Ch. 54-Basic Genetics Principles Flashcards
What is the difference between monogenic, polygenic and complex diseases
Mono=single gene causing disease
Poly=multiple genes
Complex=genes + environment
What is allelic heterogeneity vs. locus heterogeneity and an example of both
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
What is penetrance
Applies to AD condiutions
Percentage of people with gene mutation/alteration that express the condition in any way
What is expressivity
Applies to AD
Degree of phenotypic expression for given gene defect
AR: describe risk of transmission, if parents have it, sex differences, risk factors
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
AD: describe risk of transmission, if parents have it, sex differences, risk factors
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
X-recessive: describe mode and risk of transmission, if parents have it, sex differences
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)
X-linked dominant: pattern transmission
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
Name 4 conditions that are AD
EB simplex
Darier
Hailey–Hailey diseases
nail–patella syndrome.
Describe pedigree of AD
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)
Give an example of an AD condition heterozygous vs homozygous
Almost never homo since often lethal
KRT14 heterozygosity= EB simplex localizd
KRT14 homo= EB simplex generalized
What are 2 exceptions of AD pattern inheritance
Incomplete penetrance
Variable expressivity
What 2 ways can a mutation give rise to a dominant phenotype
- Haploinsufficiency
the protein produced from one wild-type (non-mutant) allele is not sufficient to sustain normal function - 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).
What is a compound heterozygote? What mode mendelian transmission does it apply?
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)
What sex are x-linked recessive patients
Males typically
In X-linked recessive are the parents affected? What is a caveat to this?
No
Females may express some due to mosaicism though
Give one example AR genodermatosis
Oculocutaneous albinism type 1
Give one example of X-linked recessive genoderm
X-linked ichtyosis, hypohidrotic ectodermal dysplasia, congenital generalized hypertrichosis
What is on exception to the no “male-male transmission” in XLR transmittion?
Affected male + female carrier
Risk of transmission to offspring with female carrier of X-linked recessive
1 in 2 daughters will be carriers
1 in 2 sons will have full disease
Risk transmssion in X-linked recessive if Father affected and mother non affected
Males-no disease
Daughters-100% carriers
What is lyonization
Random epigenetic inactivation of 1 of 2 x chromosomes in each cell
What pattern of cutaneous lesions is often seen in X-linked dominant genoderms in females and why?
Mosaicism
Lyonization causes X-linked inactivation resulting in the dominant gene causing disease being inactivated.
Who has milder disease in X-linked dominant conditions?
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
Name 2 X-linked dominant conditions that display mosaic pattern skin findigns
Incontinentia pigmenti
Goltz=focal dermal hypoplasia
What is genetic anticipation?
Tendency of certain traits (often NM diseases) to increase in severity in succesive generations
- A form of variable expression
Give 2 examples where variable expression occurs in Dermatology ?
NF-1
Dariers
In a pedigree, how does reduced/incomplelete penetrance present?
In AD conditions, may appear to skip a generation
How does incomplete penetrance present present in pedigree of AD?
May appear to skip a generation
What is age dependent pentrance and give 2 examples in derm where this applies
In some diseases, may not be old enough to express manifestations
Darier
Hailey-Hailey
What is skeweed/non random x-inactivation
NEgative selection against cells with mutant allele (favors wild type allele selection)
Compare female phenotypic expression in X-linked dominant vs. X-linked recessive conditions
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
Give 2 examples of genoderms where de novo mutations occur in over 50% of cases
30-50% patients with NF1 are de novo
60% with Tuberous sclerosis
What is genomic mosaicism? At what point does mutation occur in embryogenesis?
POST ZYGOTIC mutation, resulting in genetically heterogenous organism
What is somatic mosaicism
Post zygotic mutation that does not occur in gonadal cells and thus cannot be transmitted to offspring
What is gonadal mosaicism
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
What is type 1 mosaicism. Contrast with type 2 mosaicism? (In AD disorders) Give example of both
*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
Loss of heterozygosity in AD tumor predisposition syndromes—> what is the concern in these patients
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
