Ch. 54-Basic Genetics Principles

Question 1

What is the difference between monogenic, polygenic and complex diseases

Answer 1

Mono=single gene causing disease
Poly=multiple genes
Complex=genes + environment

Question 2

What is allelic heterogeneity vs. locus heterogeneity and an example of both

Answer 2

Allelic=mutations in same gene can cause different disease
e.g Erythrokeratodermia variabilis
AR and AD non-syndromic hearing impairment
AD peripheral sensory neuropathy and hearing impairment
all causes by mutation in GBJ3

Locus= mutations in different genes can cause same gene
E.g. Epidermolytic ichthyosis from KRT1 and KRT10

Question 3

What is penetrance

Answer 3

Applies to AD condiutions

Percentage of people with gene mutation/alteration that express the condition in any way

Question 4

What is expressivity

Answer 4

Applies to AD

Degree of phenotypic expression for given gene defect

Question 5

AR: describe risk of transmission, if parents have it, sex differences, risk factors

Answer 5

Parents: not affected (carriers)
M=F
1 in 4
RF: consanguinity, isolated pop’n

Disease seen in siblings of proband, not in parents or offspring
Usually only in one generation

Question 6

AD: describe risk of transmission, if parents have it, sex differences, risk factors

Answer 6

Parents: yes (unless de novo)-1 carrier all needed
Risk transmission: 50%
M=F
Disease seen in every generation unless reduced penetrance
RF: de novo mutations

Question 7

X-recessive: describe mode and risk of transmission, if parents have it, sex differences

Answer 7

Parents: Mother a carrier (should be not expressed)

Transmission:
Males have the “complete” disease
Female “carriers” may have mild manifestations (e.g. in a mosaic pattern)

No male-to-male transmission (but all daughters of an affected male are “carriers”)

Risk transmission: 1 in 2 male children born to a female “carrier” will be affected (and 1 in 2 of her female children will be carriers)

Question 8

X-linked dominant: pattern transmission

Answer 8

Parents affected
Mostly females, if lethal to male in embryo
Otherwise milder in females (often with a mosaic pattern of skin lesions) and more severe in males

Affected males have:
(1) no affected sons; and (2) all daughters affected

No male-to-male transmission
1 in 2 children born to affected female; may spontaneously abort male fetuses if “male-lethal” condition

Question 9

Name 4 conditions that are AD

Answer 9

EB simplex
Darier
Hailey–Hailey diseases
nail–patella syndrome.

Question 10

Describe pedigree of AD

Answer 10

Other than original person who had de novo, every person affected has affected parent

Equal sexes

Vertical transmission from gen to gen(1 in 2 risk to children)

Question 11

Give an example of an AD condition heterozygous vs homozygous

Answer 11

Almost never homo since often lethal

KRT14 heterozygosity= EB simplex localizd
KRT14 homo= EB simplex generalized

Question 12

What are 2 exceptions of AD pattern inheritance

Answer 12

Incomplete penetrance

Variable expressivity

Question 13

What 2 ways can a mutation give rise to a dominant phenotype

Answer 13

1. Haploinsufficiency
   the protein produced from one wild-type (non-mutant) allele is not sufficient to sustain normal function
2. Dominant negative effect the mutated proteins physically interfere with wild-type proteins and prevent them from functioning properly (often occurs when the mutated protein forms dimers or polymers; examples include keratins (e.g. KRT14 in EB simplex) and tyrosine kinase receptors (e.g. KIT in piebaldism).

Question 14

What is a compound heterozygote? What mode mendelian transmission does it apply?

Answer 14

In AR conditions, Patient has 2 mutant alleles

Two different mutations in the same gene passed onto the offspring, so 2 mutant alleles but different mutations, can also cause disease (i.e not homozygous bit still have disease possibly)

Question 15

What sex are x-linked recessive patients

Answer 15

Males typically

Question 16

In X-linked recessive are the parents affected? What is a caveat to this?

Answer 16

No

Females may express some due to mosaicism though

Question 17

Give one example AR genodermatosis

Answer 17

Oculocutaneous albinism type 1

Question 18

Give one example of X-linked recessive genoderm

Answer 18

X-linked ichtyosis, hypohidrotic ectodermal dysplasia, congenital generalized hypertrichosis

Question 19

What is on exception to the no “male-male transmission” in XLR transmittion?

