7 - Pedigrees and Linkage Analysis

Question 1

How are genetic disorders classified? Include names of categories.

Answer 1

Based on type of genetic defect causing the phenotype: chromosomal, monogenic (single-gene), and complex (polygenic, multifactorial).

Question 2

What are chromosomal disorders?

Answer 2

Can be associated with aneuploidy (add/loss of chrom), deletions or duplications of chrom material, and translocations of chrom material.

Question 3

How do chromosomal defects occur? What do they result in?

Answer 3

Usually sporadically during gamete formation but can be inherited.

Result in complex phenotypes with multiple abnormalities.

Question 4

How are chromosomal disorders detected?

Answer 4

By modern cytogenetic or microarray techniques.

Often difficult to determine which gene(s) are responsible.

Question 5

What are monogenic disorders? What are ways that they can be inherited? Are they common?

Answer 5

Determined primarily by a single mutant gene.

Can be aut dominant and recessive, X-linked dominant and recessive, Y-linked and mito inheritance.

Relatively rare, ~6-8% among hospitalized children

Question 6

How are monogenic disorders detected? What causes them?

Answer 6

Usually at the molecular level.

Gene mutations that can be identified by genetic testing such as CNV analysis or whole exome sequencing.

Question 7

What are complex disorders caused by?

Answer 7

Mutations at more than one gene locus (polygenic inheritance) or a combination of genetic and environmental factors (multifactorial inheritance).

Question 8

What is the pattern of inheritance of complex disorders? What is the recurrence risk?

Answer 8

There is no pattern of inheritance in pedigrees, but rather show familial clustering (genetic predisposition).

Risk much lower than with single gene disorders.

Question 9

What is the function of pedigree analysis?

Answer 9

Collect info, for purpose of diagnosis, about a disease such as the mode of inheritance.

Used to quantify the risk for developing the disease for family members.

Question 10

What is a medical pedigree?

Answer 10

Graphical representation of family’s genetic interrelationships and health problems.

Usually focuses on specific diagnosis observed on multiple family members.

Question 11

What type of information does a medical pedigree contain?

Answer 11

Information about ethnicity, religious heritage, and country of origin.

Question 12

Monogenic disorders exhibit characteristic patterns of inheritance based on what?

Answer 12

Chromosomal location of the gene and the dominance/recessivity of mutant allele associate with the disease.

Question 13

What are Mendel’s four laws?

Answer 13

Genetic traits are controlled by alleles, that exist in pairs.

Question 14

What is mendel’s second law?

Answer 14

When two unlike hereditary determinants responsible for a single trait are present in a single individual, one is dominant and one is recessive

Question 15

What is mendels third law?

Answer 15

In formation of gametes, the paired hereditary determinants separate (segregate) so that each gamete is equally likely to contain either member of the pair.

Question 16

What is mendel’s fourth law?

Answer 16

During gamete formation, segregating pairs of determinants assort independently of each other.

Question 17

What is the probability of one or the other of two mutually exclusive possibilities A and B?

Answer 17

The sum of their separate probabilities.

A + B

Such that 1/2 + 1/2 = 1.

Question 18

What is the probability of simultaneous realization of two independent possibilities A and B?

Answer 18

The multiplication product of their separate probabilities.

Question 19

What are the common pedigree symbols for man and woman? What does it mean when the shape is filled in?

Answer 19

Male - square
Female - circle

Filled in means that they are affected with the disease.

Question 20

What does a double line between two people on a pedigree mean?

Answer 20

Consanguinity - an incestual relationship.

Question 21

What are typical features of an autosomal dominant pedigree?

Answer 21

Each affected individual has an affected parent.

Normal children of affected individual will have normal offspring.

Male and female offspring affectedness is the same.

Each generation has an affected individual.

Question 22

What are typical features of an autosomal-recessive pedigree?

Answer 22

Parent carriers are normal, and have a .25 chance of having an affected child, .50 for a heterozygote, and .25 for a non-carrier.

The less freq the mutant allele, the stronger likelihood the child is a product of a consanguineous marriage.

