Clinical Genetics
Renata Gaillyová
Clinical genetics
• Dept. of medical genetics
• Genetic diseases
• Rare diseases
• Patients on the departement of clinical genetics
• Genetic counselling
• Genetic prevention
• Chromosome abnormalities
• AD,AR,XR inheritance, disorders
• Multifactorial inheritance
• Teratogenes, Environmental hazards
• Prenatal diagnosis
• Neonatal screening
• Reproductive genetics
Dept. of Medical genetics
• Genetic ambulance
genetic counselling
• Laboratory part
• Cytogenetic laboratories
Prenatal cytogenetics
Postnatal cytogenetics
Oncocytogenetics
Molecular – cytogenetics
• Lab. for DNA and RNA analysis
(clinical genetics and oncogenetics)
Medical Genetics
• Preventive Medicine
• Interdisciplinary cooperation
• Information from genetics (disease,
posibilities of testing, prenatal
analysis)
• Voluntary choice for patients
• Informed agreement
Genetics diseases
• Chromosome abnormalities
• about 0,6 - 0,7%
• Monogen diseases
• about 0,36%
(study in 1 000 000 newborns)
• most then 90% of monogen diseases occur in
childhood
• Multifactorial (polygenic or complex) disorders
• Occur in about 80% in the population
Rare diseases
• A disease is defined as rare if it
affects less than 5 people out of
10,000, (i.e. less than 1 patient out of
2,000).
• We currently know of more than 8,000
various rare diseases.
• The number of patients with rare
diseases is not small.
What are the major issues affecting people
with rare diseases?
• Late or incorrect diagnosis
• Inaccessible expert health care
• Inaccessibility of so-called orphan drugs (i.e.
drugs for rare diseases)
• Failures in the social support and benefits
network due to lack of knowledge on the part
of assessing doctors, social workers, etc.
• People with similar diseases who lack patient
organizations have limited possibilities to
share experiences
Rare diseases
• Rare disease often manifest soon after birth,
affecting about 4-5% of newborns and infants (for
example - some congenital defects, genetic
metabolic disorders, genetically conditioned diseases
and rare tumours). They can, however, occur during
childhood or later in adulthood.
• About 80% of rare diseases have a genetic origin.
• In the case of incorrect or late diagnosis,
especially in patients with a disease for which there
is already a treatment option, there is irreversible
damage to health. This leads to a psychic domage
not only in the patients, but also their families,
including the distrust to the quality health system.
What is a Rare Disease?
• A disease or disorder is defined as rare in Europe
when it affects fewer than 1 in 2000.
• A disease or disorder is defined as rare in the USA when
it affects fewer than 200,000 Americans at any given
time.
• One rare disease may affect only a handful of patients in
the EU (European Union), and another may touch as
many as 245,000. In the EU, as many as 30 million
people may be affected by one of over 6000 existing
rare diseases.
What is a Rare Disease?
• 80% of rare diseases have identified genetic origins
whilst others are the result of infections (bacterial or
viral), allergies and environmental causes, or are
degenerative and proliferative.
• 50% of rare diseases affect children.
• Over 6000 rare diseases are characterised by a
broad diversity of disorders and symptoms that vary
not only from disease to disease but also from
patient to patient suffering from the same disease.
• Orpha.net
Rare Disease
• Relatively common symptoms can hide underlying
rare diseases leading to misdiagnosis and delaying
treatment. Quintessentially disabling, the patients
quality of life is affected by the lack or loss of
autonomy due to the chronic, progressive,
degenerative, and frequently life-threatening aspects
of the disease.
• The fact that there are often no existing effective
cures adds to the high level of pain and suffering
endured by patients and their families.
Rare Disease
• The lack of scientific knowledge and
quality information on the disease often
results in a delay in diagnosis. Also the
need for appropriate quality health care
engenders inequalities and difficulties in
access to treatment and care. This often
results in heavy social and financial
burdens on patients.
Rare Disease Day
• takes place on the last day of February each year. The
main objective of Rare Disease Day is to raise
awareness amongst the general public and decisionmakers
about rare diseases and their impact on
patients' lives.
