This document discusses the increasing use of genetics in clinical medicine. It covers topics like germline alterations, genetic susceptibility to common diseases, the role of primary care physicians in genetics, and advances in genetic testing techniques. The importance of understanding a patient's family history and genetic risks is emphasized. Different patterns of genetic inheritance for various conditions are reviewed, along with examples of monogenic disorders and cancer syndromes. Emerging areas like pharmacogenomics and personalized medicine are also mentioned.

1. THE PRACTICE OF GENETICS IN
CLINICAL MEDICINE
PRESENTER- Dr. Mahendra debbarma
Medicine

2. Introduction
• In the practice of clinical medicine there is is increasing use of
Genetic testing for inherited abnormalities associated with
disease risk.
• Germline alterations- chromosomal abnormalities, specific
gene mutations with autosomal dominant or recessive patterns,
and single nucleotide polymorphisms
• Germline alterations are responsible for disorders beyond
classic Mendelian conditions with genetic susceptibility to
common adult-onset diseases such as asthma, hypertension,
diabetes mellitus, macular degeneration, and many forms of
cancer.
• For many of these diseases, there is a complex interplay of
genes (often multiple) and environmental factors that affect
lifetime risk, age of onset, disease severity, and treatment
options.

3. • Primary care physicians are relied upon to help patients
navigate testing and treatment options.
• Physicians should understand the genetic basis for a
large number of genetically influenced diseases, through
personal and family history to determine the risk for a
specific mutation, and be positioned to provide counseling
• The field of clinical genetics is rapidly moving from single
gene testing to multigene panel testing, with techniques
such as wholeexome and -genome sequencing.

4. Importance of clinical genetics
• Awareness of genetic etiology can have an impact on
clinical management, including prevention and screening
for or treatment of a range of diseases.
The Genetics course
Basics
Structure &
Facts
Functions
Inherited
disorders
Diseases Applications
Gene Therapy
Cloning
Stem Cell
Genetic Testing

5. Basic Principles of Medical Genetics
1.The Human Genome
2.DNA structure and packaging
3.Mitochondrial DNA
4.Chromosomal Morphology
5.Chromosome Replication
6.Gene Expression
7.Meiosis , Mitosis and Gametogenesis
8.Epigenetics

6. 9. Population Genetics
10. Consanguinity
11. Family medical History
12. Inherited disorders
13. Mendelian inheritance
14. Non Mendelian inheritance
15. Cytogenetic abnormalities

7. The human genome
• Genome means the entire DNA content of an organism
• Human genome consist of 3.4 billion(3 x 10^9) base pairs
on 23 pairs of chromosomes.
• Only about 2% of the human genome contains coding
genes
• Action of much of the genome is unknown
• The sequencing of whole genomes or exomes (the exons
within the genome) is increasingly used in the clinical
practise.
• Helps characterize individuals with complex undiagnosed
conditions or to characterize the mutational profile of
advanced malignancies in order to select better targeted
therapies

8. DNA Structure

9. DNA Structure

10. Karyotype of human cell

12. • Down syndrome, was demonstrated to result from having
three copies of chromosome 21 (trisomy 21)

13. • Similarly trisomy 13 is called Patau syndrome and trisomy
18 is called Edward syndrome.
• Williams syndrome, which is associated with interstitial
deletions of the long arm of chromosome 7 (7q11.23);

15. Are chromosomal abnormalities
inherited?
• Most chromosomal abnormalities are not passed from
generation to generation
• Numerical abnormalities- these changes are not inherited
but occur as random events during the formation of
reproductive cells
• Structural abnormalities- some changes can be inherited
while others occurs as random events during the
formation of reproductive cells or early fetal development.

16. Epigenetics
• Epigenetics is the study of heritable changes in
phenotype (appearance) or gene expression caused by
mechanisms other than changes in the underlying DNA
sequence, hence the name epi- (Greek: επί- over, above)
-genetics.
• These changes may remain through cell divisions for the
remainder of the cell's life and may also last for multiple
generations.

17. Clinical genetics
• Clinical genetics is the practice
of clinical medicine with
particular attention to hereditary
disorders.

