Clinical genetics for 4th year medical students

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Clinical genetics for 4th year medical students

• Kay Metcalfe

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Learning outcomes for medical students

• Understand and describe the mechanisms that
  underpin human inheritance
• Have an understanding of the role of genetic
  factors in health and disease
• Be able to identify patients with, or at risk of,
  a genetic condition
• Be able to communicate genetic information in an
  understandable, non-directive manner, being aware
  of the impact genetic information may have on an
  individual, family and society
• Be familiar with the uses and limitations of
  genetic testing and the differences between
  testing and screening
• Know how to obtain current information about
  scientific and clinical applications of genetics,
  particularly from specialised genetics services

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• Understand and describe the mechanisms that
  underpin human inheritance
• Be able to describe the structure, function and
  replication of DNA as the genetic material
• Be able to describe gene structure, expression
  and regulation
• Be able to describe the chromosomal basis of
  inheritance and how alterations in chromosome
  number or structure may arise during mitosis and
  meiosis
• Be able to describe Mendelian and non-Mendelian
  modes of inheritance
• Have an understanding of the role of genetic
  factors in health and disease
• Understand how mutations can affect gene dosage
  and function
• Understand the use of polymorphisms as genetic
  markers
• Be aware of the role of genetic and
  environmental factors in multifactorial
  conditions such as congenital anomalies, cancer,
  diabetes and psychiatric illness
• Be aware that population ancestry may affect the
  frequency of susceptibility alleles and of
  Mendelian diseases
• Be able to identify patients with, or at risk of,
  a genetic condition
• Be able to take a family history and construct
  and interpret a pedigree
• Understand the clinical implications of phenomena
  such as incomplete penetrance, variation in
  expression, anticipation and new mutations
• Be aware of the possibility of heterogeneity in a
  genetic disease and the potential impact on
  diagnosis

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• Understand the principles of risk estimates for
  Mendelian diseases
• Be aware of clinical indicators that suggest an
  inherited predisposition to cancer
• Be able to describe clinical features of common
  Mendelian diseases
• Be able to describe clinical features of common
  chromosomal disorders
• Be aware of the types of clinical features which
  suggest a dysmorphic or malformation Be aware of
  the roles of genes and teratogens in human
  congenital anomalies
• Be able to communicate genetic information in an
  understandable, non-directive manner, being aware
  of the impact genetic information may have on an
  individual, family and society
• Be familiar with the aims, methods and practice
  of genetic counselling
• Be aware of the impact of genetic diagnosis on
  the extended family
• Be able to communicate the concept of risk in a
  manner that can be understood by the patient
• Be aware of major ethical issues in genetics
• Be aware of the potential uses and misuses of
  genetic information
• Be familiar with the uses and limitations of
  genetic testing and the differences between
  testing and screening
• Understand the distinction between genetic
  screening and genetic testing
• Be aware of the differences and similarities
  between diagnostic, predictive and carrier
  genetic testing

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• Be aware that genetic tests can include
  clinical examination, metabolite assays and
  imaging as well as analysis of nucleic acid
• Be aware of the different laboratory techniques
  to investigate genetic material and their
  advantages and limitations
• Be able to interpret a standard genetics
  laboratory report (cytogenetic and molecular
  genetic)
• Be aware of parameters governing population
  genetic screening, current population genetic
  screening programs and guidelines for the
  introduction of such programs
• Know how to obtain current information about
  scientific and clinical applications of genetics,
  particularly from specialised genetics services
• Know when and where to get genetic advice and
  information
• Know when and how to make relevant referrals to
  the specialised genetics services
• Potential topics for advanced study (eg in
  Special Study Modules) Epigenetics, including
  imprinting ,The impact of selective advantage and
  natural selection on human genetic disorders ,
  Developmental genetics selective transcription
  differentiation stem cells , Gene therapy,
  Pharmacogenetics.

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• www.geneticseducation.nhs.uk/learning-genetics
• Information on pedigree drawing, patterns of
  inheritance, communicating genetic risk, ethical
  issues etc

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What is genetic counselling?
An education process that seeks to assist
affected (and/or at risk) individuals to
understand the nature of the genetic disorder,
the nature of its transmission and the options
open to them in management and family planning.
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Overview

• What is Clinical genetics?
• Pedigree drawing
• Inheritance patterns and scenarios
• Genetic testing and ethics

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Our role

• Regional centre
• Consultants, SpRs, genetic counsellors
• Liaison with cytogenetic and molecular genetic
  laboratories
• Referral and liaison across specialties
• Assessment, diagnosis, management and explanation

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Why refer to a geneticist?