• The campaign targets primarily the general public and
also seeks to raise awareness amongst policy makers,
public authorities, industry representatives, researchers,
health professionals and anyone who has a genuine
interest in rare diseases.
Czech Association for Rare Diseases
• The Czech Association for Rare Diseases (ČAVO)
was founded in March 2012.
• ČAVO's mission is to bring together the
organizations serving people with rare diseases as
well as individuals, to represent their interests and to
strengthen awareness of rare disease issues among
experts in health care, leaders of state and
international institutions and the public.
Czech Association for Rare Diseases
• The Czech Association for Rare Diseases (ČAVO)
was founded in March 2012.
• ČAVO's mission is to bring together the
organizations serving people with rare diseases as
well as individuals, to represent their interests and to
strengthen awareness of rare disease issues among
experts in health care, leaders of state and
international institutions and the public.
Patients on genetic
departements
• Dead person
• Adults
• Pregnant women
• Fetuses
• Children
Patients on genetic departements
• Positive family history (chromosome
abnormality, congenital malformations,
mental retardation, diseases…)
• Pregnant women with encrease risk
for the fetus
• Infertility – sterility, repeated fetal
loss
• Donors (gamets)
• Patients with tumours
Children
• Congenital malformations
Children
• Suspition of mongenic hereditary
diseases or inherited metabolic
disorders and their families
Children
• Suspition on congenital
chromosom aberations
(children with congenital
malformations, abnormal
face, atipical visage,
pre- or postnatal growth
retardation, premature
birth)
Children
• early or delayed puberty
• Malformations of the external or internal
genitalia
• Low or high figure
Children or adults
• Mental retardation
• Psychomotor retardation
• Developmental delay
Children and adults
• Gender identity disorder
Children and adults
• people with long-term
exposure to
environmental
pollutants
• (alcohol, cigarettes,
drugs, radiation)
Children and adulds
• patients with suspected hereditary cancer
• patients with cancer (sporadic occurrence)
Adults
• Donors of gametes
(preventive tests)
Adults
• Related partners
(increased risk for hereditary disease with
AR inheritance)
adults
• Infertility
• Repeated spontaneous abortions
Pregnant women
• With unfavorable
family history
Pregnant women
• with adverse pregnancy history (chronic
diseases with established therapies, acute
disease in early pregnancy - temperature,
drugs, X-rays, CT, vaccinations,
toxoplasmosis, rubella, ...)
Pregnant women
• Prenatal biochemical
screening
(Pathological results)
Pregnant women
• Ultrasound
prenatal screening
– pathological
results
• Congenital
malformations in
the fetus
• Risk of
chromosomal
abnormality in the
fetus
Genetic counselling
• Anamnesis
• Family history
• Pedigree analysis
• Examination of the patient
• Laboratory analysis
• Other examinations - neurology,
psychology, hematology, CT, MRI …
Three-generation pedigree
• Patient
• Siblings
• Children siblings
• Parents
• Parents siblings
• Children of parents siblings
• Parents parents
marriage
divorce
konsanguinity
monozyg. twins
dizygot. twins
childless
miscarriage
man
woman
diseased
Unknown gender
carrier
proband
dead person
Clinical
examination
Usually the
child is like
their parents.
Next steps
• Recommend the laboratory genetic
testing
• Recommend other specialists if needed
• Require medical records
• Make photodocumentation
The result of genetic
counselling
• Specify exact diagnosis (if possible)
• Determine genetic prognosis
• Is the disease hereditary?
• Type of inheritance
• Genetic risks for other family members
• Posibilities of treatment, prenatal
analysis
Patient
Cell
Chromosome
DNA
Patient
Primary genetic prevention
• Before pregnancy
• Folic acid (cca 0,8 mg/day, 3+3 months)
• Vaccination (rubella)
• Genetic counselling
• Contraception, family can opt for adoption
or donor of gamets (oocytes, sperm)
• Pregnancy planning
• Rediction of environmental hazards (drugs,
radiation, chemicals…)
Reproduction of the optimal age
• In women increases the risk of
accidental congenital chromosomal
aberrations in the offspring
• In men may increase the risk of de
novo mutations in some monogenic
diseases (Neurofibromatosis I,
Achondroplasia..)
