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Genetics - PowerPoint PPT Presentation

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Genetics . 15 th June 2010. Learning objectives. Be able to identify genetic disorders Knowledge of genetic basis & inheritance patterns Awareness of clinical features of common & important genetic conditions seen in GP Ability to take & interpret FH

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15th June 2010

Learning objectives
Learning objectives

  • Be able to identify genetic disorders

    • Knowledge of genetic basis & inheritance patterns

    • Awareness of clinical features of common & important genetic conditions seen in GP

    • Ability to take & interpret FH

    • Awareness of implications of antenatal & neonatal screening programmes

  • Clinical management

    • Ability to seek help with patients with possible/definite genetic disorders & refer appropriately

    • Awareness of management options & issues surrounding genetic testing

  • Communicating genetic information

Modes of inheritance chromosomal inheritance
Modes of inheritanceChromosomal inheritance

  • Incidence increases with increasing maternal age

  • Consider chromosomal translocation if children with multiple malformations & stillbirths in several generations

Chromosomal disorders
Chromosomal disorders

  • Down’s syndrome (47 T21)

  • Turner’s syndrome (45 XO)

  • Klinefelter’s syndrome (47 XXY)

  • Edward’s syndrome (47 T18)

  • Patau’s syndrome (47 T13)

Turner s syndrome
Turner’s syndrome

  • 1/2500 female births

  • Sporadic, low risk recurrence

  • Gonadal hypoplasia

  • Features

    • Short stature

    • Webbed neck

    • Low set ears

    • Widely spaced nipples

    • Short 4th metacarpal

    • Hypoplastic nails

    • Normal IQ

Modes of inheritance autosomal dominant
Modes of inheritanceAutosomal dominant

  • Males & females affected in equal proportions

  • Transmitted from one generation to next (vertical transmission)

  • All forms transmission observed (I.e. male to male, female to female, male to female)

Autosomal dominant disorders
Autosomal dominant disorders

  • Adult polycystic kidney disease

  • Neurofibromatosis

  • Tuberous sclerosis

  • Huntingdon’s disease

  • Hypercholesterolaemia

  • Achondroplasia


  • Affects 1/26,000 births, most are sporadic

  • Diagnosed in first years of life

  • Full penetrance & little variation in expressivity

  • Normal trunk but short limbs, enlarged skull vault

  • Normal IQ

  • Complications – hydrocephalus & spinal stenosis


  • 2 types

    • Type 1

    • Type 2

  • Type 1

    • Chromosome 17

    • 1/3000 births

      • ½ have affected family members

    • Multi-system

  • Type 2

    • Chromosome 22

    • Bilateral acoustic neuromas

Modes of inheritance autosomal recessive
Modes of inheritanceAutosomal recessive

  • Males & females affected in equal proportions

  • Individuals affected in single sibship in one generation (horizontal transmission)

  • Consanguinity provides further support of AR inheritance

Autosomal recessive disorders
Autosomal recessive disorders

  • Cystic fibrosis

  • Sickle cell disease

  • Thalassaemia

  • Haemochromatosis

Cystic fibrosis
Cystic fibrosis

  • Most common AR disease in UK

  • Affects 1/2500 infants

  • 1/20 are carrier

  • Chronic suppurative lung disease & exocrine pancreatic insufficiency

  • 10% newborns have meconuim ileus

  • Other features – male infertility & cirrhosis

Modes of inheritance x linked recessive
Modes of inheritanceX-linked recessive

  • Males affected almost exclusively

  • Transmitted through carrier females to sons (knight’s move pattern)

  • Affected males cannot transmit disorder to sons

X linked recessive disorders
X-linked recessive disorders

  • Duchenne & Becker muscular dystrophy

  • Haemophilia

  • Fragile X

Duchenne muscular dystophy
Duchenne muscular dystophy

  • Aggressive & progressive course

  • 30% new mutations

  • 1/3500 male births & 1/50,000,000 female births

  • Clinical features

    • Delayed walking

    • Waddling gait

    • Gowers sign

    • Muscular weakness/wasting

  • Present between 3-6yrs

  • Frequently fatal by 20yrs

Modes of inheritance x linked dominant
Modes of inheritanceX-linked dominant

  • Males & females affected but affected females occur more frequently than affected males