Answer 19

Affected male + female carrier

Question 20

Risk of transmission to offspring with female carrier of X-linked recessive

Answer 20

1 in 2 daughters will be carriers

1 in 2 sons will have full disease

Question 21

Risk transmssion in X-linked recessive if Father affected and mother non affected

Answer 21

Males-no disease

Daughters-100% carriers

Question 22

What is lyonization

Answer 22

Random epigenetic inactivation of 1 of 2 x chromosomes in each cell

Question 23

What pattern of cutaneous lesions is often seen in X-linked dominant genoderms in females and why?

Answer 23

Mosaicism

Lyonization causes X-linked inactivation resulting in the dominant gene causing disease being inactivated.

Question 24

Who has milder disease in X-linked dominant conditions?

Answer 24

Females due to inactivation (heterozygous in females vs. Homozygous in males)
Can occur in both sexes but often in females since can be lethal in males

Question 25

Name 2 X-linked dominant conditions that display mosaic pattern skin findigns

Answer 25

Incontinentia pigmenti

Goltz=focal dermal hypoplasia

Question 26

What is genetic anticipation?

Answer 26

Tendency of certain traits (often NM diseases) to increase in severity in succesive generations

• A form of variable expression

Question 27

Give 2 examples where variable expression occurs in Dermatology ?

Answer 27

NF-1

Dariers

Question 28

In a pedigree, how does reduced/incomplelete penetrance present?

Answer 28

In AD conditions, may appear to skip a generation

Question 29

How does incomplete penetrance present present in pedigree of AD?

Answer 29

May appear to skip a generation

Question 30

What is age dependent pentrance and give 2 examples in derm where this applies

Answer 30

In some diseases, may not be old enough to express manifestations

Darier
Hailey-Hailey

Question 31

What is skeweed/non random x-inactivation

Answer 31

NEgative selection against cells with mutant allele (favors wild type allele selection)

Question 32

Compare female phenotypic expression in X-linked dominant vs. X-linked recessive conditions

Answer 32

In general, X-L dominant traits are milder in females than in males, and female “carriers” of X-L “recessive” conditions can exhibit some symptoms

Question 33

Give 2 examples of genoderms where de novo mutations occur in over 50% of cases

Answer 33

30-50% patients with NF1 are de novo

60% with Tuberous sclerosis

Question 34

What is genomic mosaicism? At what point does mutation occur in embryogenesis?

Answer 34

POST ZYGOTIC mutation, resulting in genetically heterogenous organism

Question 35

What is somatic mosaicism

Answer 35

Post zygotic mutation that does not occur in gonadal cells and thus cannot be transmitted to offspring

Question 36

What is gonadal mosaicism

Answer 36

Post zygotic mutation that occurs in gonadal cells (sperm or ova) and can therefore be passed on to offspring.

Parents may be unaffected or mosaic, but kids will be generalized in AD condition

Question 37

What is type 1 mosaicism. Contrast with type 2 mosaicism? (In AD disorders) Give example of both

Answer 37

*Cutaneous mosaicism can result in skin changes along lines of blaschko or in other segemental patterns

Type 1: Segmental affected skin is HETEROZYGOUS for a dominant mutation, with wild type unaffected background
—> Epidermal nevi, Linear Dariers
*Counselling—> gonadal mosaicism could result in more generalized disease in offspring

Type 2: Genetic background is heterozygous for mutation that causes AD disorder, then a post-zygotic mutation in the other allele (second hot, loss of heterozygosity) leads to region of skin with 2 mutations and more SEVERE disease
—> Linear porokeratosis superimposed on superficial actinic porokeratosis, Hailey-Hailey in setting of milder classic symmetric disease

Question 38

Loss of heterozygosity in AD tumor predisposition syndromes—> what is the concern in these patients

Answer 38

Affected patients are heterozygous for a loss-of-function mutation in tumor supressor gene—> At risk for tumor formation due to single somatic mutations (second hit) inactivating 2nd nromal allele of same gene
=“loss of heterozygosity” now with 2 mutant alleles

E.g. Gorlins