Prevention of spontaneous and induced
mutations
• Healthy Lifestyle
• The restriction of harmful substances drugs,
environmental hazards
Vacctination, infection prevention
• Prevention of rubella
embryopathie
Prevention of congenital
toxoplasmosis
• Testing for infectious
disease risk in mothers
(CMV, varicella-zoster
virus, ...)
Vitamin prevention of neural tube
defects, anterior abdominal wall
defects, clefts
• Folic acid at a dose of 0.8 mg daily (twice
the dose in non-pregnant) for 3-6 months
prior to conception and till the end of 12.
week of pregnancy
Examination of acquired chromosomal
aberrations
• Preventive examinations of persons
exposed to environmetal risks at work or
persons with risk of long-term therapy
(immunosuppressants, cytostatics, ....)
• The possibility of vitamin therapy to
improve repair of DNA (3-6 months)
Contraception, sterilization
• Contraception - temporarily prevents
conception in the limited impact of risk
(treatment)
• Sterilization - the long-term inhibition
of pregnancy in a high risk of disease
in the offspring
(Hereditary disease)
Adoption
• Alternative family care as an option at
high genetic risk families
Donation
• of sperm, oocytes and
embryos
• reduction in high
genetic risk
• reproductive problems
Secondary genetic prevention
• Prenatal diagnosis
• Prenatal screening
• Prenatal tests
• Genetic counselling
• Termination of pregnancy (the law in
Czech Republic- end of 24. week of
gestation)
• Postnatal screening
• Newborn screening
Chromosome abnormalities
0,6-0,7% live born
Congenital chromosome
abnormalities
• Autosomes
• Gonosomes
• Numerous
• Structural
• Balanced
• Unbalanced
Populations frequency
Trisomy 21 1,5 per 1000 live
births
Trisomy 18 0,12
Trisomy 13 0,07
Klinefelter
syndrome
1,5
Turner syndrome 0,4
XYY syndrome 1,5
XXX syndrome 0,65
Chromosome abnormalities
in spont. abortions
All spont. abortions 50 %
Up to 12 weeks 60 %
12-20 weeks 20 %
stillbirths 5 %
trisomies 52 %
45,X 18 %
Translocations 2 – 4%
Maternal age and chromosome
abnormalities in AMC (per 1000)
years +21 +18 +13 XXY All
35 3,9 0,5 0,2 0,5 8,7
37 6,4 1,0 0,4 0,8 12,2
40 13,3 2,8 1,1 1,8 23,0
43 27,4 7,6 4,1 45,0
45 44,2 7,0 62,0
47 70,4 11,9 96,0
Down syndrome
• 47,XX,+21 or 47,XY,+21
• About 1/800-1000 newborns, 1/75 SA
• Hypotonia, joint laxicity, soft skin, flat
face, prominent intercanthal folds, slanted
palpebral fissurs, Brushfield´s spots of the
irides, small, down set ears, small nose,
protruding tongue, simian crease in the
hands (about 45%), short statue, mental
retardation, congenital heart disease in
about 50% of patients with DS,
(atrioventricular canal)
Down syndrome- prenatal diagnosis
• I. trimester screening – combined screening
• 10.-14. week of gestation
• Ultrasound
• Nuchal translucency - NT ( )
• (Absence of nose bone)
• Blood
• PAPP-A ( )
• free-beta hCG ( )
• Fals positive results less then 5%
• Reveals about 95% of fetuses with Down syndrome
• 1/100 – positiv – genetic counselling and karyotiping
• 1/100-1/1000 – US and genetic counselling
• 1/1000 – negativ - US
Down syndrome- prenatal diagnosis
• II. trimester screening – biochemical screening
• 16. -18. week of gestation
• AFP – alpha-fetoprotein ( )
• total hCG - chorionic gonadotropin ( )
• uE3 - unconjugated estriol ( )
• Fals positive results about 5%
• Reveals about 70% of fetuses with Down syndrome
• 1/250 – positiv
• 1/250-1/350 – border
• 1/350 - negativ
Down syndrome- prenatal diagnosis
• Ultrasound
• 10.-14. week
• NT
• NB
• 20. week
• US- congenital heart disease and other
malformations
Down syndrome- prenatal
diagnosis
• non - invasive prenatal testing of
fetal (placenta) DNA in the mothernal
plasma
• reliability of the tests is 98 - 99%
• also for +18, +13, 45,X, 47,XXY,
microdeletions…
Edwards syndrome
• 1:5000
• IUGR, hyopotrophie
• microcephalie
• dolichocephalie
• Cleft palate
• Down set ears
• micromandibula
• Hands, feets
• Other cong.