  • Females usually less severely affected then males

  • While affected females can transmit disorder to sons & daughters, affected males transmit only to daughters (all affected)

X linked dominant disorders
X-linked dominant disorders

  • Rett syndrome

  • Vitamin D resistant rickets

  • Incontinentia pigmenti

  • Alport’s syndrome

Features suggestive of genetic condition1
Features suggestive of genetic condition

  • Multiple closely related individuals affected with same condition, particularly if rare condition

  • Disorders with earlier age onset than typical, e.g.

    • Breast ca <45-50yrs (premenopausal)

    • Colon ca <45-50yrs

    • Dementia <60yrs

    • Heart disease <40-50yrs

  • Bilateral disease in paired organs, e.g. eyes/lungs

  • Sudden cardiac deaths in people who seemed healthy

  • Individual or couple with 3 or more pregnancy losses

  • Medical problems in offspring of parents who are blood related

  • 2 or more medical conditions occurring together, e.g. hearing loss & renal disease

  • Multiple congenital anomalies, dysmorphic features; developmental delay & growth delay

Taking a fh
Taking a FH

  • Start from case & work up

  • Ideally include 3 generations

  • Record names & dob

  • Be careful to ask (sensitively!) about:

    • Previous relationships

    • Whether half-siblings/children

    • Consanguinous relationships

    • Miscarriages/stillbirths/childhood deaths

Now it s your turn
Now it’s your turn….

  • Jane is in early stages of pregnancy & consults you about the risks to her baby having CF. Her nephew (brothers son) diagnosed as having CF as a result of the neonatal CF screening programme. She wants to know if this is a cause for concern as he is the only person affected in the family and his brother does not have the condition.

  • More information: Jane 6 weeks pregnant with 1st pregnancy. Husband Chris is 29 & fit and well. He has no brothers or sisters. His parents William & Margaret fit and well and aged 60 & 59.

  • Jane has brother John who is 34 & well. Their father George died at age of 66 of MI but mother Joan is fit and well at age 64.

  • In Johns first marriage to Alice (aged 33), they had a son David who is 10 & well. His second marriage is to Cathy (29), knows no details of her parents and family (adopted). Had miscarriage at 9 weeks before Richard, who is 4 and has CF. No couples are blood relations.

Interpreting family trees
Interpreting family trees

  • CASE 1

    • Ryan Johnson (III-1) is concerned that he, or his children, might be at risk of fractures. Several members of his family have sustained fractures – in varying numbers and degree of severity. Some members of his family have fractured a bone after very minor trauma. The information that Ryan has provided about his family is shown in the family tree.

Interpreting family trees1
Interpreting family trees

  • From the family tree, what are the likely features of the condition associated with the fractures & who in Ryan’s family is likely to be affected?

  • Does the pattern of affected people suggest a mode of inheritance?

  • What is probability that Ryan Johnson’s children will be affected by the condition?

  • What is the probability that Gemma Fox’s children will be affected by the condition?

Interpreting family trees2
Interpreting family trees

  • Mode of inheritance

    • Is condition present in each generation?

    • Are males & females both affected?

    • What forms transmission seen between affected patients & their children, ie male to male?

    • Do affected people have affected or unaffected children?

    • Do unaffected people have affected children?

    • How are affected people related to each other?

    • What are proportions of affected to unaffected people in a generation?

Interpreting family trees3
Interpreting family trees

  • CASE 2

    • Sam Webb (IV:1) is thinking of getting married and is concerned about the risk to his children of developing kidney problems and of needing a renal transplant. As part of a recent examination for life insurance he was found to have haematuria. The information he has about his family is shown in the family tree

Interpreting family trees4
Interpreting family trees

  • What are the likely features of the condition associated with the kidney problem & who in Sam’s family is likely to be affected?

