Download 2. Introduction to the diagnostics of genomic diseases

SYLLABUS
Name of the department / clinic providing the course:
Chair of Clinical and Laboratory Genetics
Department of Clinical Genetics
Course title:
Clinical Genetics
Course profile:
Academic
Specialty:
Level of course unit:
master
1. Course unit title: Clinical Genetics
2. Course unit code:
3. Type of course unit: compulsory
4. Course aims:
Making students familiar with: participation of genetic factors in the aetiopathogenesis of
diseases, laboratory diagnostics, used in the routine diagnostics of genomic diseases and
diseases determined by rearrangements of genes, the principles of pre- and postnatal genetic
counselling, ethical, legal and sociological problems, associated with genetic counselling and
with the future of clinical genetics – from preconception till maturity. Regarding abilities and
skills: teaching students how to carry out physical examination and determine diagnostic
algorithm, to identify a genetically determined disease, interpretation of specialist prognostic
analysis of disease, screening tests to identify genetically determined diseases and interpret
laboratory test results which may be prognostic for an increased risk of genetically determined
diseases.
5. Form of study:
Full time
6. Year of study: 2nd, 4 year MD program
7. Types of educational activities and number of hours allocated:
60 hrs:
Lectures – 20 hrs
Seminars – 25 hrs
Clinical classes – 15 hrs
8. Number of ECTS credits allocated and their structure according to students’ from of
learning:
4
9. Names of course unit’s faculty:
Prof. Maciej Borowiec, dr Zofia Helszer, dr Maria Constantinou, dr Edyta Borkowska,
dr Michał Pietrusiński
Prerequisites:
Reminder messages in the field of medical genetics and molecular biology from the
previous years of study
10. Learning activities and teaching methods:
lecture, seminars and classes
11. Course unit content:
Lecture contents:
1. Introduction to clinical and laboratory genetics
2. Introduction to the diagnostics of genomic diseases
3. Introduction to prenatal diagnostics of genetically determined diseases
4. Clinical management of sex development disorders. Diagnosis, treatment and prognosis
5. Ethical borders of genetic counselling
The subjects of classes in joint groups:
1. Clinical genetics as medical specialisation: genetically determined diseases, classification
of diseases – genomic diseases, monogenic diseases, the mode of inheritance: autosomal
dominant, recessive, X-linked, multigenic diseases, epigenetic diseases, trinucleotide
expansion diseases, multifactorial diseases, mitochondrial diseases, the incidence rates, lateonset genetical diseases, expression and penetration, incomplete penetration, pleiotropy, the
definition of phenocopy, genetically determined diseases in particular clinical specialties,
genetically determined diseases vs. familial diseases, the risk for genetically determined diseases.
1.1 Medical history specific for genetic counselling, physical examination and
dysmorphological evaluation of patient’s phenotype, application of clinical, diagnostic
examinations, indications to laboratory diagnostics of genetically determined diseases, genetic
risk assessment, the principles of genetic counselling, the principles of informing patient and
family about the results of genetic examination.
2. Laboratory diagnostics of genomic diseases: chromosome organisation of human genome,
classical and molecular techniques of cytogenetic studies, diseases determined by structural and
numerical aberrations of chromosomes – the aetiopathogenesis of diseases, polymorphism of
chromosomes, balanced and imbalanced chromosomal aberrations, the carriers of balanced
aberrations, uniparental disomy at chromosome level. Medical indications to the application of
karyotype studies, banding techniques, molecular cytogenetics in the diagnostics of diseases,
hybrydisation technique application for microarray studies, the diagnostic algorithm of genomic
diseases. Description of cytogenetic study results, according to international standards.
Preparation of diagnostic description of disease in selected clinical situations and with
consideration of the above-mentioned results of studies.
2.1 Clinical genetics of common autosomal trisomies
Syndromes determined by common chromosomal aneuploidies

Down’s syndrome,

Patau’s syndrome,

Edwards’ syndrome
2.2 Clinical genetics of sex chromosomes:

Turner’s syndrome, phenotype of Turner’s syndrome

patients with marker chromosome derivable from gonosomes in karyotype

Klinefelter’s syndrome

XXX woman’s syndrome

XYY man’s syndrome

“ sex-reversal patients”, hermaphrodite XX(SRY+), XY (SRY-)
2.3 Clinical genetics of deletions and other structural aberrations:

patients with procreations failures, infertility – carriers of balanced reciprocal
translocations and other balanced chromosomal aberrations

patients with imbalanced variant of reciprocal translocation

patients with balanced variant of reciprocal translocation and abnormal phenotype

patients with Robertsonian translocation

patients with inconsistency between phenotype and karyotype

patients with mosaic karyotype

microdeletion syndromes, with a particular consideration of – Prader-Willi syndrome,
Angelman syndrome, Beckwith-Wiedemann syndrome, Williams syndrome (WS) and
Wolf-Hirschhorn syndrome (WHS)

patients with uniparental disomy – clinical consequences, resulting from the loss of
heterozygosity, the loss of genomic imprint and the presence of trisomic line at the stage of
early embryonal development

patients with marker chromosome, originating from the autosome in karyotype

phenotype modelling via microdeletions and microduplictions of single genes in patients
with chromosomal aberration in karyotype
3. Laboratory diagnostics of mutation-determined diseases: monogenic and multigenic
diseases, epigenetic diseases, mutation-dependent sex development disorders, metabolic diseases
– aetiopathogenesis, patient’s phenotype-genotype correlation, diagnostics, genetic counselling.
Resolution of diagnostic methods and the molecular basis of genetically determined diseases.
Terminology used in the diagnostics of monogenic, multifactorial, metabolic and neoplastic
diseases, interpretation of study results, determination of the analytical and diagnostic sensitivity
of genetic studies, writing a diagnostic disease description in selected clinical situations, taking
into account the above-mentioned results of studies.
3.1 Diseases determined by monogenic mutations: the incidence; an analysis of pedigrees and
its role in the identification of inheritance mode; discussion on selected diseases entities.

Autosomal dominant diseases: achondroplasia (OMIM 100800), the syndrome of
polycystic kidney disease (OMIM 173900), Charcot-Marie-Tooth disease of type 1A
(OMIM 118220) and 2, familial hypercholesterolaemia (OMIM 143890), Marfan’s
syndrome (OMIM 154700), congenital bone fragility (osteogenesis imperfecta) of type 1
(OMIM 166200), claviculo-cranial dysplasia (OMIM 119600), Treacher-Collins syndrome
(OMIM 154500).

Autosomal recessive diseases: cystic fibrosis (OMIM 219700), congenital adrenal
hyperplasia (CAH) (OMIM 201910), haemochromatosis (OMIM 235200), Wilson’s
disease (OMIM 277900), lamellar ichtyosis LI1 (OMIM 242300), diastrophic dysplasia
(OMIM 222600), neurodegeneration, associated with pantothenate kinase (PKAN) (OMIM
606157).

X-linked diseases: Duchenne muscular dystrophy (OMIM 310200) and Becker’s muscular
dystrophy (OMIM 300376), haemophilia A (OMIM 306700),

Polygenetic diseases : the principles of inheritance, the pathomechanism and general
diagnostics of the most frequent multigenic diseases, hyperplastic cardiomyopathy (OMIM
192600), Hirschsprung’s disease (OMIM 142623).
3.2 Exceptions from classical mendelian inheritance: epigenetic diseases (UPD and
uniparental imprinting), diseases resulting from trinucleotide expansions, mitochondrial diseases
and their clinical significance, mutation-dependent sex development disorders.
Epigenetic diseases

Prader and Willi syndrome (OMIM 176270)

Angelman’s syndrome (OMIM 105830)

