Patterns Of Inheritance

Front 1

In a pedigree, what are the standard symbols for male, female, unknown sex, pregnancy, adopted, deceased, affected, X-linked carrier, consanguineous union, sibship, infertility, divorced/separated, miscarriage (unaffected), miscarriage (affected), termination of pregnancy (unaffected and affected), dizygotic twins, monozygotic twins, proband, no children?

Back 1

Here

Front 2

What is the definition of genotype? Phenotype? Penetrance?

Back 2

Genotype: Genetic composition at a given location (allele) in the genome.

Phenotype: Observable expression of a genotype (morphological, clinical, biochemical)

Penetrance: Probability that an individual carrying a specific genotype will express the phenotype. May be complete (100%, like sickle cell) or incomplete (<100%)

Front 3

What are some reasons for reduced penetrance:

Back 3

1.) Developmental Processes -- Other factors (like environmental, other genes required, exposure, sequence of events) beyond genetic change is required to cause phenotype (Ex: holoprosencephaly)
2.) Time related – Findings have an onset in older age (ex: Huntington disease, colon cancer)
3.) Sex limited – ex: male pattern baldness

Front 4

What is expressivity? Why does it vary?

Back 4

Expressivity is the degree to which the phenotype is apparent (i.e. SEVERITY of the disease) Thus – even if the penetrance is 100%, the severity of the phenotype is not the same in every individual. (Ex: Down’s syndrome → may or may not have heart disease, varying levels of mental retardation per individual.)

Reasons for variance:
“Intrafamilial variability” → modifier genes, environment, stochastic (non-deterministic – “a state does not determine the next state”)

“Interfamilial variability” → all of the above, plus allelic and locus heterogeneity → the mutation itself falls on a spectrum. May be milder in some cases, while other mutations lead to complete loss of function.

Front 5

What is Allelic Heterogeneity? What is locus heterogeneity? Give examples of each

Back 5

Allelic: Different mutations at the same locus. (leading to similar pattern of traits, though possibly with different severities)
**(EX: Hbb S (Glu6Val) = classic sickle cell disease; Hbb C (Glu6Lys) = less severe sickle cell disease)

Locus: Mutations at different loci leading to the same (or similar) phenotype.
**(EX: BRCA1 & BRCA2 genes → different alleles, same result)

Front 6

What is phenotypic heterogeneity? Give an example.

Back 6

Mutations in one gene can cause different phenotypes.

Ex: Different mutations in same gene for RET (Receptory Tyrosine Kinase) can cause both 1.) Hirschsprung disease (no parasympathetic innervation to distal colon) or 2.) Multiple Endocrine Neoplasia 2 (Endocrine tumors).

Front 7

What is pleiotropy? Give an example.

Back 7

A single abnormal gene produces diverse phenotypic effects (especially in multiple organ systems). (SYNDROMIC)

EX: Marfan syndrome affects the eye, bone, heart, etc.
Also, Down Syndrome.

Front 8

What are the 5 modes of inheritance?

Back 8

Autosomal recessive
Autosomal dominant
X linked
Mitochondrial inheritance
Multifactorial

Front 9

What are some characteristics associated with an autosomal dominant inheritance?

Back 9

*Affected person usually has at least one affected parent.
*Affects both sexes equally (unless it’s a sex-linked phenotype like baldness)
*Transmitted by either sex
*Child of an affected parent has a 50% risk of inheriting the disease.

Front 10

What are examples of exceptions to the rules of autosomal dominant transmission? (i.e. reasons for not seeing same phenotype in multiple generations)

Back 10

*It’s a new mutation (ex: lethal autosomal dominant)
*It has low penetrance
*Expressivity is variable
*Germline mosaicism (in this case, you may see affected children with unaffected parents)

Front 11

Lethal autosomal dominant conditions are usually _______ mutations.

Back 11

De novo (NEW!!!!) → so you won’t see population differences in these.

Front 12

In X-linked disorders, there cannot be _____ to ______ transmission. Why?

Back 12

Male-to-male
Because fathers always contribute the Y chromosome to their sons.

Front 13

What are the characteristics of autosomal recessive traits?

Back 13

*Affected individuals usually born to unaffected parents.
*Affects either sex.
*Observed more frequently with consanguinity
*25% risk of having an affected child if both parents are carriers

“Out of the blue” mutations are often autosomal recessive.

1:2:1 ratio (normal : carrier : affected)

Front 14

Almost all inborn errors of metabolism are _______ inherited. Why?

Back 14

Autosomally recessively.

Having 50% of the enzymatic activity is usually OK to get by (there’s usually excess of enzymes)

Front 15

What is X linked recessive. Which sex is more affected and why?

Back 15

Carried on sex chromosome (instead of autosome).

Men are more affected b/c they only have one X chromosome, so they’re “flying more
unprotected”

Front 16

What types of disorders are observed more frequently with consanguinity?

Back 16

Recessive

Front 17

What are the characteristics of X-linked Recessive Inheritance?

Back 17

*Usually affects males
*Affected males usually born to unaffected parents
*May be other affected male relatives on the MATERNAL side of the family
*No male-to-male transmission

Front 18

When might a female show signs of an X-linked recessive disorder?

Back 18

1.) Unfavorable lyonization. (Lyonization is the silencing of one of the female X chromosomes → a.k.a. “X-inactivation”) This is so that females have the same amount of X gene products as males. The process is random, so if by CHANCE the female is a carrier for an X-linked disorder and the bulk of the good X genes get turned off, a female could show signs of the disorder.
2.) Homozygous for the mutation → both mother and father transmit a mutated X. Especially true for common traits (ex: red-green color blindness)
3.) Uniparental Isodisomy → inherit both Xs from your mother. (Rare)
4.) Chromosomal abnormalities → i.e. 45X or 46 XY females

Front 19

What is lyonization? What is uniparental isodisomy?

Back 19

Lyonization → X-inactivation. Happens in females to silence X genes to have the same amount of gene product as males.

Uniparental isodisomy → females inherit BOTH X’s from mother.

Front 20

What are some differences between X linked dominant and X linked recessive? What would you see on a pedigree for a LETHAL X-linked dominant condition? How does X linked dominant differ from autosomal dominant?

Back 20

Heterozygous females CAN be affected in XLD. Males are often more affected, but not always. Some XLD are MALE LETHAL → so on the pedigree you’ll see no affected males, a female to male progeny ratio of 2:1 overall (i.e. there is a paucity of males), and an increased incidence of miscarriages and infertility.

Difference between X linked dominant and autosomal dominant: Still no male-to-male transmission in X linked dominant, but there is in autosomal dominant.

Front 21

What is incontinentia pigmenti? What kind of inheritance has taken place? Why do the children affected look the way they do?

Back 21

This is a lethal X-linked dominant disorder. Since this is lethal in males, you’ll only ever see heterozygous females with a mosaic patern = “Zebra skin.” The females who have this have stripes of hyperpigmented skin – the stripes are a result of the X-inactivation process (think calico cat).

Front 22

What are the characteristics of mitochondrial inheritance? What can be done as a preventative measure?

Back 22

*Inherited ONLY from the MATERNAL line.
*Both Males and Females may be affected
*Huge VARIABILITY IN EXPRESSION: Phenotype dependent on % abnormal mitochondria per cell (heteroplasmy) & energy requirement of the cell
*Can affect any organ (CNS, heart, GI, any combination)

Embryos can be synthesized with genetic material from two mothers. Currently being done in the U.K. “Pronuclear Transfer” → get rid of bad mitochondria from an egg and use good mitochondria from an egg donor.