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Prescreening of Genetic Diseases (It’s worth & potential). Dr Pupak Derakhshandeh, PhD Ass Prof of Medical Science of Tehran University. Prescreening for. Down syndrome and trisomy 13 & 18 Breast cancer (BRCA1 AND BRCA2 GENES) Colorectal cancer SMA carrier testing Factor V Leiden

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Prescreening of Genetic Diseases (It’s worth & potential)

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Prescreening of Genetic Diseases (It’s worth & potential)

Dr PupakDerakhshandeh, PhD

Ass Prof of Medical Science of Tehran University

Prescreening for

  • 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

Prescreening for Down syndrome and trisomy 21, 13 & 18

Down Syndrome (Trisomy 21(

Down Syndrome (Trisomy 21(

Trisomy 2(

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

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

Nuchal translucency screening involves the measurement by ultrasound of the skin thickness at the back of the neck of a first trimester fetus

Identification about 85-90% of affected fetuses in the first-trimester

  • maternal age was combined with fetal NT

  • and maternal serum biochemistry (free β-HCG and pregnancy-associated plasma protein (PAPP-A)

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

Maternal serum alpha-fetoprotein (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


  • the gestational age must be known with certainty

  • the amount of MSAFPincreases with gestational age

  • Neural tube defect

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 !


  • 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

Neural tube defect

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

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 withamniocentesis for diagnosis of affected fetuses

    • folic acid supplements for prevention of the disorder

Anencephaly (failure of closure at the cranial end of the neural tube)

Spina bifida (failure of closure at the caudal end of the neural tube)

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

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

  • 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 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

    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 Downsyndrome

    Maternal serum estriol

    • made by the fetal adrenal glands

    • Estriol tends to be lower when Down syndrome is present


    • 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

    Trisomy 21

    MSAFP / beta-HCG

    estriol / inhibin-A

    overlapping are typical for trisomy 18

    PrescreeningBRCA1 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

    • 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

    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

    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

    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

    BRCA2-associated cancers

    • 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

    BRCA 1

    • The gene Locus for BRCA1: 17q21

    • a large gene

    • 24 exons

    • encoding a 220 kD

    • 1863 amino acids

    • Two recognizable motifs


    • 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 genomicDNA

    BRCA1 Gene

    BRCA2 Gene


    single strand conformation polymorphism

    • simplicity

    • clearly by heteroduplex analysis (HA)

    Pedigree of a selected family with breast cancer

    SSCP AnalysisBRCA1 Exon 15, 4650delCA

    Pedigree of a selected family with breast cancer

    SSCP AnalysisBRCA1, Exon 20,Nt 5382

    SSCP AnalysisExon 11pi BRCA1 MS R1347G

    Breast Cancer Families

    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

    Mutations in BRCA1/2 gene

    Prescreening for colorectal cancer

    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

    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

    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

    Crohn’s disease

    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

    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


    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 cancer

    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

    Mutations in the human mismatch repair genes (MMR MLH1, MSH2, MSH6, PMS1, PMS2)

    • responsible for the MIN of the HNPCC tumors

    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

    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)

    • 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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