Transcript Translokacje chromosomowe u dzieci z zaburzeniami rozwoju

Indications for genetic research in Obstetrics and
Gynecology
1. Prenatal diagnosis
2. Reproductive failures (both parents)
- miscarriage (2 and more)
- stillbirths
- children with birth defects
3. Disorders of sex determination
4. Hereditary cancers
Prenatal diagnosis
The etiology of congenital
malformations
Prenatal diagnosis defonition
Diagnosis before birth. Methods for prenatal diagnosis include
ultrasound of the uterus, placenta, and/or developing fetus;
chorionic
villus
sampling
(CVS)
to
obtain
tissue
for
chromosome or biochemical analysis; and amniocentesis to
obtain amniotic fluid for the analysis of chromosomes,
enzymes, or DNA. A growing number of birth defects and
diseases can be diagnosed prenatally and in some cases
treated before birth. Also known as antenatal diagnosis.
Congenital anomalies 3-4% of newborns
0,4 – 0,6% - newborn affected by a chromosomal
aberrations
(reprodactive failure and stillbirths)
More than 10 000 monogenic diseases
10% - causes of hospitalization – monogenic diseases
7% stillbirthsm and perinatal deaths)
- mitochondrial myopathies conditional mutations in
mitochondrial or nuclea DNA
20% - poligenic diseases
Malformations and genetic diseases cause a higher
incidence causes:
- hospitalization,
- morbidity,
- mortality,
Social and economic problem
Most genetic diseases manifested by symptoms:
- physical disability
- intellectual disability
Methodology in genetic counseling
1. The correct diagnosis of the disease,
2. Construction and analysis of pedigree:
- family members who incur greater risk,
- how extensive diagnostic tests should be foreseen and
planned.
3. Assessment of genetic risk.
Principles of genetic counseling
1. Genetic advice should be granted when the family is
interested in its acquisition
2. It must be informative, non prescriptive !
The content of advice has a significant impact on the decision
to abandon the planning or subsequent pregnancies, and
sometimes determine the continued operation of the famil
WHO defined ethical principles that should apply in genetic
counseling.
Principles of genetic counseling
Decisions, regarding both planning to become
pregnant,
diagnosis,
as
well
as
termination
acceptance
of
pregnancy
of
prenatal
after
the
detection of fetal disease or adoption should be made
by the same consulted in accordance with their
knowledge, beliefs, recognized worldview, life goals
and values system.
Down syndrome
- classical trisomy 95 %
- chromosomal translocations 4%
* de novo
*carriers of balanced translocation of chromosome
21 to another acrocentrical chromosome
- mosaicism 1-3%
Downa syndrome
1:680
Patau syndrome
1:5000
-
47, XY,+21
47,XY,+13
Frequency of population is1:680
Genetic risk of aneuploidy
1. The risk of many aberrations
(tris. 21, 13, 18)
- increases with maternal age.
No risk for sex chromosome aberrations (X i Y)
- decreases with advancing pregnancy
(greater risk of fetal death)
The risk of trisomy 21 in each age group.
3,00
2,50
2,00
12 Hbd
40 Hbd
1,50
1,00
0,50
0,00
20
25
30
35
40
>40
The risk for trisomy 21:
Increases with maternal age
Decreases with gestational age because about 30% of affected
fetuses die between the 12th and 40th week of pregnancy
Maternal age
The risk for trisomy 21 increases with maternal age but
because there are a lot more women in the younger age
group the majority of fetuses with trisomy 21 are in the women
aged under 35 years
In the 1970’s and 1980’s screening for trisomy 21 was based
on maternal age and amniocentesis or CVS was offered to
those aged 35 years or older.
About 5% of pregnant women were
≥35 years and a policy of screening
based on maternal age would result
in:
Invasive testing rate
Detection rate of trisomy 21
5%
30%
In most developed countries in the last
30 years the maternal age of pregnant
women has increased and now about
20% of pregnancies, including 50% of
fetuses with trisomy 21, are in women
aged ≥35 years
Determination of recurrence risk of aneuploidyi
Pregnancy with trisomy - the risk
increased by 0.75 per cent. than the
risks arising from the patient's age
3
2,5
2
Ryzyko wynikajace z wieku
1,5
Ryzyko wynikajace z urodzenia
dziecka ZD
1
0,5
0
20
25
30
35
40
>40
The causes of aneuploidy repeat
- < 35 r.ż. - the tendency to non - disjunction
- gonadal mosaic
- chapter gene defect
- >35 r.ż. accumulation of errors
(free radicals, hormonal disorders)
The risk for relatives of second and third degree - no more
than population
Mejotic division
Parents
Meiosis
Mejosis
normal gamete
failed separation of chromosomes during meiosis
Parents
Meiosis I
Meiosis II
normal gamete fertilization
offsprong
46,XY,+t(14;21)(q10;q10)+21
46,XY,+t(21;21)(q10;q10)+21
The distribution of risk in the event of a merger centric carrier 14; 21 eg.