malformations
Patau syndrome
• 47,XX(XY),+13
• 1/5000-10 000 in newborns, 1/90 SA
• 95% SA
• death before 1 year mostly
• cleft lip and palate bilateral,
congenital defects (CNS, eyes,
postaxial hexadactily…)
Turner syndrom 45,X
• 1:2000
• hygroma colli
• hydrops
• Low weight in newborns
• Lymfoedema
• Pterygia
• Cubiti valgi
• Aortal stenosis
• Small statue
• Sterility
Klinefelter syndrome
• 47,XXY
• relatively frequent 1/600-1000
liveborn males
• tall stature
• hypogonadism, gynekomastia
• sterility, infertility
Others gonoseme
abnormalities
• 47,XXX
• 47,XYY
• 48,XXXX
• 48,XXYY….
Structural chromosomal
aberrations
• deletion or a duplication of the genetic
material of any chromosome, atypical
structure - side by side to get the
genetic material, which there normally is
not - the effect of positional
• partial-partial deletions
• partial trisomy
• inversions, insertions, duplications ....
Syndrom Wolf-Hirshorn
46,XX(XY),4p•
severe mental retardation
• typical craniofacial dysmorphia hypertelorism,
pear nose, carp mouth,
• pre-and postnatal growth retardation,
• failure to thrive
• other associated developmental
defects - heart, urogenital tract ...
Syndrom Cri du chat
46,XX(XY),5p•
anomalies of the larynx causes the
characteristic cry of a similar feline meow
(only in infancy)
• low birth weight and length
• mental retardation, short stature, failure
to thrive, small moon shaped face, the
position antimongoloid eye slits,
mikrocephalie
• Other malformations and birth defects
Cri du chat 46,XX(XY),5p•
1:50 000
• Typicaly cri in
newborns
• laryngomalacie
• antimongoloid
• epicanthi
• hypotonie
• hypotrofie
Other structural chromosomal aberrations
Mikrocytogenetic
Molekular cytogenetic
• FISH (fluorescenc in situ hybridisation),
M-FISH, SKY (spektral karyoptyping), CGH
(komparativ genom hybridisation), MLPA,
array-CGH, NGS
• mikrodeletions or mikroduplications, marker
chromosoms, complex rearegements, oncology –
oncocytogenetics,fast prenatal diagnostics …)
• fast methods (possible for prenatal dg)
• metafase and intesfase examination
Microdeletions
• Di George syndrome
(del 22q11)
• Prader-Willi / Angelman syndrome
(del15q11-13)
• Williams Beuren syndrome
(del7q11.23)
Williams - Beuren syndrom
• del 7q11.23
• Facial dysmorfie - Elfin face, congenital
heart disease, aortal or pulmonal
stenosis, hypokalcemie, small statue, MR,
hernie,...
