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Lecture 47: Genetics I (Chromosomal Abnormalities), Screen Shot 2020-09-14…
Lecture 47: Genetics I (Chromosomal Abnormalities)
PLOIDY
Polyploidy
Triploidy
(69 chrom)
1: 10,000 births
Die shortly after birth
Dispermy
Incidence of Spont. Abortions:
15%
Tetraploidy
Rare at conception
5%
spontaneous abortion
Aneuploidy
Monosomy
missing chromosome
Autosomal
- incompatible w/life!
Trisomy
Viable Autosomal Trisomy Syndromes
Trisomy 13
(
Patau syndrome)
80% full trisomy
1:
16K-20K births
5% survival (1st yr)
Hypotonia
Orofacial clefs
Extra finger/toes
Microcephaly
Microphthalmia
Central N.S. defects
90%- cardiac defects
Trisomy 18
(
Edwards syndrome)
1:
6,000
births
5% survive to term
5-8% live past 1 year
Overlapping fingers
Rocker-bottom feet
90% VSD (cong. heart defect)
Severe cog impairment
Severe dev delay
Trisomy 21
(
Down syndrome)
1:
800-1K births
Gene Imbalance
(90% from Nondisjunction of
maternal
chrom.)
Hypotonia
30-40% struc heart defects
15-20x inc risk- leukemia
More common- resp infections
Intellectual disability varied
Dysmorphic features
microbrachycephaly w/flat occiput
flat nasal bridge
single palmar crease
wide 1st-2nd toe gap
brachydactyly
upslanting palpebrae
Risk with AGE
(for females, 40+ is <1 in 100)
Nondisjunction
mitosis or meiosis
Meiosis I
50% monosomy
50% trisomy
Meiosis II
50% normal
25% monosomy
25% trisomy
Aneuploidy of
Sex
Chromosomes
Incidence
1: 400 M
1: 650 F
LESS severe than autosomal aneuploidies!
Examples- Sex Chromosome Aneuploidies
Klinefelter (XXY)
1:
500-1K
births
taller,
hypotonia
mild learning diff
30%
gynecomastia
sterile,
hypogonadism
Increased risk for:
Osteoporosis
Breast cancer
Treatment
:
testosterone
(enhance
secondary
sex char)
Condition
under-diagnosed
Turner Syndrome (XO)
1:
500-10K
births
50% (45, X)
30-40% mosaic
10-20% del Xp
60-80% absence
paternal
X
Traits
short stature
webbed neck
infertile
ovarian dysgenesis
LACK secondary sex char
cong. heart defects
normal intelligence
spatial perception dec.
Trisomy X
affects ONLY females
1: 1000
95% maternal X
NO physical abnorm
XYY
Male-extra Y
Few symptoms
Taller stature
Reduced IQ
Inc. incidence- ADD/ADHD
X Chromosome Inactivation
Early embrogenesis
Somatic cells-keep
Barr body
Random!
Not all genes silenced
Need
X inactivation center (Xic)
reg:
XIST gene
(
non-coding RNA)
TRANSLOCATIONS/REARRANGEMENTS
Balanced
Unbalanced (
gain/loss
)
Due to:
unequal crossing over
chromosome breakage
clastogens (radiation, etc.)
Reciprocal
carrier OK
Offspring- maybe issues
Philadelphia chromosome
(b/w chrom 9 & 22)
BCR-ABL1 fusion protein
Commonly found:
CML
ALL
(
kinda of leukemia
Robertsonian
q arms
fuse
p arms
lost
confined to
acrocentric chrom
13, 14, 15, 21, 22
Carrier normal
offspring- signif issues
DELETIONS/
DUPLICATIONS
Most common after aneuploidies!
Cri-du-chat
46,
XY deletion
(
5p
)
1:
15-50K
births
low IQ (~35)
microcephaly
cardiac/neuro/renal malformations
Charcot-Marie-Tooth disease
(
micro
duplication)
PNS condition
(prog atropy of distal limb mm.)
1: 2500 births
small duplication on Chr. 17
Inc.
PMP22 gene
(
myelin component
GENOMIC IMPRINTING
Central dogma
equal allelic exp regardless of parental origin
BUT allelic exp dependent on parental origin
Epigenetic change
DNA methyl at
CPG
islands
Prader-Willi (PWS)
small 4mb deletion 15q11.2-q13
Del in paternal 15q
1: 15K births
short stature
neonatal hypertonia
small hands/ft.
hypogonadism
obesity
mild/mod int disability
dev delay
Angelman (AS)
("happy puppet syndrome"
small 4mb deletion 15q11.2-q13
Del in maternal 15q
1:
15K
births
short stature
seizures
ataxic gate
severe speech imp
small head
severe int dis
dev delay
Beckwith-Wiedmann Syndrome
Clinical Features:
overgrowth-macrosomia
growth asymmetry
organomegaly
inc tumor incidence
Chrom. 11
10-30% uniparental pat disomy
50-60% improper methlyation
Uniparental Disomy
Heterodisomy
2 chrom
different
copies of same chrom
due to
meiosis I error
Isodisomy
both chrom from 1 parent=
identical
meiosis II error
/
post-zygotic duplication of chrom
