mandatory.

- Inbreeding: When individuals of a small population (due to geographic, cultural, religious, among others) tend to choose their partners in the

population. Even though they are not related, as it is an isolated population, in some generations it ends up forming a common ancestor, leading to consanguinity. An example of religious issues are Ashkenazi Jews, who select their partners within their own community, favoring the incidence of autosomal recessive diseases.

weight-bearing joints. Clinically indistinguishable from hemophilia B, distinct only genetically, as they are different genes. The modified gene is the clotting factor 8 gene, located on the X chromosome, and can be classified depending on the level of factor 8 that the individual is able to produce. There is currently treatment, and factor 8 can be replaced intravenously.

SEX-LINKED INHERITANCE

•

Duchene Muscular Dystrophy (DMD):

Inheritance linked to x:

- DMD gene: Xp21, 79 exons (2300kb, being 1.5% of the size of The incidence of the phenotype is much higher in men than in women. They are located on the non-homologous portion of

chrom X), encodes the dystrophin protein.

the X chromosome (which is not paired with Y). Women have two X's are still classified as homozygous or heterozygous, whereas men who only have one X are classified as hemizygous. Most of these X-linked diseases are recessive. And there will be an importance regarding the inactivation of

- Mutations: large deletions (60-65%), large duplications

X in women, which generated important clinical changes.

- Heterozygous women: Half of the cells will express the disease allele and the other half the normal allele: 50% of the normal level of the gene product is usually sufficient for the normal phenotype.

(5-10%) and small deletions, insertions or point mutations (25-30%). Most frequent type of muscular dystrophy that affects boys (1:3500).

Dystrophin: protein intracellular express predominantly in skeletal and cardiac muscles, and some neurons in the brain. - Absence of dystrophin: sarcolemma disruptions, increasing the passage of calcium into the cell, resulting in segmental fiber necrosis and loss of contractile property. The necrotic fibers are replaced by adipose and connective tissue.

- Manifesting heterozygotes: two heterozygous women can have very different clinical presentations: deviation in X inactivation.

- DMD causes progressive and irreversible degeneration of skeletal muscles, leading to generalized muscle weakness. The

- Affected women: homozygous (inbreeding) or

modified gene is on the short arm of the X chromosome that

most frequent characters.

encodes the dystrophin protein. In 2/3 of the cases the affected offspring come from a carrier mother, and 1/3 of the cases have a new mutation.

X-LINKED INHERITANCE TRANSMISSION PATTERN

The most common is the clinically normal (but carrier) woman. This woman can pass the mutated X to a boy and he will be affected. If she passes to a girl, this girl will be a carrier, however, normal. An affected man married to a normal woman will pass the mutated X to all his daughters (all of them will be carriers) and for the boys he will pass only the Y, so the children will be normal.

- An affected man will have an X with an “a” Y, not being able to produce dystrophin. In heterozygous women, there may be an X with an “A” that has been inactivated in some cells, and in other cells it has the X with an “a”, in which case some cells do not have dystrophin marking and others have the marking. This 50% balance is not enough for women to develop DMD. In case they manifest the disease, this is due to a deviation in the X inactivation, which instead of inactivating 50% as expected, further inactivates the normal X, leaving the mutated X.

Heterozygous women are generally unaffected, and when they are, they may have variable intensity, with clinical differences. Heterozygous women have an X "A" and an X "a", however, the inactivation of the X happens by chance, it is expected that in half of the cells it inactivates a mutated X, and in the other half it inactivates the normal X, that is, this woman will have half of the cells in her body with a normally functioning X and half with a mutated X. However, this is not enough for a woman to develop the disease, so heterozygous women usually do not express X-linked recessive disease.

•

Queen Victoria's Genealogy:

However, comparing two affected women, the higher the percentage of normal cells, the milder the disease phenotype. Even so, the two will present more lenient pictures than the men. - Symptoms: They start with the beginning of walking and progress as the child learns to walk. She presents difficulties and performs the Gowers maneuver to get up from the ground. In addition, pseudohypertrophy occurs in the calf (increased size), and walks on tiptoe. Typically, children who have DMD use a wheelchair at age 12 and have a life expectancy of 18 years. Currently, the expectation has increased, as there is treatment.

