2014 - СумДУ

Topic_2.docПетрашенко Вікторія Олександрівна

2014

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ЗмістTopic 2: “CLINICAL GENEALOGICAL ANALYSIS. METHOD OF GENEALOGYconstruction”Main materialCharacteristics of pedigrees with different types of inheritance

Sample

Topic 2: “CLINICAL GENEALOGICAL ANALYSIS. METHOD OF GENEALOGY construction” 3

Topic 2: “CLINICAL GENEALOGICAL ANALYSIS. METHOD OF GENEALOGY construction”Main materialCharacteristics of pedigrees with different types of inheritance

Sample

Topic 2: “CLINICAL GENEALOGICALANALYSIS. METHOD OFGENEALOGY construction”

1. The general aim to know the main principles of clinical-genealogical method and to use clinical-genealogical analysis in clinical practice.

2. Student must know:

Bases of clinical-genealogical method for diagnostics of the inherited pathology.

Features of different types of inheritances.Types and examples of inheritance diseases.

General principles of making pedigree.

3. Student must be able:

To collect anamnesis of the patient with inheritance pathology.To define the type of inheritance of disease.To calculate the genetic risk.

4. Plan of conducting of studies

Introduction Classroom 5 min

Control and correction of initial level of knowledges Computer class10min

Features of different types of inheritance Classroom20min

Working with genealogical trees, calculating the genetic risk Classroom10min

Demonstration of patients with inheritance pathology Departments ofhospital

10min

Educational control and correction of level of knowledges Classroom10min

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Independent work of students with the different types of genealogicaltrees Classroom

10min

Conclusion Classroom 5 min

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Clinico-genealogical method is based on making and analyzing pedigree of the family. This is a requiredstep in the examination of the patient with hereditary pathology. The word "pedigree" and "genealogy" -synonymously.

The method allows answering the following questions:

1. whether the sign is a single family or has few cases of this pathology (familial);2. identify the type of inheritance;3. identify persons that need medico-genetic consulting and to define the risk of having a sick child;4. make clinical prognosis for the proband and his family, taking into account the features of the

disease and its genetic characteristics;5. estimate the expressivity and penetrance of the gene.

The method does not require difficult equipment, long laboratory analysis, and simple, accessible to eachdoctor. It includes three stages: 1) the collection of genealogical information (genealogical history) 2)construction of pedigree 3) genealogical analysis of pedigree 4) calculation of the genetic risk.

Stage I - collection of the information- starting with the proband - a man whose pedigree will bedrawn. Most of all - it's a patient with a hereditary disease, with less probability it can a healthy personwith diseased relatives. Proband is often called a counselee. This is followed by questions about the sibs,that is, brothers and sisters of the proband, parents and relatives on the maternal side, relatives on thepaternal side. You must collect information about any illnesses, pay attention to spontaneous abortions,stillbirths, death in early childhood. It should specify the age of died, cause of death.

The information of sibs (and other relatives) are collected in order of birth .It is important to determine whether there are married relatives in this family, because close relatives

more likely to be heterozygous for the same abnormal gene.During collecting genealogical history you should answer the following questions:

1. How the account was praband of a child in the family.2. How many pregnancies the mother of the proband had.3. What ended the first pregnision, the second and so on?4. If the sisbs were ill?5. Cause and age at death of siblings?6. In what period and why was the abortion?

Questions about the mother's family:

1. How the account was the mother of a child in the family?2. If mother’s sisters and brothers have there own children?3. Number of children in order of birth of, their health status.4. Causes of death and age of mother’s relatives.

The same information must be finding out about my grandmother from the mother, grandfather, theirfamily members.

After this, go to the collection of information about a father and all relatives of his father.It is desirable to examine the closest relatives of the proband personally. If this is not possible for any

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It is desirable to examine the closest relatives of the proband personally. If this is not possible for anyreasons , we need to analyze the phenotype of family from family photo . In some cases, need to get ahistory, information about the results of the autopsies of the dead and study medical documents. All thisis necessary to clarify the type of inheritance in the family.

Stage II - construction of a pedigree. Pedigree is a graphic representation of family tree. Themain characters that are used to build the pedigree are shown in pic.

Fig.1. Symbols using for pedigree

Some rules are used during making a pedigree.