• Diagnosis
• - Common conditions that appear to be inherited
• - Uncommon presentations of common problems
• - Rare conditions
• Communication
• - condition information (easy?)
• - recurrence risks (difficult?)
• Informed decision making non directive
• Management and follow up
• Families

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Pedigree drawing
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EDD
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Patterns of inheritance andhow to interpret a
pedigree
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Autosomal dominant inheritance

• Shows vertical transmission
• New mutations may be common
• Both males and females have equal chance to
  inherit gene
• Both can transmit disorder to both sons and
  daughters
• 1 in 2 offspring risk to affected parent
• Some autos dom conditions show variable
  expression and reduced penetrance
• HMZ often more severely affected than HTZ

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Variable expression
Treacher-Collins syndrome

• Manifestations or degree of severity vary from
  individual to individual and between families

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Reduced penetrance

• Penetrance proportion of heterozygotes who show
  evidence of the effects of mutation.
• Expressed as
• May be age dependent eg HD, ADPKD

retinoblastoma
?
Risk ½ x P 0.4
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Approximate risks of HD
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Autosomal dominant

• Achondroplasia
• Adult polycystic kidney disease
• Familial adenomatous polyposis coli
• Hereditary motor and sensory neuropathy
• Huntington disease
• Marfan syndrome
• Myotonic dystrophy
• Neurofibromatosis

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Autosomal recessive condition or Gonadal mosaicism
Osteogenesis imperfecta Type II
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Autosomal recessive inheritance

• Manifest only in homozygous state
• Carriers (HTZ) unaffected
• Both males and females affected equally
• Usually affects single sibship
• Consanguinity increases risk of recessive
  disorder

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Autosomal recessive inheritance
affected 1 in 4
unaffected 2 in 3 are carriers
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X-linked recessive inheritance

• Caused by mutation on X chromosome
• Expressed in males but not usually in females
• Carrier female -50 risk of affected sons
• -50 risk of carrier
  daughter
• Affected male - all daughters carriers
• - all sons unaffected
• Knights move pattern

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X-linked recessive inheritance

• Haemophilia
• Duchenne and Becker muscular dystrophy
• Androgen insensitivity syndrome
• Hunter syndrome
• Glucose-6-phosphate-dehydrogenase deficiency
• Bruton agammaglobulinaemia

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XLR-affected females

• Homozygosity

• Skewed X-inactivation

XX XY XX

• Female with only one X chromosome
• 45, X Turner syndrome
• 46XY female eg.AIS

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XLD
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X-linked dominant

• Males and females affected, females usually less
  severely affected than males
• 1 in 2 risk to children of affected female (MF)
• All daughters of affected male affected but no
  male to male transmission

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X-linked dominant inheritance

• Males and females affected
• Vitamin D resistant rickets
• OTCD
• Fragile X syndrome

• Lethal in males
• Incontinentia pigmenti
• Rett syndrome
• XL chondrodysplasia punctata
• Goltz syndrome

If male lethality affected female produces
offspring in 111 ratio normal femaleaffected
female normal male
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Questions to ask yourself

• Are successive generations affected?
• Is a parent of an affected person affected
• Is there consanguinity?
• Are males and females both affected?
• Are males and females equally affected?
• Is there male to male transmission?

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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 0-100

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Frax
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Chromosomes

• Number Aneuploidy - trisomy
• -
  monosomy
• Polyploidy - triploidy
  (69chr)
• Structure deletion/insertion/ inversion/ring
• translocation
  

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Trisomy

• Trisomy 21
• Trisomy 18
• Trisomy 13
• No survivable autosomal monosomy
• Sex chromosome aneuploidy
• 45X 47XXX 47 XXY 47XYY

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Chromosomal syndromestrisomy 21

• Learning disability
• Hypotonia
• Nuchal thickening, short neck
• Flat face, brachycephaly
• Epicanthic folds, Brushfield spots
• Small mouth and large tongue
• Small square ears
• Transverse palmar creases, sandal gap

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Chromosomal syndromestrisomy 21

• 1 in 700 births - maternal age related
• IQ 20-85
• CHD rate 16-62. Actual likely 42
• AV canal defect 40, Fallot other complex CHD
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• 2-15 duodenal atresia
• 2 have Hirschsprung
• ALL and ANLL. Rate in DS x20 general pop. Risk 1
  in 150
• Hypothyroidism 1/3rd have thyroid antibodies
• Most DSgt40yrs have neuropathology of Alzheimer

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Chromosomal syndromestrisomy 18

• 1 in 6000 births
• Common in growth retarded malformed fetuses
• Low birth weight, IUGR appearance
• Small placenta
• Survival poor median lt 1 week
• 90 die by 6 months BUT 5 alive at 1 year

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Chromosomal syndromestrisomy 18

• Round head with small facial features
• Small mouth and micrognathia
• Small, low set, posteriorly rotated ears
• Short palpebral fissures /- adhesions
• scraggy body
• Short sternum
• Typical hands and feet

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Chromosomal syndromestrisomy 18

• Cardiac defects, often large VSD
• Oesophageal atresia, Anal atresia
• Diaphragmatic hernia
• Exomphalos
• Horseshoe kidney
• Limb defects radial aplasia, ectrodactyly
• Profound mental and growth retardation joint
  contractures in survivors

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Chromosomal syndromestrisomy 13

• 1 in 12,000 live births
• LBW and big placenta
• 50 detected prenatally in UK
• HPE in 60 (?), 40 HPE have 13
• Median survivallt 1 week
• 80 die in 1st month
• 3 alive at 6 months
• Profound disability in survivors

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Chromosomal syndromestrisomy 13