Question 23

What are typical features of an X-linked dominant pedigree?

Answer 23

The disease is never passed from father to son.

All daughters of an affected male and normal female are affected.

Question 24

For an X-linked disease in which the mother is affected and the father is normal, what are the chances that a boy or girl child has for being affected? How does severity differ?

Answer 24

1/2 of the sons will be affected

1/2 of the daughters are affected

Females more likely to be affected than males from X linked dominant disease, but males are sometimes more severely impacted.

Question 25

What are the typical features of an X-linked recessive pedigree?

Answer 25

1. Disease never passed from father to son. 2. All affected males daughters will be unaffected carriers. 3. Disease passed from affected grandfather, through his carrier daughters, to 1/2 of his grandsons. (more likely in males) 4. All affected males in a family are related through their mothers.

Question 26

When can females get an X-linked recessive disorder?

Answer 26

When an affected male marries a carrier female.

Question 27

What are the typical features of a Y-linked pedigree?

Answer 27

Disease only observed in males, and follows inheritance of Y chromosome (if a male has the disease, then so does his father and grandfather, and so will his sons).

Question 28

What are the features on a pedigree of a disease with mitochondrial inheritance?

Answer 28

Affected fathers produce no affected offspring, while offspring of affected mothers are all affected. Disease caused by mutations in mitoDNA that's maternally inherited.

Question 29

What is variable expressivity?

Answer 29

Variations in clinical presentation (type and/severity) of a genetic disorder between individuals carrying the same disease-associated genotype. (everyone is affected, but to varying degrees).

Question 30

What is incomplete penetrance?

Answer 30

When a person with a disease-associated genotype does not exhibit any clinical symptoms of that disorder.

Question 31

What is genetic anticipation?

Answer 31

When members of a pedigree exhibit progressively earlier age of onset and an increased severity of the disorder in each successive generation.

Question 32

What is genomic imprinting? What is maternal imprinting?

Answer 32

Epigenetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. When the allele of a gene inherited from the mom is transcriptionally silent and the paternally inherited allele is active.

Question 33

For genomic imprinting, what does the phenotype of the offspring depend on? How does this differ from X-linked inheritance?

Answer 33

Which parent transmits the mutated allele. It is the sex of the parent that transmits the allele that is most important, not the sex of the offspring.

Question 34

What is mosaicism?

Answer 34

Pathogenic mutation originated as a somatic mutation during embryogenesis of one of the parents or the affected child. Two cells types present, one normal and one with mutant allele. Can be somatic or germline/gonadal mosaicism.

Question 35

How does a mosaic individual get affected by a disease? What is the risk for the offspring of a mosaic individual?

Answer 35

They may be unaffected, depending on the proportion/type of cels carrying the mutation. Risk for offspring may be the same as from an affected parent (if germline is involved).

Question 36

What are de novo mutations? What is the risk of future offspring being affected?

Answer 36

Pathogenic mutations originating spontaneously in parental gamete. Risk for future offspring is the same as the risk of having a new mutation occur again.

Question 37

What are late onset phenotypes?

Answer 37

Pathogenic mutation that results in a phenotype that's expressed later in life, often beyond reproductive years.

Question 38

What is genetic locus heterogeneity?

Answer 38

Existence of multiple genes which, when mutated, could cause the same phenotype.

Question 39

How can population characteristics influence the frequency of a mutant allele (as seen in common recessive alleles/isolates)?

Answer 39

Cultural/geographical isolation Founder effect Increased risk of recessive disorders: pedigree resembles dominant Ashkenazi Jewish Pop

Question 40

What are some modern genetic screening approaches?

Answer 40

1. Single gene/region assays: targeted sanger sequencing or CN analysis. 2. Multigene next gen sequencing 3. Whole genome CNV analysis 4. Whole exome/genome sequencing analysis

Question 41

What are the benefits of genetic testing?

Answer 41

Positive result can provide definitive diagnose and direct people towards specific disease monitoring and treatment. Helps determine risk for passing the disease on to his/her children. Negative result can eliminate need for procedures and provide sense of relief.