Learning outcomes

See the “content” section

Goals

Genetics is taking an increasingly important place in the biomedical field, both in diagnostics and in therapeutic perspectives. The genetics course addresses the fundamental concepts from a specifically human angle, ranging from molecular genetics to population genetics. The structure of DNA and genes and the regulation of their expression in eukaryotes are studied. The study of gene transmission is illustrated with examples of dominant, recessive, or X-linked diseases. The main genetic syndromes, whether of chromosomal or gene origin, are presented (molecular aspects, phenotypic features, and genetic counseling). Concepts of multifactorial inheritance are covered. Cytogenetics, human genome organization, and the principles of genetic mapping are explained using examples to help understand their current applications. The course emphasizes understanding of mechanisms and scientific reasoning.


For the section on clinical genetics (Prof. I. Maystadt), the objectives are as follows:


INTRODUCTION : The profession of clinical geneticist and the genetics consultation

  • To know the different stages of a classical genetics consultation
  • To understand the difference between a diagnostic test and a predictive test


CHAPTER 1: Clinical Cytogenetics

  • To be able to cite various chromosomal analysis techniques and briefly describe them:

- Standard karyotype

- Fluorescence in situ hybridization (FISH)

- Molecular karyotype: CGH-arrays and shallow whole genome sequencing (SWGS)

  • To understand the advantage of molecular karyotyping compared to standard karyotyping
  • To be able to cite the three viable constitutional autosomal trisomies
  • To know the main clinical features of trisomy 21, trisomy 18, and trisomy 13
  • To understand the difference between constitutional trisomy and mosaic trisomy
  • To understand and explain the mechanisms leading to trisomy and to understand the implications for genetic counseling (recurrence risk):

- Constitutional trisomy due to meiotic nondisjunction

- Constitutional trisomy due to parental translocation

- Mosaic trisomy due to mitotic nondisjunction 

  • To understand the relationship between trisomy risk and maternal age
  • To know the cytogenetic and clinical characteristics of the following syndromes:

- Turner syndrome (45,X)

- Klinefelter syndrome (47,XXY)

  • To know the consequences of sex chromosome anomalies other than 45,X and 47,XXY
  • To know the cytogenetic and clinical characteristics of the following microdeletion syndromes:

- Cri du Chat syndrome (5p deletion)

- Velocardiofacial syndrome (22q11 microdeletion)

Note: Wolf-Hirschhorn syndrome, Williams-Beuren syndrome, Smith-Magenis syndrome: not included in exam content

  • To be able to define a risk factor. To understand and define the concepts of "incomplete penetrance" and "variable expressivity"
  • To understand and define the principle of parental imprinting
  • To know the main clinical features and underlying molecular mechanisms of the following syndromes and to understand the implications of the molecular pathophysiology mechanisms for genetic counseling (recurrence risk):

- Prader Willi syndrome

- Angelman syndrome

Note: Beckwith-Wiedemann syndrome and Silver-Russell syndrome: not included in exam content


CHAPTER 2 : Monogenic Diseases

  • To understand and define the concepts of "monogenic disease," "genetic heterogeneity," and "genic or allelic heterogeneity"
  • To be able to cite various gene analysis techniques and briefly describe them (see also modules 4 and 5):

- Sanger sequencing

- Next Generation Sequencing (NGS) (see also module 4 below)

- Southern Blotting

  • To know the molecular and clinical features of the following syndromes:

- Marfan syndrome

- Neurofibromatosis type 1

- Rett syndrome

- Noonan syndrome

  • Regarding NGS techniques:

- To understand the difference between gene panel analysis, mendeliome, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS)

- To understand the process and criteria used for variant filtering in NGS

- To know the classification of variants (class 1: benign, class 2: likely benign, class 3: uncertain significance, class 4: likely pathogenic, class 5: pathogenic)

- To know the limitations of NGS methods

  • To know the molecular and clinical features of Fragile X syndrome
  • To be able to define the term "anticipation"

Note: Myotonic dystrophy (Steinert disease): not included in exam content


CHAPTER 3: Diagnostic Strategy (review)

  • To be able to identify the most appropriate technique according to the suspected pathology (see modules 1 to 4)


CHAPTER 4: Disclosure of diagnosis

Not included in exam content but highly important for future practice


Content

1.Introduction


  • The germline is continuous
  • Genetics, human genetics, medical genetics, somatic “genetics”
  • Impact of genetic diseases on human health
  • Relationships between genes, environment, and phenotypes
  • Historical background of some fundamentals of genetics
  • Mendel’s discoveries: the concept of the gene
  • Mendel's laws
  • Chromosome theory of inheritance
  • Genes are linked to chromosomes
  • Meiosis
  • Genetic linkage and crossing-over
  • Chromosome mapping
  • The origin of genetic variability, mutations
  • Nucleic acids transmit genetic information
  • Avery’s unexpected discovery: DNA can carry genetic specificity
  • The double helix
  • Genetic information contained in DNA is encoded in the sequence of the four nucleotides
  • The central dogma
  • Crick’s adaptor hypothesis
  • Discovery of tRNAs
  • Discovery of mRNAs
  • Establishment of the genetic code

2. Structure of Nucleic Acids


  • The DNA double helix
  • DNA topology
  • Structure and functions of RNA (including slides on RNA viruses and their cycle)