in the mother
14;21
Healthy child
The egg in the mother can randomly hit
chromosomes indicated its karyotype
It was assumed that sperm is always correct the
chromosomal
Healthy carrier
The distribution of risk in the event of a merger centric carrier 14; 21
in the mother.
Trisomy 14 - lethal
Trisomy 21; Downa syndrome
The distribution of risk in the event of a merger centric
carrier 21; 21 eg. in the mother
mother with a pair of chromosomes 21, but connected to each othe
No chromosomal
21
materna
Trisomiy 21; ZD
Monosomy 21; lethal
100% risk score for each child
born ZD
the risk of repetition
t(14;21)(q10;q10)
Mother 10- 15 %
Father 5 – 10 %
t(21;21)(q10;q10)
Mother 100 %
Father 100 %
46,XY,+t(14;21)(q10;q10)+21
VSD
VSD
VSD
VSD
3
2
Comprehensive prenatal diagnosis:
Non-invasive prenatal diagnosis
1. Ultrasound of 11, 20, 30 weeks of pregnancy.
11 -13.6 hbd (45 - 84 mm) - Nuchal scan, NB, TV, DV.
- first trimester test (double test (PAPP A + beta hCG)
(11 -13.6 hbd) (sensitivity 70%)
- second trimester test (triple test (beta hCG, AFP, estriol)
(sensitivity 60%)
NT + T I + T II sensitivity = 85 – 90 % !
False positive results - 5 %
Invasive prenatal diagnosis !
- chorionic villus sampling >12Hbd
- amniocentesis > 15 HBD
- cordocentesis >18 Hbd
Nuchal translucency (NT) is the sonographic appearance of a
collection of fluid under the skin behind the fetal neck in the first
trimester of pregnancy
47,XY,+21
47,XY,+21
46,XY,+13
Patau Syndrome
45,XX,+t(13;14)(q10;q10)
47,XY,+13
47,XY,+13
47,XY,+13
The increased translucency can be present in:
- syndromes associated with chromosome aberrations:
z. Syndrome, z. Edwards
- syndromes with normal karyotype:
with. Noonan, SLOS
- heart defects coexisting with defects in other organs
- 1/3 of the lack of reasons - healthy children
NT>95 percentile - assess the fetal karyotype percentile
Attention !
Each invasive procedure should be preceded by an
exhaustive conversation with the patient, during which
detailing all of the risks that the mother and the child
brings
with
it
the
treatment.
Each invasive procedure requires the written consent of
a patient's own signature confirms that it agrees to
perform the surgery and that was exhausting informed
about the surgery and its complications and risks
associated with him.
Amniocentesis
Diagnosis of fetal chromosomal abnormalities requires
invasive testing by amniocentesis or chorionic villous sampling
(CVS)
3D USG
3D USG
Risks associated with amniocentesis or CVC
0,5 –1,0 %
- Bleeding
- Amniotic infection syndrome
- Maternal - Fetal transfusion
- Premature rupture of the bladder
- Fetal / PROM /
- Hematoma or placental
- Release of uterine contraction
Risks associated with invasive procedures
Ultrasonography
- unknown
CVS < 12 tyg.
- limb defects may occur
(thrombotic lesions)
CVS > 12 tyg.
- 0,5 -1,0%
Amniocentesis
13-14 tyg. - 3%
Amniocentesis
15-17 tyg. - 0,5 – 1,0%
Cordocentesis
> 17 tyg. - 2,0 %
Doppler waves
greater thermal effec
- have a higher frequency and
Risk of Amniocentesis
Amniocentesis should not be performed before 16 weeks
because with early amniocentesis the rate of miscarriage is
about 2% higher and the incidence of talipes equinovarus is
1.5% higher than after first-trimester CVS or second-trimester
amniocentesis !.