Prader-Willi syndrom
• Hypotonie, hypotrofie in small children
• PMR, small statue, obesity, hyperfagie,
akromikrie, hypogonadismus
• mikrodeletion15q11-12 paternal
Angelman syndrom
• Severe mental
retardation
• Epilepsie
• Laughter
• severely delayed
speech development
• mikrodeletion
15q11-12 mat
The telomere
Rearangement in
about 6-8%
children with
mental
retardation with
or without
congenital
defect
(FISH, HR-CGH,
MLPA)
Mendelian inheritance
Monogenic diseases
Autosomal Dominant
• The sexes are involved equaly
• Heterozygotes are mostly affected
clinically
• risk 50% for sibs and children
• new mutations
• penetrance, expresivity
Pedigree AD inheritance
• the risk 50%
healthy
ill
AD - diseases
• Neurofibromatosis 1 and 2
• Achondroplasia
• Huntington disease
• Marfan syndrome
• Myotonic dystrophy 1 and 2
• Long QT syndrome
Neurofibromatosis I
• the frequency of the disease about 1/3000
• localization 17q11.2
• inheritance - autosomal dominanant with
nearly 100 % penetrance and variable
expressivity
• approximately 50 % of cases are new
mutations (paternal origin)
• progressive disease
• mutations in tumor supresor gene – risk of
oncologic disease
Huntington disease
is an inherited neurodegenerative brain disease
that affects individuals of both sexes
Symptoms usually begin between the 20th to
45th year , often after it has been disposition
for a disease transmitted to the next
generation, usually manifested by involuntary
movements, abnormal gait and speechimpaired,
patients are gradually reflected in
the loss of cognitive ability, mood and behavior
- senile dementia, psychiatric symptomatology
• Achondroplasia (ACH)
• 2 mutations in FGFR3 gene
• New mutations
• Paternal origin on new mutations
• older fathers
Autosomal Recesive
• Heterozygotes are generally
unaffected clinicaly
• The sexes are involved equaly
• An individual manifesting a recesive
disorder usually has heterozygous
parents
• Once a homozygote is identified, the
recurence risk for other child of some
parents is 25%
Pedegree - AR inheritance
•The risk for
next child 25%
carriercarrier
healthy illcarrier
healthy
AR - diseases
• Cystic fibrosis
(frequency of heterozygotes CR- 1/30)
• Phenylketounria (1/40)
• Congenital adrenal hyperplasia (1/40)
• Spinal muscular atrophy (1/60-80)
Cystic fibrosis
• disease affecting
multiple organs
• more then 2000
patological sequence
variants (mutations)
Respiratory
tract
liver
pankreas
intestine
reproductiv
failure
sweat
gland
Most frequent CFTR mutations in
Czech population
Mutation Frequency in CR (%)
F508del 70,7
CFTRdele2,3(21kb) 6,4
G551D 3,7
N1303K 2,8
G542X 2,1
1898+1 GtoA 2,0
2143delT 1,1
R347P 0,74
W1282X 0,6
X-linked Recesive
• Females are not affected as severaly as
males or are not affected
• An affected male cannot transmit the
train to his sons, becose the trait is on
X-chromosome, and the father must
necessarily transmit his Y-chromosome to
a son
• All of the daughters of an affected male
must be carriers, because the only Xchromosome
that the father can give to a
daughter contains the mutation
X-linked Recesive
• Risk for daughters of a carrier -
mother
• 50% for carrier
• Risk for sons of carrier - mother
• 50% for diseas
X- recesive inheritance
X
XY
XX
X
XY
XR - diseases
• Hemophilia A and B
• Duchenne and Becker muscular
dystrophy
• Fragile X chromosome - X-linked
disease
Duchenn/Becker muscular dystrophy
Hemofilia A
Multifaktorial –polygenic
inheritance
Dieseases with complex
heritability
Teratogens
Charakteristic
• disease with multifactorial inheritance
include not mendelian types of
inheritance
• diseases exhibit familial aggregation,
because the relatives of affected
individuals more likely than unrelated
people to carry diseases predisposing
predisposition
Charakteristic
• in the pathogenesis of the disease
play a basic role non-genetic factors
• disease is more common among close
relatives and in distant relatives is
becoming less frequent
Examples
• Congenital heart defects (VCC) 4-8/1000
• Cleft lip and palate (CL/P) 1/1000
• Neural tube defects (NTD, anencefalie, spina
bifida,..) 0,2-1/1000
• Pylorostenosis
• Congenital hip dislocation
• Diabetes mellitus – most types
• Ischemic heart desoease
• Esential epilepsy
Common congenital defects
Congenital heart diseases
• 0,5 - 1% in liveborn infantsn population
incidence
• etiology not known mostly
• about 3% combine with chromosomal
syndromes (+21,+13,+18, 45,X, 18q-,
4p-, del 22q11 Di George sy)
• some mendelian syndromes associated
with congenital heart disease (HoltOram,
Williams, Noonan, Ivemark...
