Molecular diagnostic in genetic diseases (2015/2016)

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Course code
Name of lecturer
Cristina Bombieri
Cristina Bombieri
Number of ECTS credits allocated
Academic sector
Language of instruction
II semestre dal Mar 1, 2016 al Jun 10, 2016.

Lesson timetable

Learning outcomes

The course aims to provide the proper knowledge of medical genetics for the understanding of human diseases and of advanced technologies and methods used in research and molecular diagnosis of genetic diseases.


Fundamentals of classical genetics. Genetic diseases and hereditary diseases. Mendelian inheritance and atypical inheritance patterns: Mitocondrial inheritance, heteroplasmy and mitochondrial diseases, reduced penetrance, varable expressivity; digenic and triallelic inheritance, incomplete dominance, etc. Mosaicism. X chromosome inactivation. Pedigree construction and analysis.

Molecular genetics in medicine. Gene and chromosomal mutations, mutation nomenclature. Mutagenesis and DNA repair. Molecular pathology of the gene: biological relevance and effect on the phenotype of mutations, methods for mutation classification as disease-causing. Gain and loss of function mutations, dominance and recessiveness. Genotype-phenotype correlation.

Diseases due to expansion of unstable repeat sequences (dynamic mutations). Unstable repeat expansion, premutation and full mutation, Sherman's paradox, anticipation.

Genetic variation in individuals and populations. Mutation and polymorphism. The Hardy-Weinberg law, allele and genotype frequency calculation.

Bases of human genetics. Human genome organization, gene order on human chromosomes. Structure of eukaryotic genes. Repetitive DNA. DNA polymorphisms: RFLP, SNP, VNTR, minisatellites, microsatellites. Genetic markers, physical and genetic maps. Linkage Disequilibrium.

Application of genetic polymorphism analysis: Individual identification, paternity testing. Total and partial chimerism after bone marrow transplantation. Diagnosis by linkage analysis.

Mendelian disease gene identification. Positional and functional cloning. Linkage analysis, human gene mapping, sequencing. Identification of disease causing mutations.

Cytogenetics: human chomosomes, normal karyotype. Chromosomal abnormalities, numerical and structural. Chromosomal polymorphisms and CNV.

Medical cytogenetics. Chromosomic syndromes and Genome disorders. Uniparental disomy. Uniparental diploidy: hydatiform moles and ovarian teratomas. Parent-of-origin effects, imprinting and genomic imprinting disorders.

Methods of chromosome analysis. Banding methods, karyotype analysis. Fluorescence in Situ hybridization (FISH), FISH painting, SKY-FISH. Array CGH.

Methods of nucleic acid molecular analysis. PCR, real-time-PCR, electrophoresis, Sanger sequencing, DGGE, hybridization, reverse dot blot, oligonucleotide ligation assay (OLA), primer extension (minisequencing), ARMS. Molecular diagnosis of genetic diseases, direct and indirect mutation analysis. Molecular analysis of genetic deletion/duplication (MLPA); Molecular analysis of unstable repeat expansions and VNTR.

Genetic testing. Diagnostic, presymptomatic, susceptibility, heterozygote identification, and pharmacogenetic tests. Applications and quality controls of genetic testing. Pre and post-natal diagnosis, population genetic screening, neonatal screening.

Medical genetics. Examples of single-gene diseases (Marfan S.; Becker and Duchenne Muscular Dystrophy; Cystic Fibrosis) and chromosomal disorders (Chromosomal Abnormalities due to balanced reciprocal translocation; Di George S.; Down S.). Modifier genes and complexity in single-gene disorders.

Determination of genetic risks. Bayesian analysis. Consanguinity and genetic risk.

The inheritance of multifactorial traits. Genetics of common disorders with complex inheritance, genetic and environmental factors, qualitative and quantitative traits, genetic predisposition to common diseases. General aspects od the identification of genetic factors in complex diseases. Segregation analysis: Mapping of complex traits, Familial and twin studies. Linkage and association analyses. Candidate gene studies, genome wide association studies (GWAS).

Genome projects. From human genome project to HapMap, 1000 Genome Project, Biological Encode Project , HGV project. Brief description and objectives.

Pharmacogenetics. Individual variation of drug response. Genes and polymorphisms of drug metabolism and mechanism of drug action. Molecular diagnostics of pharmacogenetic traits.

Cancer genetics. Cancer as genetic, somatic and multifactorial disease, hereditary and sporadic cancers, Two-Hits model (Knudson model). Classification and characterization of cancer genes (oncogenes, gatekeeper and caretaker tumor soppressor genes). Loss of heterozygosity (LOH), microsatellite instability (MIN).

Reference books
Author Title Publisher Year ISBN Note
Tobias ES, Connor M e Ferguson-Smith M Fondamenti di Genetica Medica (Edizione 1) Pearson 2014 978-88-6518-1713
Neri G e Genuardi M Genetica Umana e Medica (Edizione 3) EDRA LSWR - Masson 2014 978-88-217-3743-4

Assessment methods and criteria

oral examination