3. Organization of Genomes


  • Size, organization
  • Repeated sequences
  • Mammalian transposable elements (LINE, SINE, LTR, ERV)
  • LINE transposition


4. Structure of Chromosomes


  • Centromeres
  • Origins of replication
  • Telomeres
  • Replication of the ends of linear chromosomes
  • Telomerase
  • Chromatin structure
  • The nucleosome
  • Higher-order chromatin structures
  • Regulation of chromatin structure
  • Histone modifications


5. DNA Replication


  • Initiation, activation of replication origins
  • Helicases, topoisomerases, primase, DNA polymerases


6. Mutations


  • Different types of mutations
  • Origin of mutations


7. DNA Damage and Repair


  • Nature of DNA damage
  • Chemical modifications of the bases (altered bases, missing bases)
  • Deaminations
  • Base oxidation
  • Hydrolysis (base loss)
  • Alkylations
  • Pyrimidine dimers
  • Base mismatches
  • Intrabranch and interbranch crosslinks
  • DNA-protein crosslinking
  • Single-strand and double-strand breaks of the ribose-phosphate backbone
  • Causes of DNA damage
  • Spontaneous damage
  • Induced damage by mutagenic "agents" (chemicals, UV and ionizing radiation)
  • Ionizing radiation
  • Chemical mutagens
  • The Ames test detects the mutagenic potential of a substance
  • Repair mechanisms and “trans-lesion” DNA synthesis (TLS)
  • Repair of a damaged base
  • Direct reversal of DNA damage
  • Base excision repair (BER)
  • Repair of bulky lesions
  • Nucleotide excision repair (NER)
  • Repair of mismatches (mismatch repair, MMR)
  • Interstrand cross-link repair (ICL)
  • Repair of double-strand breaks:
  • Non-homologous end joining (NHEJ)
  • Homologous recombination, gene conversion
  • Clinical consequences of DNA repair defects


8. Cytogenetics and Concepts of Epigenetics


  • Observation and description of chromosomes (banding)
  • Chromosomal abnormalities
  • Definition
  • Different categories of abnormalities
  • Numerical and structural abnormalities
  • Cytogenetic nomenclature
  • Balanced and unbalanced abnormalities
  • De novo and inherited abnormalities
  • Causes of aneuploidies
  • Clinical consequences of abnormalities
  • Autosomal aneuploidies
  • Causes of Down syndrome
  • Sex determination
  • Sex chromosome abnormalities
  • X chromosome inactivation
  • DNA methylation and concepts of epigenetics
  • Sex chromosome abnormalities
  • Parental origin chromosomal abnormalities
  • Parental imprinting
  • Diploidy and uniparental disomies
  • Causes of Prader-Willi and Angelman syndromes


9. Genome Expression: Transcription


  • Initiation complex, transcription factors
  • Elongation
  • Termination and polyadenylation
  • Intron splicing


10. Genes in Pedigrees and Populations


  • Patterns of Mendelian pedigrees
  • Complications compared to Mendelian pedigrees
  • Genetics of multifactorial traits: the polygenic threshold theory
  • Factors affecting allele frequencies
  • Use of Hardy-Weinberg equilibrium in genetic counseling
  • New mutations, selection, genetic drift


11. Mapping and Identification of Genes Controlling Monogenic Traits


  • Positional cloning
  • Functional cloning
  • Genome-wide association studies
  • Genome and exome sequencing
  • Confirmation of the candidate gene


12. Human Genetic Variability and Its Consequences


  • Types of variation between individual genomes (SNPs, repeat number, large-scale variants)
  • Pathogenic DNA variants (missense, nonsense, frameshift mutations, dynamic mutations)
  • Molecular pathology: understanding the impact of pathogenic variants
  • Loss of function vs. gain of function
  • Allelic heterogeneity in loss of function
  • Haploinsufficiency
  • Dominant negative effect
  • Gain-of-function mutations often affect regulatory pathways
  • Allelic homogeneity is not always linked to gain of function


13. Essentials of Molecular Biology (Methods):


  • Cloning of DNA fragments in cells
  • Electrophoresis
  • Nucleic acid hybridization
  • FISH
  • Sanger DNA sequencing
  • Southern blot, Northern blot
  • PCR
  • Transcriptomics by RNA microarray and RNAseq
  • CGH array
  • CRISPR/Cas9 and genome editing (very brief)



For the section Clinical Genetics (Prof. I. Maystadt):

This introductory course in clinical genetics provides the fundamentals of the profession of clinical geneticist and the essential steps in a genetics consultation, distinguishing between diagnostic and predictive testing. It offers a structured exploration of clinical cytogenetics, presenting the main chromosomal analysis techniques and major associated syndromes, as well as the mechanisms underlying the occurrence and transmission of chromosomal and monogenic disorders. Students are also introduced to genetic counseling principles, variant classification, and diagnostic strategies tailored to each pathological context, while addressing both the human and practical considerations involved in the communication of genetic diagnoses.

Exercices

Tutorial sessions.

Teaching methods

Ex-cathedra classes and tutorials.

Assessment method

Multiple-choice questionnaire on the material covered in the ex-cathedra lessons and tutorials.

Sources, references and any support material

PowerPoint’ type support
 
 reference manuals :
 
Human Molecular Genetics (4th Ed.) Authors: STRACHAN Tom, READ Andrew

Language of instruction

French