Congenital heart diseases
prenatal diagnosis
• For most serious congenital heart
diseases
• Ultrasonography in 21. week of
gestation - by specialists for prenatal
kardiology
Congenital heart disease genetic
risks
condition 1 aff.
sibling
1 aff.
parent
Ventricular septal def. 3% 4%
Patent ductus art. 3% 4%
Atrial septal defect 2,5% 2,5%
Tetralogy of Fallot 2,5% 4%
Pulmonic stenosis 2% 3,5%
Koarctation of aorta 2% 2%
Congenital heart disease
genetic risks
Risk in %
More than two affected
firstdegree relatives 50
Sib of isolated case 2 - 3
Second-degree relatives 1 – 2
Offsprin- affected father 2 - 3
Offsprin – affected mother 5
Two affected sibs 10
Cleft lip and palate (CLP)
genetic risks
Relationship to index case CLP CP
Sibs (overall risk) 4% 1,8%
Sib (no other affected) 2.2%
Sib(2 affected sibs) 10% 8%
Sib and parent affected 10%
Children 4,3% 3%
Second-degree relatives 0,6%
CLP - Diff. Dg.
• Patau syndrome, 47,XX,+13
• EEC syndrome
• Van der Woude syndrome
• Sequence Pierre Robin
Neural tube defects
• Multifactorial inheritance (risk for I.
degree relatives about 2 - 4%)
• Maternal serum screening – elevated
level of AFP
• Prenatal diagnosis by ultrasonography
• Raised AFP levels in amniotic fluid
• Primary prevention in pregnancies folic
acid
• Risk in the population - probably
related to nutritional status
Teratogens
• teratogen is a substance whose
effect on embryo or fetus may cause
abnormal development
action may be direct or through the
maternal organism
Human Teratogens
• Physical (radiation, heat (fever),
mechanical impact)
• Chemical (chemicals, drugs)
• Biological (infection, fungus ...)
• Metabolic imbalance (disease mother)
The effect of teratogens depends on :
• dose
• length of the action
• contact time
• genetic equipment of the fetus and
the mother
Critical period
• 14.-18. days after conception – the
rule „all od nothing “
• 18.-90. day – organogenesis
• The most sensitive period for the
emergence of developmental defects
Drugs
• Distribution of medicines practice into
categories
• A
• B
• C
• D
• X
• Food and Drug Administarion, 1980
A
• in controlled studies have shown no
evidence of risk to the fetus in the
first trimester of fetal development
or influence in the next period of
pregnancy
product appears to be safe
B
• Animal reproduction studies
demonstrate a risk to the fetus, but
there's no controlled studies in women
Animal reproduction studies have
shown adverse effects, but in
controlled studies in women have not
been confirmed
C
• Animal studies confirm the teratogenic
embryotoxic or other adverse effects on the
fetus,
• non-controlled studies in women
• lack of studies in animals and humans
product should be administered with caution
and only in cases where the benefit for the
woman of his administration exceeds the
potential risk to the fetus
D
• risk to the human fetus is known
• medicine may be administered in a
situation where its use for a woman
needed (lifesaving)
• no other safer drug is available
X
• studies in animals and in humans
clearly demonstrate a teratogenic
effect
• drugs absolutely contraindicated in
pregnancy
Drugs with teratogenic effect
• Thalidomid
• Hydantoin
• Valproic acid
• Anti coagulans - Warfarin
• Trimetadion
• Aminopterin
• Methotrexat
• Cyklophosphamid
Drugs with teratogenic effect
• Retinoids
• Lithium
• Thyxreostatic drugs
• Androgens
• Penicilamin
• Enelapril, Captopril
• Antituberkulotics-Streptomycin
Thalaidomid
• congenital heart defects
• limb reduction anomalies
• Other congenital defects
(gastrointestinal, urogenital tract
orofacial – ears anomalies, CNS
defects..)
Hydantoin
• Atypicaly face, growth retardation, mild
mental retardation, behavioral problems,
hypoplastic nails and fingers
Aminopterin a Methotrexat
• folic acid antagonist
facial dysmorfism, cleft lip and/or
palate, small mandible, ears
anomalies, hydrocephaly, growth
and mental retardation, miscarriage
Warfarin
• coumarin antikoagulans
• facial dysmorfism – nasal cartilage
hypoplasia, CNS - defects
Retinoids
• Cleft lip and palate, mikrognatia, eyes
anomalies, ears dysplasia
• Defects of CNS
• Thymus hypoplasia
• Limb defects
Infection
• Toxoplasmosis
• Rubella
• Cytomegalovirus
• Herpesvirus
• Others (parvovirus, antropozoonosy, chlamydia..)
