Mendelian Inheritance II Flashcards
what is hemizygosity?
having only one member of a chromosome pair or segment, rather than 2 (males are homozygous for the X chromosome)
describe X-linked recessive d/o (5)
- single mutant allele for males and two mutant alleles for females needed to cause disease
- never passed father to son
- incidence of trait higher in males
- males more severely effected
- affected man will transmit to all of his daughters
when will females be affected by x-linked recessive d/o?
1- homozygous female- 45,X (turner syndrome)
2- translocation of X and autosome with preferential inactivation of the normal x (only express mutant X)
3- skewed x inactivation- mutant X expressed more
4- females are homozygous for the mutation (two affected Xs)
discuss male-male inheritance of X-linked d/o?
father will not pass on to son bc he gives son Y, not X
why is the phenotype for x linked recessive more severe for males than females?
due to hemizygosity of the X in males, the mutant allele is fully expressed
what is X inactivation?
only one of the X chromosome’s genes are expressed in each cell so that males an females express the same dosage of X-linked genes
describe x-linked dominant d/o
lethal in the homozygous state (no affected males)
what are the recurrence risks for an affected mother with an X-linked dominant d/o?
33% unaffected daughter
33% affected daughter
33% unaffected son
affected son will to survive
what are examples of X linked dominant d/o?
goltz syndrome- usually de novo
incontinentia pigmenti- inherited or de novo
rhett syndrome
what is a trinucleotide repeat d/o?
described by the expansion (within affected gene) of a segment of DNA that contains a 3 nt repeat
what is “expansion”?
increase in the number of repeats that is passed to subsequent generations, eventually leading to expression of the d/o
what d/o was trinucleotide repeat first discovered?
fragile X syndrome
what is repeat size in trinucleotide repeat d/o?
of repeats, allows for range of phenotype from mild to severe
what is anticipation in trinucleotide repeat d/o?
the occurrence of a disease at an earlier age of onset or with increasing severity in successive generations, basis for anticipation is expansion of the repeats
what are 4 common trinucleotide repeat d/o?
Huntington’s disease
fragile X
Myotonic dystrophy
Friedrich ataxia
what are “long expansions” in trinucleotide repeat d/o?
repeat usually more than 10x normal size, present outside the coding region, CCG/CGG or CTG, assoc with fragile sites in some cases
examples of long expansion trinucleotide repeat d/o
fragile X, FXTAS, FRAXE, myotonic dystrophy, spinocerebellar ataxia type 8
what is the age of onset of myotonic dystrophy type 1?
20-40
what are the sx of myotonic dystrophy type 1?
muscular weakness, wasting, cardiac arrhythmia, cataracts, male balding/infertility
what is the inheritance pattern for myotonic dystrophy type 1?
autosomal dominant
when is anticipation a factor with myotonic dystrophy type 1??
when it is inherited from the mother
10% risk of congenital myotonic dystrophy type 1
what gene is affected in myotonic dystrophy type 1?
19q13, myotonin protein kinase
what/where is the repeat in myotonic dystrophy type 1?
CTG, 3’-UTR
what are the normal/asymptomatic/affected/congenital repeat ranges for myotonic dystrophy type 1?
normal- 5-35
asymptomatic- 35-49 *risk for expansion
affected- over 50
congenital- large # (1000s)
what are the phenotypic features of myotonic dystrophy type 1?
hypotonia, tented mouth, absent suck/swallow, dev delay, club feet
what gene is affected in fragile X syndrome?
FMR1 on X chromosome
what is the repeat in FXS?
CGG with AGG interrupting at every 9-10 repeats
what is the purpose of AGG repeats?
anchor sequences that protect against expansion
what will increase the risk for instability of maternal alleles and expansion with FXS?
uninterrupted CGG repeats beyond the last AGG triplet, greater than 33-39
what causes the FXS phenotype?
loss of protein product
what is the consequence of methylation of CGG expansion?
results in decreased or absent FMR1 transcription and loss of protein
when does expansion of FXS repeats occur?
oogenesis
what are the repeat ranges for FXS?
normal/intermediate/premutation/ full mutation
normal- 5-44
intermediate- 45-54
premutation- 55-200
full mutation- over 200
what is the phenotype of someone with intermediate # of repeats in FXS?
learning/behavioral problems
what is the phenotype of someone with premutation # of repeats in FXS?
increased risk of FXTAS, POF
possible subtle intellectual problems- social anxiety, learning d/o
what are some implications for women with premutation # of repeats in FXS?
increased risk for having children with FXS due to repeat instability, also increased risk of POF and may also develop tremor and ataxia
what is the phenotype of someone with full mutation # of repeats in FXS?
mental retardation, characteristic physical features (long face, big head, joint laxity, large testes), possibly autism
what is FXTAS?
fragile X assoc tremor/ataxia syndrome
occurs in males with FXS pre-mutation
late-onset/progressive cerebellar ataxia and intention tremor
what is POF?
premature ovarian failure
who will males with FXTAS transmit their pre-muations to?
all daughters, no sons
what is the penetrance of FXTAS?
age related, increases with age
what is the phenotype of a female with full mutation in FXS?
mental retardation, although can be mild secondary to lyonization
what are “short expansions” in trinucleotide repeat d/o?
less than 100 copies
repeats present in protein coding region
CAG sequence forms polyglutamine tracts = gain of function
2 examples of “short expansions” trinucleotide repeat d/o?
Huntington’s disease
Friedrich ataxia
what inheritance pattern is Huntington’s disease?
autosomal dominant
what is the basis for age of onset with Huntington’s disease?
35-44 years, based on size of repeats
what are the trinucleotide repeat ranges in Huntington’s disease? normal/risk for expansion/affected
normal- under 26
risk for expansion- 27-35
affected- over 36
when is there an increased risk of expansion in huntington’s disease?
if inherited from the father
what is Friedreich ataxia?
characterized by slowly progressive ataxia with average onset between ages 10-15 and usually before 25
sx of Friedreich ataxia?
dysarthria, mm weakness, spasticity in lower limbs, scoliosis, bladder dysfunction, absent limb reflexes, loss of position/vibratory sense
what is the inheritance pattern of Friedreich’s ataxia?
autosomal recessive
what/where is the repeat?
GAA in intron 1 of FXN
what are the repeat number in Friedreich’s ataxia?
normal/pre-mutation/borderline/full
normal- 5-33
Pre-mutation- 34-65
borderline- 44-66
full disease- 66-1700
what is “non-penetrance”?
the expected disease state is not expressed