1. Pedigree shall include not less 3-4 generations.2. Drawing pedigree starting with the proband. Proband is indicated by an arrow and drawn in the

middle of the sheet.3. Siblings represent from left to right in order of birth.4. Every previous generation of the proband depicted above the line, and the next generation below

it. The procedure for compiling - of future generations to the previous (first generation of theproband and his children, that - his parents). All members of one generation portrayed in one line.

5. For convenience, first draw a communication relating to the line of motherer. A mother and herrelatives are having in the pedigree on the left. The father and the family relatives depicted on theright. Proband and his siblings have a place between the families of his father and mother.

6. Generations are numbered from left numbers down. Members of one generation are numberedfrom left to right Arabic numerals. Thus, everyone in the family tree has its own code (1-5, P-7,etc.).

7. Indicate the age of family members near the symbol.8. Personally surveyed indicate.9. Spouses of relatives of the proband can not portrayed in a large pedigree if they are healthy and

"no effect" on the transmission of the disease.10. You must specify a date of making a pedigree.

Along with the pedigree accounting written application to it, is called the legend of the pedigree. Thelegend include all information that may be useful in analyzing pedigree (nationality, place of birth andaddress, the results of clinical tools, etc.), and the conclusions reached.

Stage 3 - the genealogical analysis. The first question that must be answered by analyzing apedigree, whether the sign has hereditary nature or not, the second question - whether the disease is

Characteristics of pedigrees with different types of inheritance 6

the result of a new mutation or inherited and what type of inheritance of the disease in this family.Knowing the type of inheritance, we can determine the genotype of the parents and to calculate the riskof having the sick child.

Stage 4 - the calculation of genetic rick. Based on analysis of pedigree is possible to determine therange of persons who consider to need medical and genetic counseling. Knowing the type of inheritance,determine the genotypes of family members and expect the magnitude of genetic risk of counselee. Thisallows you to plan a range of preventive measures for prevention of recurrent cases of illness in thefamily.

Fig.2 Procedure of genetic diagnosis

Characteristics of pedigrees withdifferent types of inheritance

AUTOSOMAL DOMINANT INHERITANCEThe pattern of autosomal dominant inheritance is perhaps the easiest type of Mendelian inheritance

to recognize in a pedigree. One dose of the mutant gene, one mutant allele, is all that is required for theexpression of the phenotype. There are three reasons why an individual with an autosomal dominantdisease should always be considered as being a heterozygote until proven otherwise:

1. 1. The disease is usually rare, with only about 1/10,000 individuals affected as an order ofmagnitude. To produce a homozygote, two affected heterozygotes would have to mate. This


probability is 1/1,000,000 and then they would have only a 1/4 chance of having a homozygousaffected offspring. Affected individuals are most likely to come from affected by normal matings.The normal parent is homozygous recessive, thus assuring that each product of the mating has atleast one normal gene.

2. 2. In the extremely rare instances where two affected individuals have mated, the homozygousaffected individuals usually are so severely affected they are not compatible with life. Theexceptions are the autosomal dominant diseases caused by the somatic expansion oftrinucleotide repeat sequences (e.g., Huntington's disease) that we will study later.

3. 3. The mating of very closely related individuals, the most likely way for two affected individuals toknow each other, is forbidden in our society.

With the understanding that almost all affected individuals are heterozygotes, and that in most matingsinvolving a person with an autosomal dominant trait the other partner will be homozygous normal, thereare four hallmarks of autosomal dominant inheritance.

Except for new mutations, which are rare in nature and extremely rare on examination pedigrees,and the complexities of incomplete penetrance to be discussed later, every affected individual hasan affected biological parent. There is no skipping of generations.Males and females have an equally likely chance of inheriting the mutant allele and being affected.The recurrence risk of each child of an affected parent is 1/2.Normal siblings of affected individuals do not transmit the trait to their offspring.The defective product of the gene is usually a structural protein, not an enzyme.

Fig.3. Autosomal dominant type of inheritance

The most widespread autosomal dominant diseases:

Neurofibromatosis of the 1 and 2 typesMarfan’s syndromeElerrs – Danlos’AchondroplasiaOsteogenesis imperfecta congenitalMyotonic dystrophyHuntington’s hereditary chorea etc.

AUTOSOMAL RECESSIVE INHERITANCEThe most important, thing to remember about autosomal recessive inheritance is that most, if not all,

affected individuals have parents with normal phenotypes.There are five hallmarks of autosomal recessive inheritance:


1. Males and females are equally likely to be affected.2. On average, the recurrence risk to the unborn sibling of an affected individual is 1/4.3. The trait is characteristically found in siblings, not parents of affected or the offspring of affected.4. Parents of affected children may be related. The rarer the trait in the general population, the more

likely a consanguineous mating is involved.5. The trait may appear as an isolated (sporadic) event in small sibships.

