Download Down syndrome

Prescreening of Genetic
Diseases
(It’s worth & potential)
Dr Pupak Derakhshandeh, PhD
Ass Prof of Medical Science of Tehran University 1
Prescreening for
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Down syndrome and trisomy 13 & 18
Breast cancer (BRCA1 AND BRCA2 GENES)
Colorectal cancer
SMA carrier testing
Factor V Leiden
Cardiovascular risk with C-reactive protein
and Apolipoprotein E
2
Prescreening for Down
syndrome and trisomy
21, 13 & 18
3
Down
Syndrome
(Trisomy 21(
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Down Syndrome (Trisomy 21)
Trisomy 2(
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First trimester screening for Down
syndrome and trisomy 13 & 18
(up to12W)
• The availability and acceptability of early
invasive diagnostic methods (eg, chorionic
villus sampling, CVS)
• The continued need for second trimester
screening for open fetal neural tube
defects
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Women with singleton pregnancies:
first-trimester combined screening
–measurement of Nuchal translucency
–pregnancy-associated plasma protein
A [PAPP-A]
–The free beta subunit of human
chorionic gonadotropin (HCG) at 10
weeks 3 days through 13 weeks 6
days of gestation
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Nuchal translucency screening involves the
measurement by ultrasound of the skin
thickness at the back of the neck of a first
trimester fetus
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Identification about 85-90% of
affected fetuses in the first-trimester
• maternal age was combined with fetal NT
• and maternal serum biochemistry (free βHCG and pregnancy-associated plasma
protein (PAPP-A)
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Second-trimester (13-24W)
quadruple screening
–measurement of:
• alpha-fetoprotein
• total human chorionic gonadotropin
(HCG)
• unconjugated estriol
• inhibin A at 15 through 18 weeks of
gestation
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Maternal serum alphafetoprotein (MSAFP)
• fetus has two major blood proteins:
• albumin and alpha-fetoprotein (AFP)
• Since adults typically have only
albumin in their blood
• the MSAFP test can be utilized to
determine the levels of AFP from the
fetus
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MSAFP
• the gestational age must be known with
certainty
• the amount of MSAFP increases with
gestational age
• Neural tube defect
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Neural tube defect (NTD)
• in the fetus:
• from failure of part of the
embryologic neural tube to close
• there is a means for escape of
more AFP into the amniotic fluid !
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Note!
• the MSAFP can be elevated for a
variety of reasons
• which are not related to fetal neural
tube or abdominal wall defects, so
this test is not 100% specific
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Neural tube defect
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Maternal blood sampling for fetal
blood cells
• This is a new technique
• use of the phenomenon of fetal blood
cells gaining access to maternal
circulation through the placental villi
• only a very small number of fetal cells
enter the maternal circulation in this
fashion
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Prenatal screening and
diagnosis of neural tube defects
• Neural tube defects (NTD): second most
prevalent congenital anomaly in the United
States
• Two factors have played a significant role in
the prevention of this disorder in developed
countries:
– Sonographic imaging combined with
amniocentesis for diagnosis of affected
fetuses
– folic acid supplements for prevention of the18
Anencephaly (failure of closure at
the cranial end of the neural tube)
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Spina bifida (failure of closure at the
caudal end of the neural tube)
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Environmental factors
• The frequency of NTDs is increased with
exposure to certain environmental factors:
– drugs (valproic acid, carbamazepine, Folic acid
deficiency)
– diabetes mellitus
– Obesity
• Adequate folate is critical for cell division due to
its essential role in the synthesis of:
– nucleic
– certain amino acids
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Genetic factors
the observations that NTDs have a high rate:
– in monozygotic twins
– more frequent among first degree relatives
– more common in females than males
• The risk of recurrence for NTDs: approximately 2
to 4 percent when there is one affected sibling
• With two affected siblings, the risk is
approximately: 10 percent
• to be higher in countries such as Ireland
where the prevalence if NTDs is high
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NOTE:
• The genetic polymorphisms :
• mutations in the methylene tetrahydrofolate
reductase gene
• may increase the risk for NTDs
• Folate is a cofactor for this enzyme
• which is part of the pathway of homocysteine
metabolism in cells
• The C677T and the A1298C mutations are
associated with elevated maternal
homocysteine concentrations and an increased
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risk for NTDs in fetuses
Prevention of neural tube defects
• can be accomplished by supplementation
of the maternal diet with only 4 mg of folic
acid per day
• but this vitamin supplement must be taken
a month before conception and through
the first trimester
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Maternal serum beta-HCG
• the beta-HCG can be used in conjunction with
the MSAFP to screen for chromosomal
abnormalities, and Down syndrome in particular
• An elevated beta-HCG coupled with a
decreased MSAFP suggests Down syndrome
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Maternal serum estriol
• made by the fetal adrenal glands
• Estriol tends to be lower when Down
syndrome is present
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Inhibin-A
• An increased level of inhibin-A is
associated with an increased risk for
trisomy 21
• A high inhibin-A may be associated
with a risk for preterm delivery
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Trisomy 21
MSAFP / beta-HCG
estriol / inhibin-A
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overlapping are typical for
trisomy 18
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Prescreening BRCA1 AND BRCA2
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GENES
BRCA1 AND BRCA2 GENES
• Breast cancer develops in about 12 percent of
women who live to age 90
• a positive family history is reported by 15 to 20
percent of women with breast cancer
• They are associated with an inherited gene
mutation
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• Two major susceptibility genes for
breast cancer, BRCA1 and BRCA2
• Testing for mutations in these
genes, is available
• Clinicians and patients must decide