Risk of CVS
CVS should not be performed before 11 weeks because earlier
CVS is associated with fetal transverse limb abnormalities,
micrognathia and microglossia
The necessity for the future
- better screening test currently performed by biochemical
assessment of plasma markers
(low sensitivity and specificity, high cost)
- comparable costs
During the last 30 years, extensive research has aimed at
developing non-invasive methods for prenatal diagnosis
based on the isolation and examination of fetal cells, DNA
or RNA found in the maternal circulation. However, these
methods have so far been unsuccessful in the diagnosis of
chromosomal abnormalities
History of research material of fetal origin in
maternal blood
- Schmorl – a case of eclampsia
- Walknowska – metaphase in peripheral blood
- Merkatz – biochemical markers
- Bianchi – FISH in interphase nuclei (FACS)
- Gaenshirt, Holzgreve – FISH i PCR in onterphase nuclei
magnetically sorted (MACS)
- Lo – free DNA in mother blood
Justification advisability of fetal cell research
in maternal blood
The development of non-invasive prenatal diagnostic
methods
Purpose of a preliminary - to reduce the number of invasive
procedures in women with positive prenatal screening
Purpose definitive - eliminating the need for invasive tests
and perhaps screening
A more effective method of screening is based in the
combination of:
1. Maternal age
2. A maternal blood sample for the measurement of the
placental products of free ß-hCG and PAPP-A
3. An ultrasound scan at 11-13 weeks:
- to measure the collection of fluid behind the fetal neck (nuchal
translucency)
-to examine the fetal nose and palate
- to measure the fetal heart rate
- to assess the flow of blood across the tricuspid valve of the
fetal heart and the ductus venosus
KLINEFELTER SYNDROME
PATHOGENESiS
Chromosomal aberrations
47,XXY; 46,XY/47,XXY; 47,XXY/48,XXXY;
48,XXYY
CLINICAL EFFECTS ASSOCIATED WITH CHROMOSOMAL
ABERRATION
*impaired spermatogenesis; azoospermia; sterility;
*neurological disorders; skeletal and vascular anomalies in some
cases of more
*complex X and Y polysomies; deviations of dermatoglyphs, mental
retardation
*behavioural problems
KLINEFELTER SYNDROME
SIGNS CONNECTED WITH DYSGENESIS OF TESTES
*testes markedly reduced *in size, small penis;
*in some cases cryptorchidism,
*elongated body; in some eunuchoid habitus;
*frequently gynecomastia
* the serum testosterone is lower than normal; gonadotropin
levels are elevated = *hypergonadotropic hypogonadism
TURNER SYNDROME
PATHOGENESIS
chromosomal aberrations
45,X; 45,X/46,XX; 45,X/46,XX/47,XXX;
Some od the structural aberrations of the chromosom
CLINICAL EFFECTS ASSOCIATED WITH CHROMOSOMAL ABERRATION
*short stature; gonadal dysgenesis; birth defects (np. renal anomalies, coarctation of
the aorta, skeletal anomalies)
*lymphedema in prenatal and neonatal period
*dysmorphic features;
SIGNS OF GONADAL DYSGENESIS
*primary amenorrhoea
*signs of hypergonadotropic hypogonadism
TURNER SYNDROME
* hypoplastic left ventricle,
* coarctation of the aorta and VSD
the neck"s redundant skin
Here we can see the right foot
lymphedema and the difference in size
of both legs and feet.
NOONAN SYNDROME
Autosomal dominant
inheritance
NOONAN SYNDROME
TURNER SYNDROME
TURNER
SYNDROME
„hidden” mosaicism with Y chromosome
45,X karyotype
with coexistence of Y chromosome
unremarkedly (undiagnosed) cytogenetically
Genomic DNA analysis
by PCR using selected
Y-specific primers
PURE GONADAL DYSGENESIS
Phenotypic woman 46,XY
- SRY (+) - SRY mutations in 15% of cases
normal SRY in about 75-80% of patients
- SRY (-) - Yp deletions
- Androgen insensitivity syndrome (AIS) AR
Receptor gene (Recessive inheritance linked to the X)
High risk of malignant transformation gonads !
Androgen
Katedra i Zakład Genetyki Klinicznej
CM im. dr L. Rydygiera w Bydgoszczy UMK
ul. M. Skłodowskiej – Curie 9
85-094 BYDGOSZCZ
Tel./fax (052) 585 35 68
tel. (052) 585 36 70
[email protected]