18. Inherited disorders
• Cytogenetic
• Single gene
• Polygenic
• Multifactorial

19. Clinical Genetics
• Genotype: An individual’s genetic makeup - forms of a particular
gene at a given locus
• Phenotype: The observable expression of a genotype
• Homozygous: Identical forms of a particular gene
• Heterozygous: Different forms of a gene– CARRIER if one
normal and one abnormal
• Dominant: Condition phenotypically expressed in someone
carrying one copy of a mutant gene
• Recessive: Condition phenotypically expressed only in someone
with two copies of the mutant gene

20. Autosomal dominance
• Vertical transmission
• Manifest in heterozygous state, no skipped generation
• Unaffected individuals do not transmit trait
• Males and females can be affected

21. Autosomal Dominant Conditions
• Marfan Syndrome
• Tuberous Sclerosis
• Achondroplasia
• Familial (early-onset) Alzheimer Disease
• Huntington Disease
• Familial Hypercholesterolemia
• Familial Breast Cancer (BRCA1 or BRCA2 mutations)
• Hereditory spherocytosis
• Acute intermittent porphyria
• Hypertrophic Obstructive Cardiomyopathy (HOCM)
• Von Willebrand Disease
• Osteogenesis Imperfecta

22. Autosomal Recessive Inheritance
• Horizontal transmission; disease in siblings but usually not in earlier
generations (unaffected, carrier parents)
• On average, 25% recurrence risk
• Males and females can be affected
• Increased consanguinity (relatedness) seen

23. Autosomal Recessive Conditions
• Sickle cell disease
• Cystic fibrosis
• Tay-Sachs disease
• Hemochromatosis
• Phenylketonuria
• Thalassemias
• Wilson disease
• Freidreich ataxia

24. X-linked recessive inheritance
• Incidence of trait is much higher in males than females
• No father-to-son transmission
• 100% of daughters of affected males are (unaffected)
carriers
• 50% of sons of carrier females are affected and 50% of
daughters are carriers
• Trait may be transmitted through series of carrier females

25. X-linked recessive conditions
• Haemophilia
• Duchenne and Becker muscular dystrophy
• Androgen insensitivity syndrome
• Hunter syndrome
• Glucose-6-phosphate-dehydrogenase deficiency
• Bruton agammaglobulinaemia

26. X- linked dominant
• Males and females affected, females usually less
severely affected than males
• 1 in 2 risk to children of affected female (M+F)
• All daughters of affected male affected but no
male to male transmission

27. X-linked dominant inheritance
Males and females
affected
• Vitamin D resistant
rickets
• Fragile X syndrome
Lethal in males
• Incontinentia
pigmenti
• Rett syndrome

28. Mitochondrial inheritance
• Mitochondria are
exclusively maternally
inherited
• Males and females
affected but only
females will transmit to
offspring
• Risks to offspring of
affected or carrier
females are difficult to
determine

29. Mitochondrial inheritance

30. Epigenetic inheritance and
imprinting
• Several loci have been identified where gene repression
is inherited in a parent of origin-specific manner; these are
called imprinted loci.
• Within these loci the paternal alleles of a gene may be
active while the maternal one may be silenced, or vice
versa.
• Mutations within imprinted loci lead to a very unusual
pattern of inheritance where the phenotype is only
manifest if inherited from the parent who contributes the
transcriptionally active allele

32. COMMON ADULT-ONSET GENETIC DISORDERS
INHERITANCE PATTERNS
• Adult-onset hereditary diseases follow multiple patterns of
inheritance.
• Some are autosomal dominant conditions.
• common cancer susceptibility syndromes such as
hereditary breast and ovarian cancer (due to germline
BRCA1 and BRCA2 mutations)
• Lynch syndrome (caused by germline mutations in the
mismatch repair genes MLH1, MSH2, MSH6, and PMS2).
• In the above examples, inherited mutations are
associated with a high penetrance (lifetime risk) of cancer,
although risk is not 100%.

33. • In other conditions, although there is autosomal dominant
transmission, there is lower penetrance, thereby making
the disorders more difficult to recognize.
• For example, germline mutations in CHEK2 increase the
risk of breast cancer, but with a moderate lifetime risk in
the range of 20–40%, as opposed to 50–70% for
mutations in BRCA1 or BRCA2.

34. • The genetic risk for many adult-onset disorders is multifactorial.
• Risk can be conferred by genetic factors at a number of loci,
individually have very small effects (relative risks of <1.5).
• These risk loci (generally single nucleotide polymorphisms
[SNPs]) combine with other genes and environmental factors in
ways that are not well understood.
• SNP panels are available to assess risk of disease, but the
optimal way of using this information in the clinical setting
remains uncertain.
• Personal and family histories provide important insights into the
possible mode of inheritance

35. Common monogenic disorders affecting
major organ systems

36. Common monogenic disorders affecting
major organ systems cont.

37. Examples of familial cancer syndromes

38. FAMILY HISTORY
• When two or more first-degree relatives are affected with
asthma, CVD, type 2DM, breast cancer, colon cancer, or
melanoma, the relative risk for disease among close
relatives ranges from two- to fivefold
• Family history should be recorded in the form of a
pedigree.
• Pedigrees should convey health-related data on first- and
second degree relatives.
• When such pedigrees suggest inherited disease, they
should be expanded to include additional family members.