when it is appropriate to screen for
their presence
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BRCA mutations
• The reason why BRCA mutations
predispose mainly to breast and ovarian
cancers is unclear
• intact BRCA1 represents a barrier to
transcriptional activation of the estrogen
receptor
• that functional inactivation could lead to
altered hormonal regulation of mammary
and ovarian epithelial proliferation
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BRCA1 or / and BRCA2 gene
abnormalities
• Cancer risk with a high penetrance
• women who have inherited mutations
• the lifetime risk of breast cancer is
between 65 and 85 percent by age 70
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Ovarian cancer
• Ovarian cancer is also linked to the
presence of BRCA mutations
• the lifetime risk of ovarian cancer:
– between 45 and 50 percent in women who
have a deleterious BRCA1 mutation
– and 15 to 25 percent for those with a BRCA2
mutation
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BRCA2-associated cancers
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prostate cancer
male breast cancer
pancreatic cancer
Although the risk of male breast cancer
and pancreatic cancer may be under 10
percent
• the risk of prostate cancer in BRCA2
carriers may be as high as 35 to 40
percent
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BRCA 1
• The gene Locus for BRCA1:
17q21
• a large gene
• 24 exons
• encoding a 220 kD
• 1863 amino acids
• Two recognizable motifs
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BRCA2
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BRCA2 (13q12.3)
was identified by Wooster et al. in 1995
It encodes for 384 kD nuclear protein
3418 amino acids
BRCA2 bears no homology to any
known tumour supressor genes
• contains 27 exons
• spread over 70 kb of genomic DNA 39
BRCA1 Gene
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BRCA2 Gene
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SSCP
single strand conformation
polymorphism
simplicity
clearly by heteroduplex analysis (HA)
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Pedigree of a selected family
with breast cancer
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SSCP Analysis
BRCA1 Exon 15, 4650delCA
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Pedigree of a selected
family with breast cancer
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SSCP
Analysis
BRCA1, Exon 20,
Nt 5382
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SSCP Analysis
Exon 11pi BRCA1 MS R1347G
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Breast Cancer Families
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Significance of family history
• Degree of relatedness to affected
relatives
• Number of affected relatives
• The age of the relative (s) when
breast cancer occurred
• Whether there is a family history of
ovarian cancer
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Mutations in BRCA1/2 gene
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Prescreening for colorectal
cancer
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Screening for colorectal cancer
• Colorectal cancer (CRC) is
– common
– Lethal
– preventable disease (98%)
• It is infrequent before age 40
• the incidence rises progressively to
3.7/1000 per year by age 80
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Clinical detection of increased risk
• Before deciding how to screen:
• clinicians should decide whether the individual patient is at
average or increased risk
• based on his or her medical and family history
• A few simple questions are all that is necessary:
• Have you ever had colorectal cancer or an adenomatous polyp
• Have you had inflammatory bowel disease (Crohn disease)
• Has a family member had colorectal cancer or an adenomatous
polyp
• If so, how many
• was it a first-degree relative (parent, sibling, or child)
• and at what age was the cancer or polyp first diagnosed
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Crohn’s disease
• an inflammatory bowel disease
• causes inflammation of the
gastrointestinal tract in both men
and women
• persistent diarrhea, abdominal
pain, fever, and at times rectal
bleeding
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Crohn’s disease
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screening for Colorectal cancer
(CRC)
• Patients at highest risk with familial
syndromes (HNPCC, FAP)
• should be screened for CRC with
colonoscopy at frequent specified
intervals
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People at high risk
• a first-degree relative with colon cancer
• or adenomatous polyp diagnosed at age
<60 years
• or two first-degree relatives diagnosed at
any age
• should be advised to have screening
colonoscopy starting at age 40 years
• or 10 years younger than the earliest
diagnosis in their family
• whichever comes first, and repeated every
five years
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HNPCC
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Microsatellite Instability (MIN) in
Adenomas as a Marker for Hereditary
Nonpolyposis Colorectal Cancer
•Hereditary nonpolyposis colorectal cancer
(HNPCC)
•the most common of the well-defined
colorectal cancer syndromes
•HNPCC: accounting for at least 2% of the
total colorectal cancer
•carrying a greater than 80% lifetime risk of
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cancer
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Microsatellite instability
(MIN)
• can be detected in approximately 90%
of tumors from individuals with
Hereditary Non-Polyposis Colorectal
Cancer (HNPCC)
• MIN is also reported in approximately
15% of sporadic colorectal carcinomas
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Mutations in the human mismatch
repair genes
(MMR MLH1, MSH2, MSH6, PMS1, PMS2)
• responsible for the MIN of the
HNPCC tumors
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Reduction in cancer morbidity
and mortality of HNPCC patients
• can be accomplished by appropriate
clinical cancer screening of HNPCC
patients with mutations in mismatch
repair (MMR) genes
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Germline mutation analysis
• In individuals with cancer
• mutation detection can be
accomplished relatively efficiently
by germline mutation analysis of
individuals (blood) whose cancers
show microsatellite instability
(MIN)
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• Among 378 adenoma patients
• six (1.6%) had at least one MIN adenoma
• Five out of the six patients (83%) had a
germline MMR gene (mismatch repair gene)
mutation
• MIN analysis is a useful method of
prescreening colorectal adenoma patients
for HNPCC
Microsatellite Instability in Adenomas as a Marker for Hereditary
Nonpolyposis Colorectal Cancer
Anu Loukola et al. American Journal of Pathology. 1999;155:1849-1853
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