• Holoprosencephaly spectrum, including clefting
• Scalp defects
• Cardiac and renal defects
• Abdominal wall defects
• Prune belly
• Postaxial polydactyly of hands and feet

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45,X

• Turner syndrome 11000 female births
• Cardiac defects especially coarctation
• Horseshoe kidney
• Short stature
• Streak gonads and infertility
• Webbed neck, ptosis
• IQ in normal range, some specific learning diffs

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47XXX

• Triple X syndrome
• Tall stature in childhood
• Normal appearance and fertility
• Not associated with structural abnormalities
• Learning disability, speech delay, passive
  personality

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47,XXY

• Klinefelter syndrome
• Males
• Tall stature, eunuchoid fat distribution
• Small testes and low testosterone
• Poor beard growth, gynaecomastia
• IQ usually within normal range but lt sibs
• Some increase in behaviour problems
• Increased risk diabetes, varicose veins, breast
  cancer

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47, XYY

• Male
• Tall stature
• Usually normal IQ but ltsibs
• May have oppositional behaviour

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Microcephaly Cardiac defect
holoprosencephaly
holoprosencephaly
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Chromosomal inheritance

• Pedigree doesnt conform to mendelian pattern
• May be history of miscarriages
• Affected children may have different patterns of
  physical and developmental abnormality

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Robertsonian translocation
Whole arm translocations of acrocentric
chromosomes 13,14,15,21,22
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Robertsonian translocation
Normal balanced trisomy 13
trisomy 21
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Reciprocal translocations
7
16
Balanced reciprocal translocation
7q- 16p
balanced translocation
7q 16p-
Normal
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Cleft lip
CL/P
CL
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Multifactorial conditionsfactors increasing
risk to relatives

• High heritability of disorder
• Close relationship to index case
• Multiple affected family members
• Severe disease in index case
• Index case being of sex not usually affected

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Prenatal testing

• Informed decisions (non coercion)
• Tests in pregnancy- CVS v amnio
• Alternatives- PGD, gamete or embryo donation,
  adoption
• The optimal time for determination of genetic
  risk and discussion of the availability of
  prenatal testing is BEFORE pregnancy!

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Genetic testing and ethics

• Diagnostic- ethically not different to any other
  medical diagnostic test
• Carrier testing- person will not be usually be
  affected but may be at risk of having affected
  child.
• Predictive testing- shows whether someone has
  inherited the genetic predisposition and may
  become affected in the future

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Carrier testing

• Autosomal recessive , X linked recessive or
  chromosomal rearrangements
• Only implications are for reproduction
• General ethical principle is against testing in
  childhood (autonomy, labelling and stigma,
  ensuring appropriate counselling)

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Predictive testing

• Eg for Huntingtons disease, BRCA1, FAP
• Burden of disease
• Burden of guilt
• Effect on family
• Effect on relationships
• Insurance and employment etc
• Generally not lt18y unless condition has
  implications then eg FAP

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Huntingtons disease

• Predictive testing request from woman at 25 risk
• Estranged from father
• She intends to keep result private from family
• What would be your usual approach?

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HD (2)

• She has a 16y old brother
• Would this change your approach?
• Would your approach be different if this was
  breast cancer?

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HD (3)

• She is tested
• Unfavourable result communicated
• Further counselling issues?

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Can you explain to the public

• DNA
• Gene
• Chromosome
• Genotype
• Phenotype
• Meiosis
• Allele
• Mutation

• Homozygous
• Heterozygous
• Inheritance
• Dominant
• Recessive
• Translocation
• Aneuploidy

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Sources of further information

• Teaching medical genetics to undergraduate
  medical students
• http//www.bshg.org.uk/documents/official_docs/und
  ergrad.doc
• Online medical inheritance in man
  www.ncbi.nlm.nih.gov
• Gene clinics www.geneclinics.org
• Contact a family www.cafamily.org.uk
• Books
• ABC Clinical genetics- Helen Kingston
• New Clinical genetics Read and Donnai
• Oxford desk reference Clinical genetics Helen
  Firth and Jane Hurst

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If time remaining
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Genomic imprinting

• Most genes expressed equally from both alleles
• Small number of genes show differential
  expression dependent on parent of origin (mainly
  on chromosomes 6,7,11,14,15)
• Imprint is mediated by methylation
  ?transcriptional inactivation
• Imprint persists through cell divisions in embryo
• Imprint removed at gametogenesis and then
  re-established according to sex of transmitting
  parent

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Uniparental disomy

• A situation in which both copies of homologous
  chromosome pair come from the same parent

Trisomy rescue
2 copies of same homologue uniparental
isodisomy (non disjunction at meiosis II)

• Both homologues uniparental disomy(non-disjuncti
  on at meiosis I)

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Genomic imprinting may manifest if

• Microdeletion of imprinted region
• Uniparental disomy occurs for imprinted region
• A mutation occurs in an imprinting regulatory
  gene
• May unmask a recessive gene

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Angelman syndrome
Prader-Willi syndrome
70 Deletion of paternal 15q11-q13 25 Maternal
UPD 15 Smaller molec deletions Paternal 15 IC
deletion/mutation