Beckwith-Wiedemann syndrome (OMIM 130650)
Trinucleotide expansions disorders

Huntington’s disease (HD) (OMIM 143100),

a group of spinal-cerebellar ataxias (SCA); SCA1 (OMIM 164400),

spinal-bulbar muscular atrophy (SBMA) (OMIM 313200),

the syndrome of fragile X chromosome (FRA X) (OMIM 300624),

myotonic dystrophies: DM1 (OMIM 160900) i DM2 (OMIM 602668)
Mitochondrial diseases

cardioencephalomyopathy with COX (SCO2) deficiency (OMIM 604377)
3.3 Mutation-dependent sex development disorders :
 androgen insensitivity syndrome OMIM 300068),
 gonadal dysgenesis 46,XY (OMIM 400044),
 congenital adrenal hyperplasia(CAH)(OMIM 201910),
 Kallmann’s syndrome (OMIM 308700).
4. Genetically determined metabolic diseases; prenatal and postnatal diagnostics of metabolic
diseases. Application of biochemical methods and molecular diagnostics:
A list of diseases:
 Organic acids metabolism disorders– methylmalonic acidosis (OMIM 251000)
 Defects of amino acid metabolism – albinism (OMIM 203100), alkaptonuria (OMIM
203500), phenylketonuria (OMIM 261600), nonketotic hyperglycinemia (OMIM
605899), homocystinuria (OMIM 236200)
 Defects of the urea cycle – deficit of ornithine transcarbamylase (OMIM 311250)
 Lipid metabolism disorders – MCAD ( OMIM 201450)
 Defects in carbohydrate metabolism – galactosemia (OMIM 230400)
 Peroxisomal diseases – Zellweger syndrome (OMIM 214100)
 Purine metabolism disorders – Lesch-Nyhan’s syndrome (OMIM 300322)
 Disorders of transport of heavy metals: haemochromatosis (OMIM 235200)
 Mucopolysaccharydosis: Hunter disease (OMIM 309900)
 Lipid storage disorders: Gaucher diseases of type II (OMIM 230900), Tay-Sachs disease
(OMIM 272800)
4.1 Selection of tissue for investigation, depending on clinical situation, the principles of
material acquisition for further investigation, storage and archiving of material for investigation.
5. Laboratory and clinical prenatal diagnostics: medical indications to prenatal diagnostics,
methods of prenatal diagnostics: screening studies (biochemical markers measured in blood of
pregnant women) towards malformations in the central nervous system (CNS) and Down’s
syndrome, biochemical markers measured in the amniotic fluid towards identification of open
CNS malformations; medical and ethical problems associated with prenatal diagnostics.
Organisation of prenatal diagnostics in Poland.
5.1 Non-invasive prenatal diagnostics: medical history, so-called „genetic ultrasonography of
the fetus” (4 D), ultrasonography with doppler technique, screening tests in serum of pregnant
women - sample collection and storage, measurement of biochemical markers – PAPPA, αphetoprotein, β-hCG, free estriol, tests of the 1st and the 2nd trimester of gestation and the
integrated test (diagnostic sensitivity, specificity and clinical significance) – determination of the
risk for fetal aneuploidy by means of the ALPHA program, revealing of results and providing
medical counselling, the influence of non-invasive prenatal screening tests on the modification of
medical indications to invasive prenatal diagnostics.
5.2 Invasive prenatal diagnostics: medical history, procedure – trophoblast biopsy (9 – 13
weeks), amniocenthesis (14 - 20 weeks), cordocentesis (>20 weeks) – diagnostic value and
limitation of examinations; patient’s preparation to amniocenthesis, amniocenthesis technique,
care over the patient after the procedure, the volume of collected material and storage of
amniotic fluid samples, diagnostics towards open neural tube defects, studies of fetal karyotype,
possibilities of monogenic disease identification, UPD in the fetus, microarray studies of the
fetus (clinical importance and limitations of the study), the principles of revealing the results.
6. Laboratory and clinical genetics of neoplasms – multistage genetic diseases. Actual views
on the genetic aetiopathogenesis of neoplasms, oncogenes, supressor genes, sporadic and familial
neoplasms, hereditary neoplasms, the influence of molecular cytogenetics and molecular biology
on the diagnostics, therapy and prognostics of noplastic disease.
6.1 Genetic predispositions to cancer. Which clinical and pedigree features decide about the
diagnosis of hereditary neoplasm? Which family member(s) should become subject of genetic
studies in case, when mutation is confirmed in the gene, responsible for hereditary predisposition