Fig.4. Autosomal recessive type of inheritance

The most frequent diseases, which are inherited autosome recessive:

MucovicedosisPhenylketonuriaGalactosemiahepatolenticular degeneration (Wilson disease)adrenogenital syndromemucopolysacchandosises

X-LINKED DOMINANT INHERITANCEWhen an X-linked gene is said to express dominant inheritance, it means that a single dose of the

mutant allele will affect the phenotype of the female. A recessive X-linked gene requires two doses of themutant allele to affect the female phenotype. The following are the hallmarks of X-linked dominantinheritance:

1. The trait is never passed from father to son.2. All daughters of an affected male and a normal female are affected. All sons of an affected male

and a normal female are normal.3. Matings of affected females and normal males produce 1/2 the sons affected and 1/2 the

daughters affected.4. Males are usually more severely affected than females. The trait may be lethal in males.5. In the general population, females are more likely to be affected than males, even if the disease is

not lethal in males.

Sample


Fig.5. X-linked dominant type of inheritance

The most frequent diseases which are inherited X-linked dominant:

Vitamin D-resistant ricketsFocal skin hypoplasiaIncontinentia pigmenti (Bloch – Sulzberger syndrome).Orofaciodigital syndromeHypophosphatemia

X-LINKED RECESSIVE INHERITANCEEveryone has heard of some X-linked recessive disease even though they are, in general, rare.

Hemophilia, Duchenne muscular dystrophy, Becker muscular dystrophy, and Lesch-Nyhan syndrome arerelatively rare in most populations, but because of advances in molecular genetics they receive attentionin the media. More common traits, such as glucose-6-phosphate dehydrogenase deficience or colorblindness, may occur frequently enough in some populations to produce a few affected females.However, their effect on individuals is rarely life threatening and medical intervention is not needed.Pedigree 7 shows one typical inheritance pattern for a rare X-linked recessive disease.

The hallmarks of X-linked recessive inheritance.

1. As with any X-linked trait, the disease is never passed from father to son.2. Males are much more likely to be affected than females. If affected males cannot reproduce, only

males will be affected.3. All affected males in a family are related through their mothers.4. Trait or disease is typically passed from an affected grandfather, through his carrier daughters, to

half of his grandsons


.Fig.6. X-linked recessive type of inheritance

The most frequent diseases which are inherited X-linked recessive:

Mental retardation with fragile X-chromosomeHaemophiliaDuchenne’s muscular dystrophyLesch-Nyhan syndromeHunter’s syndrome (type II mucopolysaccharidosis)

Y-LINKED INHERITANCE

1. Only boys are ill2. Ill men transmit pathological sign (if fertility is not disturbed) to all sons and don’t transmit to

daughters.

SEX LIMITED INHERITANCESome X-linked recessive diseases, such as Duchenne muscular dystrophy, expression of the disease

phenotype is limited exclusively to males. In some X-linked dominant traits, such as incontinentiapigmenti or orofaciodigital syndrome (OFD 1), expression is limited to females, males do not survive toterm. However, the expression of a disease in only one gender does not necessarily imply that thedisease is X-linked. There are autosomal diseases that are limited to expression in only one sex.Precocious puberty and beard growth are factors expressed only in males. The hereditary form ofprolapsed uterus is expressed only in females. These are called sex limited traits.

MITOCHONDRIAL INHERITANCEThe DNA of mitochondria contains about ten genes involved in oxidative phosphorylation, as well as a

few other genes. This DNA is capable of mutation, so it is not surprising that a few human diseases havebeen found to be associated with mitochondrial inheritance. Leber optic atrophy is a classic example of adisease of mitochondrial DNA. The ovum, originating in the female, has about 100,000 copies ofmitochondrial DNA; the sperm, originating in the male, has fewer than 100 copies, and these areprobably lost at fertilization. Virtually all of ones mitochondria come from his, or her, mother. Affectedfathers produce no affected offspring, while the offspring of affected mothers are all affected. Figure 3below shows the typical mitochondrial inheritance pattern.

Sample


Fig.7. Mitochondrial inheritance


2014 - СумДУ

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