• TORCH
Toxoplasmosis
• chorioretinitis
• hydrocephaly or microcephaly
• intracranial calcification, mental retardation
• icterus, hepatosplenomegalia, carditis
• prematurity
• positiv IgM in the mother – treatment with
Rovamycin
• Prenatal dg.: serology, DNA-PCR)
Rubella
• hearing and vision impairment (cataract,
glaucoma, mikroftalmia, blidness)
• mental retardation
• Cong. heart defects
• icterus, hepatosplenomegalia
• prevention- vaccination
Cytomegalovirus
• Intrauterin growth retardation
• mikrocephaly, cacification in the
brain, mental retardation,
• hepatosplenomegaly
• Repeated maternal infection is
possible
• Prenatal dg.: serology,DNA-PCR
Varicella zoster
• Skin lesions and defects
• Brain domage, mental retardation
• Eye defects
• Prenatal dg. - serology, DNA-PCR
Metabolic dysbalance
• Fetal alcohol syndrom (FAS)
• Maternal Phenylketonuria
• Maternal Diabetes mellitus
• Maternal Hypothyreosis
Fetal alcohol syndrom
• Hypotrophy, growth retardation, mental
retardation
• facial dysmorphism
• Congenital heart defects
• Limb defekts
• Abuse of 60g pure alcohol / day
(longterm)
• Combine with malnutrition, folic acid
deficit...
Maternal Phenylketonuria
• Low birth weith
• hypertonia
• mikrocephaly, mental retardation
• Cong. heart defects
• hyperaktivity
• newborn screening
• (frequency 1/10 000 newborns
• inheritance - AR)
• initiation of treatment within three weeks to
prevent mental retardation in the child
Reproductive Genetics
Preconceptional testing
Genetic counselling and analysis
in couples with reproductive disorders
Prenatal diagnosis
Preimplantation genetic diagnosis
Examination of potential donor gametes
Secondary prevention of genetic
• The procedures in pregnancy prenatal
diagnosis and early
postnatal diagnosis
Prenatal diagnosis
• Non invasive methods- screening
• Screening
• Invasive methods
• CVS – after the 10. week of gestation
• AMC – 15.-18. week of gestation
• Cordocentesis – after the 20. week of
gestation
Prenatal diagnosis results
• CVS – karyotype – about 5 days
• AMC – karyotype – about 14-21 days
• DNA analysis (monogen diseases)
• About 5-15 days
• DNA from amniocytes after
cultivation - exclusion contamination
by maternal tissues
Prenatal analysis of most frewquent
aneuploidias
QF PCR
• Examination of the most common
numerical changes in chromosomes 13,
18, 21, X and Y
• The result for 24-48 hours
Prenatal screening (CR)
• Ultrasound (12. - 2 0. - 33. week)
• Ultrasound 20.week – cong. defect
• Ultrasound 20-22. week – cong. heart
defect
• 10-14. week of gestation
• Free beta hCG, PAPP-A, US-NT,NB..
• 16.-18.week of gestation
• AFP, hCG, uE3
NIPT - non-invazive prenatal testing
examination of fetal DNA in maternal plasma
• aneuploidy (21, 13, 18, X/Y and others –
microdetetions…)
• Rh in the fetus
• SRY in the fetus – in X linked diseases in
the family
• Some mongenic diseases in the fetus
(achondroplasie)
Indications for prenatal
examination / genetic counselling
• US screening – congenital defects
• Family history of known conditions for
which diagnosis is possible (DNA analysis)
• Known chromosomal abnormality (de novo
finding in previous child, structural
change in parents)
• Positive prenatal screening for
chromosomal abnormalities
• Advanced maternal, paternal age
Preimplatation Genetic Diagnostics
Preimplatation Genetic Diagnostics
• IVF – assisted reproduction
• Preimplantation genetic screening
• aneuploidy - array-CGH, chip technology
• (FISH -13,18,21,X,Y, 15,16,22)
• Preimplantation Genetic Diagnostics
• Structural chromososmal aberations
• (parents are carries of balanced
rearangement)
• Monogenic diseases (known in family history)
PG Diagnostic
X
PG Screening
• PGD - high genetic risk
• PGS - (most common) aneuploidies
Genetic counselling in
infertility
Infertility
• Is the infertility one aspect of a
genetic disorder that might be
transmitted?