to neoplasms? What type of prophylactic examinations should be proposed? The ethical-moral
aspect in the specificity of genetic counselling in neoplastic disease.
Autosomal recessive example of neoplastic disease
 Ataxia – telangiectasia, early diagnostics of carrier state, the role of cytogenetics
(translocation of chromosomes 7 and 17) and of molecular biology (ATM mutation) in
the diagnostics of neoplasm.
Autosomal dominant examples of neoplastic disease
 Breast cancer, the role of hereditary dominating mutations BRCA1 (7q21) and BRCA2
(13q12.3) of high penetration. Tests for predisposition to neoplastic disease, application
of the tests in outpatient practice. The ethical and medical aspects of counselling effects.
 Colorectal carcinoma (hereditary non-polyposis colorectal carcinoma - HNPCC) the role
of hereditary, germinal mutations (MSH2,2p22-p21 and MLH1,3p21.3) of high
penetration in the aetiopathogenesis of neoplasm.
 Familial adenomatous polyposis – FAP, the role of suppressor gene - APC (APC 5q21
mutation), the role of studies on the carrier state of the 1st degree relatives in the
prophylactics of neoplasm.
 Li-Fraumeni syndrome and mutations of p53 gene as an example of transcription factor,
activating the expression of a large number of genes in many neoplastic diseases.
 Multiple endocrine neoplasia type 1 (MEN 1). The role of mutations in MEN-1 gene in
the identification of the carrier state among 1st degree relatives.
 Neurofibromatosis type I (von Recklinghausen’s disease), germinal mutations in NF1
gene (17q11), the role of mutation diagnostics in the counselling.
 Neurofibromatosis type II, NF2 gene mutation, 22q12.2 - the role of mutation diagnostics
in the diagnostics and prophylactics, a possibility of selecting a group of subjects with an
increased risk for diseases (children of sick subjects).
 Retinoblastoma, mutation (13q14.2) in RB1 gene and chromosomal deletion or
translocation as an example of the legitimacy of Knudson’s theory. The role of the 13q13
region in early diagnostics of disease.
 Wilms’ tumour, a neoplasm of the child age, mutations in WT1 11p13 suppressor gene
and WT2 11p15 gene as a frequent causative factor of disease.
 Von Hippel-Lindau disease, 3p26 mutations in VHL gene as an example of cascade of
genetic events, which lead to initiation of neoplastic transformation.
Sporadic neoplasms
 Urinary bladder carcinoma as an example of complex aetiopathogenesis of disease.
Attempts of statistical risk assessment implementation, based on the effects of somatic
genetic and environmental factors on disease prgnosis.
 Chronic myeloid leukaemia – CML, as example of a complex genetic mechanism
(translocation of chromosomes 9 and 22), resulting in fusion of BCR-ABL genes and
permanent activity of thyrosine kinases. The efficacy of therapy, monitored by the FISH
(fluorescent in-situ hybridisation) technique, as example of the role of cytogenetics and
molecular biology in effective treatment of neoplastic disease.
7. Procreation failures and infertility. Population-related, social and ethical aspects of
procreation failures and infertility. The role of genomic diseases and mutations as the causative
factors of female and male infertility.
7.1 The carrier state of balanced chromosomal aberrations as the cause of reproduction
failures. The diagnostic algorithm, applicable in similar cases .
7.2 Numerical and structural chromosomal aberrations as the cause of infertility.
7.3 The problem of decreased female fertility and male infertility (the syndrome of
congenital bilateral absence of the vas deferens - CBAVD) in patients with cystic fibrosis.
Mutations of CFTR gene as the casue of male infertility.
7.4 Interstitial microdeletions Yq (AZF – azoospermia factor - microdeletions) as the cause of
azoospermia and oligozoospermia in almost 2% of generally healthy men.
8. Genetic counselling: the goals and tasks of genetic outpatient clinic, identification of patients
with genetically determined diseases and of families with genetic risk; registers of malformations
and genetically determined diseases and their role for evaluation of the epidemiological status
and for ensurance of effective genetic care. Indications of referral to genetic outpatient clinic;
the mode of providing genetic counselling; the factors which influence the efficacy of genetic
counselling; primary ethical and moral dilemmas of genetic counselling
Subjects of clinical classes:

State-of-the-art diagnostics of genetically determined diseases (Laboratory of
Diagnostics of Genomic Diseases)

Diagnostics of microdeletion syndromes
Diagnostics of cystic fibrosis

Diagnostics of corporal-sexual development disorders

Diagnostics of congenital thrombophilia

Early, non-invasive diagnostics of urinary bladder carcinoma; monitoring of
the disease, risk evaluation, regarding disease progression and recurrence

Genetic counselling: taking medical history, dysmorphological evaluation,
ultrasonographic imaging, order of diagnostic studies, interpretation of study results,
design of genetic counsel.
12. Course objectives:
After completion of the course in clinical genetics, a student should:
- analyse genetic crosses and genealogy of human features and diseases
- determine the role of chromosomal aberrations and gene mutations in the
aetiopathogenesis of genetic diseases
- be able to determine the risk of delivering a child with chromosomal aberrations and
development al malformations
- understand the principles of pre- and postnatal counselling
- define indications to invasive and non-invasive prenatal diagnostics
- discuss psychological, legal and ethical problems, associated with genetic counselling
- be able to prepare a medical report, allowing to refer patient and her/his family to specialist
genetic outpatient clinic
- to write notations of the karyotypes of the most frequent genetic diseases
- estimate the risk of occurrence of a given disease in offspring, taking into account family
predispositions and the effect of environment al factors
- know how to use professional databases to retrieve data and information about genetic
diseases
- understand the diagnostic-therapeutic advantages, resulting from the application of genetic
diagnostics
- be aware of the necessity of continuous self-education to extend and deepen theoretical
knowledge and improve hands-on skills, as well as to implement new achievements to
practice
13. Required and recommended learning resources (readings):
Basic:
Genetics in Medicine, Thompson & Thompson, SAUNDERS, 2007, ISBN978-1-4160-3080-5
Recommended:
Clinical Genetics, Helen V. Firth & Jane A. Hurst. Oxford Desk Reference – Oxford
University Press, 2005
Medical Genetics, 4th Edition, Lynn B. Jorde, John C. Carey, Michael J. Bamshad, Elsevier
2009, ISBN: 0323053734 ISBN13: 9780323053730
14. Assessment methods and criteria:
Credits are granted for participation in seminars / exercises and for passing a written
test (25 questions) on the last day with satisfactory score at minimum. Participation in
lectures is highly recommended.
The final exam is a written test (50 questions), encompassing the knowledge of
clinical & laboratory genetics from lectures, exercises and seminars, as well as from
the manual “Genetics in Medicine”, Thompson & Thompson, SAUNDERS, 2007,
ISBN 978-1-4160-3080-5
15. Additional information:
Contact
42-632-70-02;
[email protected]
w4u.umed.lodz.pl
Head of the Chair and Department
dr hab. n. med. prof. nadzw Maciej Borowiec
[email protected]
Coordinator of the subject
dr Zofia Helszer
[email protected]
16. Statement and signature of the course coordinator :
I hereby state that the content of the curriculum included in the syllabus below are the result of
teaching staff of our Department
17. Dean’s signature:
18. Date:24.09.2012