39. • Additional variables, nonhereditary risk factors among
those with disease (such as cigarette smoking and
myocardial infarction; asbestos exposure and lung
disease; mantle radiation and breast cancer).
• Significant associated environmental exposures or
lifestyle factors decrease the likelihood of a specific
genetic disorder.
• In contrast, the absence of nonhereditary risk factors
typically associated with a disease raises concern about a
genetic association

40. • The physical examination may also provide important
clues about the risk for a specific inherited disorder.
• A patient presenting with xanthomas at a young age
should prompt consideration of familial
hypercholesterolemia.
• The presence of trichilemmomas in a woman with breast
cancer raises concern for Cowden syndrome, associated
with PTEN mutations

41. • Clustering of relatives with the same or related conditions
suggest inherited disorders
• it is important to note that disease penetrance is incomplete for
most genetic disorders.
• As a result, the pedigree obtained in such families may not
exhibit a clear Mendelian inheritance pattern, because not all
family members carrying the disease-associated alleles will
manifest clinical evidence
• Furthermore, genes associated with some of these disorders
often exhibit variable disease expression.
• For example, the breast cancer–associated gene BRCA2 can
predispose to several different malignancies in the same family,
including cancers of the breast, ovary, pancreas, skin, and
prostate.

42. Recording of Data
• Recall of family history is often inaccurate
• It can be helpful to ask patients to fill out family history
forms before or after their visits, because this provides
them with an opportunity to contact relatives.
• Ideally, this information should be embedded in electronic
health records and updated intermittently.
• Attempts should be made to confirm the illnesses
reported in the family history before making important
and, in certain circumstances, irreversible management
decisions.

43. A 36-year-old woman (arrow) seeks consultation because of her family
history of cancer. The patient expresse concern that the multiple
cancers in her relatives imply an inherited
predisposition to develop cancer. The family history is recorded, and
records of the patient’s relatives confirm the reported diagnoses.

44. Medical Genetics in Clinical Practice
Genetic testing
Genetic screening
Molecular diagnostics
Pharmacogenomics
Genetic engineering
Gene Therapy

45. GENETIC TESTING FOR ADULT-ONSET
DISORDERS
• A critical first step before initiating genetic testing is to ensure
that correct clinical diagnosis based on family history,
characteristic physical findings, pathology, or biochemical
testing.
• In the traditional model of genetic testing, testing is directed
initially.
• The patterns of disease transmission, disease risk, clinical
course, and treatment may differ significantly depending on the
specific gene affected.
• Historically, the choice of which gene to test has been
determined by unique clinical and family history features and
the relative prevalence of candidate genetic disorders.
• It is now technically and financially feasible to sequence many
genes (or even the whole exome)

46. METHODOLOGIC APPROACHES TO
GENETIC TESTING
• Genetic testing is performed largely by DNA sequence analysis
for mutations
• Genotype can also be deduced through the study of RNA or
protein (e.g., apolipoprotein E, hemoglobin S, and
immunohistochemistry)
• The determination of DNA sequence alterations relies heavily
on the use of polymerase chain reaction (PCR)
• Amplified DNA can be analyzed directly by DNA sequencing, or
it can be hybridized to DNA chips or blots to detect the
presence of normal and altered DNA sequences
• Analyses of large alterations of the genome are possible using
cytogenetics, fluorescent in situ hybridization (FISH), Southern
blotting, or multiplex ligationdependent probe amplification
(MLPA)

47. METHODOLOGIC APPROACHES
CONT.
• Massively parallel sequencing (also called next-generation
sequencing) is significantly altering the approach to genetic
testing for adult-onset hereditary susceptibility disorder
• Multiplex panels for inherited susceptibility are commercially
available and include testing of a number of genes that have
been associated with the condition of interest
• Whole-exome sequencing (WES) is also now commercially
available, although largely used in individuals with syndromes
unexplained
• In addition to technical errors, genetics tests are sometimes
designed to detect only the most common mutations.

