Block 6 Flashcards
Cytogenetics
The study of chromosomes, their structure, and inheritance
Centromere
Primary constriction of a metaphase chromosome where the kinetochore forms
Acrocentric
Centromere is located at either end of the chromosome
Sub-metacentric
Centromere is located closer to one end of the chromosome than the other
Metacentric
Centromere is located in the middle of the chromosome
Telomeres
Chromosome caps located at both ends of sub or metacentric chromosomes and one end of acrocentric chromosomes
Subtelomeric regions
Gene-rich regions located just above the telomere
Chromosome arm
Region(s) of the chromosome adjacent to the centromere
p arm
Smaller chromosome arm
a arm
Longer chromosome arm
Which tissues can be used for chromosome analysis?
Chromosome analysis requires dividing cells such as lymphocytes from peripheral/cord blood or bone marrow or fibroblasts from solid tissue biopsies, amniotic fluid, or chorionic villi
What is the procedure for chromosome analyses?
Obtain sample, culture and harvest cells, make a band, scan slides for metaphase cells, then analyze, capture, and karyotype the cells
Cytogenetic nomenclature
chromosomes, sex chromosomes, and +/- chromosome if an abnormality is present
Aneuploidy
Having a number of chromosomes not equal to a haploid number
Polyploidy
Having an abnormal number of chromosomes equal to a multiple of the haploid number, ie having an extra set(s) of chromosomes such as triploidy or tretraploidy
How does triploidy happen?
Dispermy or dygyny
Disermy
Fertilization of an egg by 2 sperm
Dygyny
Fertilization of disomic egg (n=46) by 1 normal sperm
Diandry
2 paternally-derived sets of chromosomes that results in a large placenta (often a partial hydatidiform mole) and a small fetus
How does dygyny happen?
Usually from a complete meiosis I or II error or retention of a polar body
Mosaicism
Presence of 2 or more cell lines in an individual or tissue sample
Meiosis in females
Oogonia begin division in week 12 and proceed through prophase I until the diplotene stage (~ week 12) and remain in a stage called dichytene until ovulation
Meiosis I errors
Occur during homolog pairing if both maternal and paternal chromosomes migrate to the same (instead of opposite) poles and then split as per usual; results in 2 disomic gametes and 2 nullisomic gametes (ie there will be 2 or 0 of a certain chromosome in each egg)
Meiosis II errors
Maternal and paternal chromosomes separate as expected but then the sister chromatids fails to separate so you get 1 disomic gamete,1 nullisomic gamete, and 2 normal gametes
Down syndrome
Trisomy 21; most common autosomal trisomy among liveborns
How does trisomy 21 occur?
Most cases are d/t errors in maternal meiosis (MI I more so than MI II) and the remaining result from paternal meiosis errors, mitotic errors (mosaicism), or Robertsonian chromosomal translocation (~5%)
Mosaic down syndrome
Down syndrome w/ the presence of a normal cell line in addition to the trisomy 21 line; the frequency of abnormal cells does not predict the severity of the phenotype
Translocation down syndrome
Functional trisomy 21 d/t presence of an extra portion of chromosome 21 attached to chromosome 14; results from an unbalanced Robertsonian translocation involving chromosome 21
Edward’s syndrome
Trisomy 18 characterized by prominent occiput, heart defects, low-set ears, rocker-bottom feet, and characteristic fist clenching; high infant mortality rate
Patau syndrome
Trisomy 13 characterized by growth retardation, midline defects, micropthalmia, polydactyly; rarer and more severe than trisomy 21 or 18
Turner syndrome
Monosomy X (45,X) is very rare and characterized by short stature, broad chest, cubitus vulgus, short webbed neck, congenital lymphedema of hands and feet, sensory motor integration dysfunction, streak ovaries; some cases involve mosaic or have 1 abnormal X chromosome
Klinefelter syndrome
(47, XXY); relatively common sex chromosome aneuploidy in males causing short stature and long legs, delayed puberty, infertility, small testes, tubular hyanalization, gynecomastia, menetal retardation
(47, XXX) and (47, XYY)
No phenotypic abnormalities or effects no reproductive function because extra X chromosome is inactivated but typically have mental retardation issues
SRY
Sex determining region of the Y chromosome; deleted or mutated in many XY females and often present (d/t Y translocation) in XX males
Robertsonian translocations
Rearrangements involving only acrocentric chromosomes (13, 14, 15, 21, 22) caused by fusion of 2 long arms and loss of 1 short arm (which contain only repetitive DNA and ribosomal sequences); benign since all short arms contain the same thing
Balanced Robertsonian translocations
Involve 2 breakpoints on 2 chromosomes and the swapping of material beyond the breakpoints such that no material is lost or gained, only rearranged
Unbalanced Robertsonian translocations
Involve formation of a quadrivalent during meiosis and gamete formation with the 2 derivative chromosomes and the 2 normal chromosomes aligning as completely as possible, to allow for homologous recombination however when they segregate during the first meiotic division the 2 derivative chromosomes must go to one pole and the 2 normal chromosomes must go to the other for the gametes to be balanced; risk for a translocation to malsegregate is generally a function of the size of the chromosomes and the size of the translocated segments.