• Will correction if infertility give an
increased risk of malformations in the
offspring?
• Genetic testing before use of metods
of asisted reproduction.
Infertility
• Patological examination of the abortus
where possible, this may identify major
structural malformations.
• Cytogenetic study of parents, this is
especialy important where a structural
abnormality is present.
• In general the finding of a chromosome
abnormality in the abortus but not in
parent is not likely to be relevant or
affect the genetic risks.
Infertility
• A search for possible lethal mendelian
causes (consanguinity- risk for AR
diseases, X-linked dominant disorders
lethal in male, myotonic dystrophy which
gives heavy fetal loss in the offspring of
mildly affected women)
• Inherited trombophilias in women with
recurrent abortions ( factor V Leiden,
factor II - G20210A,
hyperhomocystinaemia ? (MTHFR -
C677T)
Factor V - Leiden
• frequency in the white European population
of about 5 - 9%
• AD inheritance
• increased risk of thromboembolism in
homozygots for FVL 50-100x, in
heterozygots 5-10x
• increased risk of fetal loss after the 10.
week of gestation
Sterility in male
• Klinefelter syndrome and other chromosomal
aberations
• AZF (azoospermia factor) deletions of the
DAZ gene Yq (deleted in azoospermia)
• Infertile man – 4-5%
• Men with azoospermia – about 15%
• CFTR mutations and polymorphisms
• Other genes
Postnatal care and neonatal
screening
• Early diagnosis
Dispensary
Specialized Care
Prenatal and perinatal managment
of prenagncies with malformation or
genetic disease in the fetus
• Consultation with experts, who will continue to
take care of the pregnant woman - ultrasound
specialist, gynecologist, obstetrician,
psychological support ..
Consultions with specialists, who will care after
the birth of newborns with disabilities
The planned delivery of specialized care
workplace - kardiocentrum, pediatric surgery,
cardiology…
Newborn screening
Sampler card
NS Evrope-2009
34
44
44 45
50
53
35
51
50
32
41
47
46
37
29
29
41
48
40
DC
51
13
31
45
35
33
36
29
50
41
48
31
45
33
45
48
52
31
31
35
54
49
32
50
49
24
31
31
46
49
51
52
32
5252
31
30
NS USA-2009
Screened diseases in CR from 10/2009
• Kongenital hypothyreosis
• Kongenital adrenal hyperplasia – CAH
Screened diseases in CR from 10/2009
• Inborn errors of metabolism
• Fenylketonuria (PKU, HPA)
• Leucinosis
• MCAD
• LCHAD
• VLCAD
• Def.karnitinpalmitoyltransferasis I a II
• Def.karnitinacylkarnitintranslocasis
• Glutaric aciduria
• Izovaleric acidurie
Screened diseases in CR from 6/2016
1. argininémia (ARG)
2. citrulinémia I. type (CIT)
3. MCAD
4. VLCAD
5. biotinidasis deficiency(BTD)
6. LCHAD
7. deficit karnitinpalmitoyltransferasis I deficiencyI (CPT I)
8. karnitinpalmitoyltransferasisII def. (CPT II)
9. karnitinacylkarnitintranslokasis def. (CACT)
10. Phenylketonuria(PKU) a hyperúhenylalaninemia (HPA)
11. glutar aciduria type I (GA I)
12. homocystinuria ( cystathionin beta-syntázis def. (CBS), pyridoxin nonresponziv
form)
13. Homocystinuria (methylentetrahydrofoltred. def.)(MTHFR)
14. izovaleric aciduria (IVA)
15. leucinosis (MSUD)
Screened diseases in CR
from 10/2009
• Cystic fibrosis
• cumulative risk of all 13 screened
diseases in CR - 1/1200