48. METHODOLOGIC APPROACHES
CONT.
• Presymptomatic testing applies to diseases where a
specific genetic alteration is associated with a near 100%
likelihood of developing disease.
• In contrast, predisposition testing predicts a risk for
disease that is less than 100%.
• For example, presymptomatic testing is available for
those at risk for Huntington’s disease; whereas,
predisposition testing is considered for those at risk for
hereditary colon cancer.
• It is important to note that for the majority of adult-onset
disorders, testing is only predictive

49. • The optimal testing strategy for a family is to initiate
testing in an affected family member first.
• Identification of a mutation can direct the testing of other
at-risk family members (whether symptomatic or not).
• asymptomatic family members who test positive for the
known mutation must be informed that they are at
increased risk for disease development and for
transmitting the alteration to their children.

50. Issues related to test
• Pretest counseling and education are important, as is an
assessment of the patient’s ability to understand and cope
with test results
• several professional organizations have cautioned that
genetic testing for adult-onset disorders should not be
offered to children.
• Informed consent for genetic testing begins with
education and counseling.
• The patient should understand the risks, benefits, and
limitations of genetic testing, as well as the potential
implications of test results.

51. Indications for Genetic Counseling
• Advanced maternal age (>35 years)
• Consanguinity
• Previous history of a child with birth defects or a genetic
disorder
• Personal or family history suggestive of a genetic disorder
• High-risk ethnic groups
• Documented genetic alteration in a family member
• Ultrasound or prenatal testing suggesting a genetic
disorder

55. Pharmacogenomics(Personalised
Medicine)
• It is the science of dissecting the genetic determinants of
drug kinetics and effects using information from the
human genome.
• For more than 50 years, it has been appreciated that
polymorphic mutations within genes can affect individual
responses to some drugs, such as loss-of-function
mutations in CYP2D6 causing hypersensitivity to
debrisoquine, an adrenergic-blocking medication formerly
used for the treatment of hypertension in 3% of the
population.
• This gene is part of a large family of highly polymorphic
genes encoding cytochrome P450 proteins, mostly
expressed in the liver, which determine the metabolism of
a host of specific drugs.

56. • Polymorphisms in the CYP2D6 gene also determine
codeine activation
• Polymorphisms in CYP2C9 gene affect warfarin
inactivation.
• Polymorphisms in these and other drug metabolic genes
determine the persistence of drugs and thus provide
information about dosages and toxicity.
• At the present time it is seldom used routinely, but in the
future it may be possible to predict the best specific drugs
and dosages for individual patients based on genetic
profiling: so-called ‘personalised medicine’

57. Gene therapy
• Attempts to replace or repair mutated genes (gene therapy) in
humans have met with very limited success so far.
• Most notable has been replacement of the defective gene in
the treatment of severe combined immune deficiency
syndrome using retroviral vectors (p. 79).
• Bone marrow that has been genetically engineered ex vivo to
express the normal gene product can be returned to the
patient.
• There have been two major problems with the
1) The random integration of the retroviral DNA (which contains
the replacement gene) into the genome has caused leukaemia in
some treated children via activation of proto-oncogenes.
2) A severe immune response to the viral vector may be
induced. It has not yet been possible to use non-viral means to
introduce sufficient numbers of copies of replacement genes to
produce significant biological effects.

58. Targets for gene therapy
• Cystic fibrosis
• Familial hypercholesterolemia
• Haemophilia
• Haemoglobinopathies
• Albinism
• Phenylketonuria
• Duchenne muscular dystrophy

59. What changes in Healthcare are needed
• There has to be a shift in emphasis on prevention
• There have to be strategies for early detection
• For existing drugs and treatments, it is necessary to show
that incorporation of genetics and genomics in clinical
decision making results in better outcomes
• There has to be a change in thinking that stratifying
patient populations would provide value for all
stakeholders
• Need bold steps by regulatory agencies for
implementation
• Need a new framework to reimbursement
• Need a comprehensive training and education plan

60. Conclusion
• Although the role of genetic testing in the clinical setting
continues to evolve.
• Present challenges – expensiveness, technical standards
and laws
• Physicians and other health care professionals should
keep updated with current advances in genetic medicine
in order to facilitate appropriate referral for genetic
counseling and judicious use of genetic testing
• To provide state-of-the-art, evidence-based care for
affected or at-risk patients and their relatives.

61. References
• Harrison’s Principles Of Internal Medicine -19th edition
• Davidson’s Principles and Practice of Medicine- 22nd
Edition

62. Thank you