Chromosomal deletions
Loss of material from a single chromosome; phenotype is dependent on which portion of the genetic material is lost
Chromosomal inversions
A segment of chromosome breaks and is inverted and inserted back in
Paracentric inversion
Breakpoints occur on the same arm outside of the centromere
Pericentric inversion
Breakpoint region includes the centromere
FISH (fluorescence in situ hybridization)
Technology for IDing chromosomal abnormalities by using fluorescently labeled DNA probes; depending on the probe, can detect specific chromosomal gains, losses, or rearrangements
Locus
Location of a gene on a chromosome
Allele
Different forms of a gene that can occupy a single locus
Wild type
Most common form of a gene
Polymorphism
2 or more alleles for a given locus, each present in the population at a frequency of at least greater than 1%
Compound heterozygote
Genotype w/ 2 different mutant alleles at the same locus; ie alleles are different but both are defective
The Principle of Dominance
Genes come in pairs, one inherited from each parent and individual genes can have different alleles, some of which are expressed over the other
Principle of Segregation
Organisms inherit 2 alleles for each trait and during gamete formation allele pairs separate so that each cell has a single allele for each trait
Principle of Independent Assortment
Genes at different loci are transmitted independently and are randomly united at fertilization
What are the features of A inheritance?
Phenotype is vertically transmitted and equally likely to be transmitted by male or female; each child of an affected parent having a 50% chance of inheriting the trait and phenotypically normal family members do not typically transmit the trait
Incomplete dominance
One allele is not completely dominant and produces an intermediate phenotype; eg achondroplasia
Co-dominance
Both alleles are expressed resulting in a phenotype w. features of both alleles; eg ABO blood groups
Germline mosaicism
2 or more children are born w/ an AD dz when there is no family hx of the dz; theoretically d/t the presence of more than one genetically distinct cell line in the germline of one of the parents
Delayed age of onset
Some genetic conditions do not manifest until later in life eg Huntington dz and breast CA
Penetrance
The probability a gene will be expressed; can be all-or-nothing or reduced/variable penetrance eg HNPCC w/ 80% lifetime risk or split-hand deformity w/ 70% penetrance
Variable expression
Complete penetrance but the severity of the dz varies in people w/ the same genotype
Pleitropy
One gene produces multiple different effects on physiology or anatomy
Locus heterogeneity
A single disorder caused by mutations in genes at different loci eg breast CA
Allelic heterogeneity
A single disorder caused by different mutations in the same gene eg CF
Phenotypic heterogeneity
Different mutations in the same gene giving rise to different phenotypes eg craniosynostosis syndrome
What are the characteristics of autosomal recessive inheritance?
Clinical manifestation is usually only seen in in homozygous individuals and in sibship rather than parents, offspring, or other relatives
X-linked inheritance
Phenotype is determined by genes on the X chromosome; expressed in males bc they only have 1 X chromosome
Hemizygous
Having only one member of a chromosome pair or segment instead of 2
X-linked recessive
A single dose of a mutant allele is dz causing in males and 2 doses is dz causing in females
X-linked dominant
Phenotype is expressed in both males and females but is usually more severe in males
X-inactivation
ie Lyon hypothesis which says that one X chromosome is randomly inactivated
X-linked dominant lethal
X-linked condition that is lethal in the hemizygous state
Trinucleotide repeat dosorders
Repeated trinucleotide sequences w/i an affected gene that get expanded (ie increased number of trinucelotide repeats) as the gene is passed down through the generations leading to expression of the disorder; all involve neurological disorders
Long expansions of trinucleotide repeat disorders)
Repeats are usualy ~10x the normal size and are present outside the coding region or associated w/ fragile sites; contain CCG/CGG or CTG coding sequences and are
Myotonic dystrophy type I (DMI)
AD dz caused by CTG repeat in the 3’ untranslated region of 19q13 myotonin protein kinase characterized by muscle weakness w/ myotonia and muscle wasting, cardiac arrhythmias, cataracts, and male balding and infertility
Congenital DM
1000’s of repeats causing severe hypotonia, myopathic faces w/ tented mouthes, absent suck and swallow, mental retardation, speech delay, and club feet
FMR1-related disorders
Fragile X syndrome, Fragile X-associated tremor/ataxia (FXTAS), FMR1-related premature ovarian failure (POF)
Fragile X syndrome
Results from FMR1 full mutation causing mental retardation in males (less severe in females) and characteristic physical features including long face, macrocephaly, prominent forehead and chin
FMR1 gene
Normally has ~5-44 repeats of CGG w/ an AGG triplet every 9-10 repeats that anchor the sequence against expansion
FMR1 premutation alleles
Have ~50-200 repeats but are not associated w/ mental retardation (but can be at increased risk for FXTAS or POF)
FMR1 premutation alleles in women
Women are at increased risk of having child w/ Fragile X syndrome and may also develop tremors or ataxia
FMR1 premutation alleles in men
Premutation plus white matter lesion on brain MRI give dx of FXTAS; men w/ FXTAS will transmit premutation to all of their daughters an none of their sons
FMR1 full mutation
Greater than 200 repeats; about 50% of females will have mental retardation and all males will have Fragile X syndrome; almost all will have abnormal methylation of FMR1 gene
Short expansions
Characterized by significantly shorter expansions (<100) of repeats w/i protein coding regions; eg CAG sequence forms polyglutamine tracts in the protein product which is a gain if function
Huntington’s dz
Progressive AD neurodegenerative disorder caused by expansion of 36+ CAGs in HTT; onset is 35-44 years w/ mean survival of 15-18 years after dx
Friedreich ataxia
AR dz caused by GAA repeats that is characterized by slowly progressive ataxia w/ dysarthria, scoliosis, bladder dysfunction, absent LL reflexes, and loss of position/vibration senses; onset is 10-15 yrs and usually before age 25
