Variability in Mendelian Genetics Flashcards
variability
often refers to the expression range in phenotypes
variation
refers to the different genotypes associated with same or different phenotypes
etiologic heterogeneity
similar phenotype caused by different underlying causes (one environmental and one genetic)
example of etiologic heterogeneity (phenocopies)
thalidomide embryopathy (environmental) and Roberts syndrome (AD); causes odd limb formation
genetic heterogeneity
same or similar phenotype having different genetic cause; disease can be multifactorial, mitochondrial, chromosomal, or epigenetic but produce similar phenotypes
example of genetic heterogeneity (genocopies)
isolated human growth hormone deficiency (AR) and familial short stature (multifactorial)
locus heterogeneity
for the same kind of inheritance (i.e. mendelian), different genes cause the same basic phenotype; variations in the same basic phenotype from different genes on one locus
example of locus heterogeneity
retinitis pigmentosa - RP9 gene and RP1 gene
allelic heterogeneity
mutations at different sites in same gene may cause different disease severity in different people (variable expression)
example of allelic heterogeneity
cystic fibrosis (AR)
clinical heterogeneity
mutations at different sites in same genes cause different diseases
example of clinical heterogeneity
mutations in the FGFR3 can cause achondroplasia, hypochondroplasia, muenke, crouzon, and others
What occurs the variable expression in CF, an AR disease?
first, the number of mutations possible (each one with different effect) and second, how the two diseased alleles come together (can be compound heterozygotes with two different mutations at each allele or homozygous) and third, environmental effects and modifier genes
examples of modifying genes in CF
TGFB1 for tissue fibrosis and MBL2 for microbe elimination
How does variable expression occur in autosomal dominant disorders?
largely unknown, suspected modifier genes (definitely not allelic heterogeneity)
example of variable expressed AD disease
neurofibromatosis type 1
incontinentia pigmenti
caused by mutation in IKBKG gene on X chromosome; fatal to males before birth but females will have inflammation, blistering, and hyperpigmentation
achrondroplasia mating
can cause lethality because 1/4 of children will get the AA phenotype (lethal)
autosomal dominant adult polycystic kidney disease
two hit mechanism; ADPKD1 occurs earlier and is more severe while ADPKD2 occurs late in life and not severe
digenic inheritance
mutations at 2 separate loci cause one disease
linked genes in digenic inheritance
will display an AD characteristic inheritance
unlinked genes in digenic inheritance
will display an AR characteristic inheritance
sex-limited traits
disease will only occur in one sex, with no effect in the other
example of sex-limited traits
male limited precocious puberty (AD) that constitutively activates LH
sex-influenced traits
traits that will preferentially be expressed in one sex
example of sex-influenced trait
pattern baldness (androgenic alopecia)
skewed X-inactivation
if maternal copies are more active than they should be, a female child can develop symptoms of an XLR disorder (Duchenne muscular dystrophy)
What explains having two children with a new mutation AD disease?
gonadal mosaicism
gonadal mosaicism
normal germ cell lines and mutation germ cell lines both exist in the gonad and are passed on to child
How do CNVs occur?
non-allelic homologous recombination
dynamic mutations
mostly tri-nucleotide repeats that expand into regulatory/structural region of gene and affect transcription
pedigree of dynamic mutations
can look like AD or XLD but with reduced penetrance
Huntington disease repeat expansions occur primarily with _
paternal transmission
Fragile X expansion is primarily through _
maternal transmission
myotonic dystrophy type 1
CTG repeat in DMPK gene causes mutated mRNA that will associate with splicing proteins, preventing them from carrying out proper function
DM1 phenotype
the more repeats, the more severe the phenotype
How does mitochondrial inheritance differ from Mendelian>
males can not transmit DNA to offspring and replicative segregation in mitosis (random assortment)
expression of mtDNA mutations depends on _
- abundance of mutant mtDNAs
- threshold effect –> more mutant than normal
- tissue distribution –> which tissues have the abundant mutant mtDNA (each organ varies in threshold requirement)
