Medical genetics and pharmacogenomics (2015/2016)

Course code
Name of lecturer
Giovanni Malerba
Giovanni Malerba
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 basic knowledge of the principles and mechanisms of human and molecular genetics responsible for the transmission of normal and abnormal characters in humans, as well as the mode of occurrence of hereditary biological variation.

Professionalizing objectives
The course aims to provide the future doctor with the knowledge and tools necessary to be able to advise the patient and his family in presence of a genetic or hereditary disease, about the nature of the disease, its incidence, prognosis, risks recurrence, preventive options, available therapeutic and reproductive options, and of the available genetic tests, whether diagnostic, symptomatic, predictive, pre- or post-natal.
At the end of the course the student should be able to ask the appropriate questions to draw and interpret human pedigrees, distinguish different types of inheritance, request genetic tests to confirm (or exclude) a suspected genetic disease and interpret their results, knowing how to efficiently counsel patients and families about the nature of genetic disease, as well as to assess recurrence and occurrence of reproductive genetic risks (genetic counselling), indicating possible genetic and environmental causes in multifactorial diseases, enumerating the possible causes and types of gene mutation and be able to derive the frequency of the disease gene/allele frequency in populations.


General Genetics Mendel’s laws, dominance, recessivity, phenotypes and genotypes,single and double backcross, independent segregation, pedigree drawing, autosomal dominant traits, variable expression, reduced penetrance, late onset, new mutations, mosaicism, examples. Codominance. Autosomal recessive traits, carrier population frequencies, newborn screening, phenotypic complementation, examples. Consanguinity, genetic heterogeneity.

General and medical cytogenetics. Standard human karyotype, chromosome anatomy and classification. Molecular cytogenetics: Fluorescent In Situ Hybridization (FISH), Array-CGH. Chromosome anomalies, numerical and structural, frequency, balanced and unbalanced, aneuploidies, trisomies, Turner and Klinefelter syndromes, XXX, XYY, translocations, genetic reproductive risks, pericentric and paracentric inversions, Down syndrome and maternal age. Indications to perform a karyotype. Non equivalence of the maternal an paternal genomes.Uniparental diploidy, gynogenotes, androgenotes, parthenogenesis

Epigenetics. Genomic imprinting, Prader-Willi syndrome, Angelman syndrome, Uniparental Disomy (UPD): heterodisomy, isodisomy, trisomic rescue, clinical consequences of UPD. Cytogenetic pre- and post-natal diagnosis.

Clinical Genetics. Genetic counseling, pedigree drawing, genetic risks, risk estimation, reproductive options in at-risk couples.
Genetic risk calculation. Laws of probability, independent events, Bayes rule, examples. Consanguinity in genetic counseling.

Prenatal diagnosis. Indications and limits, invasive and non-invasive procedures, amniocentesis, CVS, NIPT, ccffDNA, Preimplantation Genetic Diagnosis (PGD), AME, Advanced Maternal Age, biochemical screening.

Prenatal genetic counseling. Dismorphology, birth defects, clinical case reports.

Prevention and treatment of genetic disease. Genetic testing, symptomatic and asymptomatic testing, predictive tests. Treatment of genetic disease, non-genetic treatment: restriction, replacement, removal; somatic gene therapy, ex vivo, in vivo, antisense RNA, RNAi, genome editing; germinal gene therapy, genetic enhancement. Regenerative medicine: stem cells, cloning, bioethical and social issues.
X-linked inheritance.
X-linked recessive and dominant disease, frequencies, clinical and genetic features, recurrence risks, examples, X inactivation (Lyonization), Barr body, Y-linked traits, SRY gene, X-Y recombination in humans. Mitochondrial (mt) genome and mt inheritance. Heteroplasmy, mt diseases, mt and early aging, degenerative diseases, myocardial ischaemia.
Mutations and mutagenesis.
The genetic code and mutations. Third base wabbling, mt code, co-linearity, reading frame, overlapping genes. The mutation, definition, onset, localization, types, causes. Spontaneous vs induced mutations, physical mutagens, radiation sourses, UV light mutation mechanisms, mutation frequencies, base tautomerism, transitions, transversions, spontaneous deamination, unequal crossing-over, purine loss, gene conversion, transposition, retrotransposons, reciprocal recombination.
Unstable triplet repeat expansions.
Premutation, full mutations, the Sherman paradox, molecular analysis of the expansions, anticipation, examples: Huntington disease, Fragile X syndrome, Steinert myotonic dystrophy, SCAs: Spino Cerebellar Ataxias.
Complex (Multifactorial) disease.
Definition, genetic and envirobmental roles, diseases of civilization, methods of analysis, segregation analysis, linkage analysis, parametric and non-parametric approaches, GWAS, candidate gene approach, SNPs and genetic profiles, normal distribution of characters, quantitative traits, twin studies, dichotomous traits, birth defects, adult-onset disease, genetic susceptibility and the threshold model, predisposing factors, early diagnosis, risk modification.
Genomic scans.
Definition, study design, data quality control, imputation, significance of results, genetic risk estimation, direct and indirect association, linkage disequilibrium, rare variants, examples of association in complex disease, disease risk and prediction.
Exome, Genome, Transcriptome.
Definition and description, sequencing strategies, genetic and transcriptome profiles, advantages and limits of NGS (Next Generation Sequencing), comparison between sequencing technologies and arrays, data significance, NGS in clinical practice, incidental findings, exome/genome as tools for mendelian and complex disorders.
Bioinformatics and Genomics.
Complexities of genomic data, numerology of the human genome, the importance of bioinformatics in the “omics” genetic studies, examples, bioinformatics and data gathering, analysis and interpretation
Individual variabilityin drug response, pharmacogenetic experiments, determinants involved in drug responses, genes associated to the variability in drug response, polymorphisms in genes involved in drug metabolism and pharmacodynamics, molecular diagnostics od pharmacogenetics traits.

Supplementary educational materials will be made available during the course on this web page:

Reference books
Author Title Publisher Year ISBN Note
Strachan, Goodship, Chinnery Genetics and Genomics in Medicine (Edizione 1) Garland Science - Taylor and Francis Group 2014

Assessment methods and criteria

Written test, contextual to the Molecular Biology test, including multiple-choice quiz, open questions and exercises. Subsequent oral test, subject to positive evaluation of the written tests.