Another example of X-linked recessive inheritance is hemophilia A. The most classic case is that of Queen Victoria, who was

- Diagnosis: Muscle biopsy with dystrophin immunoreactivity,

an asymptomatic carrier and ended up passing the mutation on the X

serum creatine kinase level, family history and DNA analysis.

“a'' to two daughters and a son.

Hemophilia A is a clotting disorder (prolonged bleeding time) in soft tissues, muscles, and

- Treatment: symptomatic = increases longevity. Glucocorticoid therapy can delay progression for a few years.

DOMINANT X LINKED HERITAGE PATTERN X-linked dominant inheritance does not skip generations, as it is dominant. Overall, more women are affected than men, thought to be sex-linked and in this case Xlinked. X-linked dominant inheritances are smaller in both number and prevalence. In this disease, an affected male usually with a normal partner will not have affected male children, but all female daughters will have the disease. Usually women have a milder clinical manifestation than men, probably because they still have cells with the normal X, which is the recessive, active. Children of both sexes of affected women have a 50% risk of giving the phenotype. A classic example is vitamin D-resistant hypophosphatemic rickets, where there is a decreased capacity of the renal tubules to reabsorb filtered phosphate. In women it is observed both the rickets part and some other symptoms are milder due to the X inactivation process.

Y-LINKED INHERITANCE (RESTRICTED TO SEX)

The Y chromosome is smaller in size and in the number of genes, which are genes that determine primary and secondary male sexual characteristics. It is a patrilineal heritage, that is, men pass on to men. They are genes that are in the non-homologous part of the X chromosome (Holandric genes = all male). 100% of the children of affected men will be affected. The classic example is auricular hopertrichosis. PSEUDOAUTOSOMIC OR PARTIALLY LINKED TO SEX

Pseudoautosomal or partially sex-linked inheritance are genes that are located in the region of homology of X and Y. This is why it is called pseudoautosomal, because they are genes that function as autosomal genes, but are located on the sex chromosomes. FEATURES LIMITED TO SEX OR INFLUENCES BY

SEX Limited to sex means that it is restricted to one sex and that it only occurs in one sex. These are characteristics or diseases of autosomal dominant inheritance, but which do not have equal proportions in the sexes. This can occur due to different anatomical characteristics, for example, the need for a uterus to express the disease. The same thing happens for testicular defects. One example is precocious puberty limited to men, where there is a mutation in the luteinizing hormone receptor, which is only expressed in boys. They will have secondary sexual characteristics and have a common growth spurt in adolescence, occurring at approximately 4 years of age.

will be genes autosomal or gives region pseudoautosomal, but that will be influenced by sex hormones. For example, baldness in men follows an autosomal dominant pattern, with a mutation being enough to manifest. In women, baldness follows an autosomal recessive pattern, requiring two mutations.

In some autosomal recessive phenotypes they are expressed in both sexes, but with different frequency or severity. In this bias, hereditary hemochromatosis is much more common in men, as women, for example, lose iron during menstruation, have a low iron diet and alcohol consumption is sometimes different.

COMPLICATING FACTORS Factors that can change the inheritance pattern: degrees of dominance, new mutation, genetic heterogeneity, variable expressivity, reduced or incomplete penetrance, late manifestation, pleiotropy, germline mosaicism, anticipation, uniparental disomy, imprinting and mitochondrial inheritance.

CODOMINANCE Some genes have different degrees of dominance, differing from the dominant allele pattern over a recessive allele. Codominance means I have two equally dominant alleles, which express themselves in the heterozygote.

In the ABO system it is a system formed by three alleles, I have the Ia; Ib and I. Ia and Ib are codominant, they both have this pattern of codominance with each other, but both are dominant over i. So, hi is recessive. Ia and Ib will determine the expression of erythrocyte surface antigens, resulting in blood groups.

- IaIa or Iai genotype: blood A - IbIb or Ibi genotype: blood B. - Genotype II: blood O, the recessive. - IaIb genotype: codominance, AB blood. NEW MUTATION If in a heredogram I see normal common parents affected child, a new mutation may have occurred. In this case, the parents are aa and this individual is Aa, a single new mutati...