4. Single-Gene Disorders: Inheritance Patterns

Question 1

Pedigrees

Answer 1

Graphical representation of a family tree that uses the standard symbols

1 gen (1^0) - parent and child; sibs - 50% of shared DNA

2 gen (2^0) - grandparent and grandchild, uncle/aunt and nephew/niece; half sibs - 25% DNA shared

3 gen (3^0) first cousins 12.5% DNA shared

Question 2

Sib (sibling)

Answer 2

Brother or sister

Series of brothers and sisters is known as a sibship

Question 3

Proband

Answer 3

First member in a family to be evaluated by a health care provider for pedigree analysis

Question 4

Dominant vs recessive

Answer 4

Dominant: human monogenetic disorder (or trait) is determined by a nuclear gene if it manifests in a heterozygote

Recessive: must have 2 defective alleles to present

Question 5

5 basic Mendelian inheritance patterns

Answer 5

1. Autosomal dominant: 1 mutant allele, heterozygote
2. Autosomal recessive: 2 mutant alleles, homozygous
3. X-linked dominant
4. X-linked recessive
5. Y-linked

Question 6

4 rules of inheritance

Answer 6

1. Dominant conditions: 50% chance each kid gets disease
2. Recessive condition: 25% chance each kid gets disease
3. Carrier status: in recessive diseases only
4. No male to male transmission in X-linked diseases (father gives Y)

Question 7

Autosomal dominant

Answer 7

One abnormal gene copy is required for individual to be affected

Both sexes are affected and may transmit the gene to offspring of ether sex - no sex chromosome relation

When affected person has children with an unaffected person = each child has 50% chance of developing disease

Question 8

Autosomal recessive

Answer 8

Two mutant alleles required (one from each parent) at the disease locus

Person affected can be of either sex and is usually born to unaffected parents (heterozygote - asymptomatic carriers)

The chance that each future child is also affected is 25%

Question 9

Consanguinity

Answer 9

Incest marriages

Couples who have one or more recent ancestors in common

A fracture of many autosomal recessive disorders, especially in rare conditions

Seen in many people with same ethnicity

Question 10

X-linked inheritance

Answer 10

Loss or gain of just one of our 46 chromosomes is lethal except for 45,X (Turner syndrome), trisomy 21 (Down syndrome) - problems with gene dosage

Most of the very few genes on Y chromosome have male specific functions or have equivalent copy on X

Question 11

X-inactivation

Answer 11

Mechanism to compensate for having different numbers of X chromosomes in males and females

Initiated after a cellular mechanism counts the number of X chromosomes in each cell of the early embryo

If the number of X chromosomes is two (or more) all except one is randomly inactivated (only in somatic cells) - induced to form transcriptionally inactive - Barr Body

Question 12

Barr body

Answer 12

Inactive due and condensed X chromosome seen in somatic cells only

Question 13

X-linked Dominant inheritance

Answer 13

Affected individuals can be of either sex and at least One parent is affected

Significantly more affected females than affected males - NO male to male transmission of disorder

affected females typically have a milder (but more variable) expression than affected males

All children born to an affected mother and unaffected father have 50% chance of being affected

Affected father with single X chromosome will consistently have unaffected sons - they do not inherit his defective X but daughters always at risk

Question 14

X-linked recessive

Answer 14

Affected individuals mostly male and affected males are usually born to asymptomatic carrier parents

• male cannot be carrier for X-linked recessive diseases -
• mother has 2 X and normal X will silence defective X

A distinguishing feature is that there is no male-to-male transmission because males pass a Y chromosome to sons

Question 15

Matrilineal inheritance

Answer 15

Tissues that have a high energy requirement - muscle and brain- are primarily affected in mtDNA disorders

Sperm does contribute mtDNA to zygote, but the patrilineal mtDNA is destroyed in early embryo - inheritance occurs exclusively through the mother

Individuals with mitochondrial DNA disorder can be of either sex - affected males do not transmit the conditions to any of their children

Question 16

Forces leading to variation between populations

Answer 16

Purifying (negative) selection - selective removal of alleles that are deleterious (dangerous)

Associative/ non-random mating: humans mate and prefer phenotypes like themselves

Genetic drift: if person is affected by genetic disease is not likely to reproduce

New mutations: causing new disease alleles and causing genes to lose their function

Influx of migrants: if population absorbs a large influx of migrants with different allele frequencies - gene pool changes

Question 17

Non-penetrance/ age-related penetrance

Answer 17

Penetrance- probability that a person who has mutant allele will express the disease phenotype

Dominantly inherited disorder = 100% inheritance (Huntington’s disease)

Some disorder have late age onset - severity of disease increases with age as harmful products slowly build up

Question 18

Locus heterogeneity

Answer 18

Production of identical phenotypes by mutations at two or more different loci/genes

Explains how parents who are both affected with a recessive disorder that has common phenotype produce multiple unaffected children

Different mutations - same disease manifestation

Question 19

Compound heterozygote

Answer 19

Presence of two different mutant alleles at a particular gene locus, one on each chromosome pair

EX: HFE gene - patients who inherit one C282Y mutation from one parent to another H63D mutation from another parent

Type of mutation is different but in the same gene = manifest disease

Question 20

Anticipation

Answer 20

Some disorders show consistent generational differences in phenotype

EX: fragile X mental retardation syndrome, myotonic dystrophy, and Huntington disease

Can be expressed at an earlier age and become increasingly severe with each new generation of affected individuals

Disease manifests earlier and earlier through generations

Question 21

Neurofibromatosis type 1

Answer 21

Autosomal dominant

Increased propensity to develop a variety of beginner and malignant tumors

Caused by mutations in gene nuerofibromin at chromosome location 12q11.2

Neurofibromas - originate from nonmeyelinating Schwann cells - tumor suppressive gene mutation

Scolesis, neurofibromas (tumors), aggregated nodules on eye (lisch nodules)

Question 22

Duchenne muscular dystrophy

Answer 22

X-linked recessive

Caused by mutations in dystrophin gene located on X chromosome

Dystrophin - maintain integrity of muscle membrane protein

Boys with this condition show a progressive degeneration of muscle that leads to weakness - problems with ambulation, then respiration and death (by late teens disease manifests by age 3)

Marked elevation in serum enzyme creating phosphokinase (CPK or CK) - correlate with degree of muscle deterioration