  • Does the pattern affected people suggest a mode of inheritance?

  • What is the probability that Sarah Webb (III:1) is a carrier for the condition?

  • What is the probability of Lucy Webb (IV:2) being a carrier for the condition?

Communicating genetics
Communicating genetics

  • Supporting families & decision making

    • Signposting appropriately

    • Remember to treat patients as individuals

    • Consider ethical, cultural & social impact

  • Communicating risk

    • Avoid jargon

    • Statistics can be common misconception for patients, ie ¼ risk

Communicating genetics1
Communicating genetics

  • Listening skills

    • Always listen to patients agenda

  • Consent & confidentiality

    • RCP guidance available

    • Remember that some patients may not want information shared

  • Remember to ask for help if needed

    • Psychiatrist/psychologist/Genetics etc.

    • Regional Genetics Centre (RGC) has genetic counsellor – resource for patients & practitioners

Ethical issues in genetics1
Ethical issues in genetics

  • Identifying others at risk

    • Tension between preserving individual confidentiality & communication of genetic risk to others

    • Confidentiality can be breached if considered in public interest to do so

  • Confidentiality

    • Need to consider both patients (ie. Both parents) if test results carry information about both

    • Good practice would be to discuss non-paternity at outset, ie before testing

    • Needs to be approached sensitively

Ethical issues in genetics2
Ethical issues in genetics

  • Testing of children & indirect testing

    • UK Clinical Genetics Society guidelines on predictive genetic testing in children

      • Where no anticipated medical benefit, testing should be deferred until child old enough to make decision

    • Added dilemma – by testing child, parent can also receive their test result

  • Prenatal genetic diagnosis

    • Law recognises women’s right to choose to test baby, without the involvement & independent of wishes of father

    • Moral argument – rights of father

    • Counselling can help to facilitate discussion & possible disclosure

    • Consider preimplantation genetic diagnosis as alternative

Antenatal sceening
Antenatal sceening

  • Individuals need to understand:

    • Issues associated with actual test

    • Implications of positive test

    • They have the right to accept or decline screening

  • GPs therefore need to aware of screening available & patient pathway

Antenatal screening what tests and when
Antenatal screeningWhat tests and when?

Antenatal screening what tests when
Antenatal screeningWhat tests & when?

  • Booking

    • Blood for

      • Sickle cell & thalassaemia if appropriate

      • Hb, group & rhesus antibodies

      • Syphilis, Hep B, HIV, Rubella Ab

  • 10-20 weeks

    • Blood/USS for Downs screening

      • 11-13+6 weeks for NT screening

  • 18-21 weeks

    • Detailed anomaly scan

Neonatal screening what tests when
Neonatal screeningWhat tests & when?

Neonatal screening what tests when1
Neonatal screeningWhat tests & when?

  • 1st 5 weeks of life

    • Newborn hearing screen

  • Approximately 7 days old

    • Newborn blood spot

      • Sickle cell disease

      • Phenylketonuria

      • Congenital hypothyroidism

      • Cystic fibrosis

      • Medium chain acyl CoA dehydrogenase deficiency (MCADD)

Akt question
AKT question

  • A pregnant patient, originally from Indonesia is found at antenatal screening to have a mild hypochomic anaemia. DNA testing for alpha thalassaemia reveals her genotype to be --/⍺⍺. Her partner is -⍺/⍺⍺. Which one of the following statements is correct?

Akt question1
AKT question

  • The baby has a ¼ chance of not surviving due to hydrops foetalis

  • Baby has ½ chance of not having clinical manifestations of anaemia

  • Baby will inevitably have some form of anaemia

  • Baby will inevitably pass on an altered gene to future generations

  • Baby will have a mild hypochromic anaemia as a worst case scenario

Akt answer
AKT answer

  • Baby has ½ chance of not having clinical manifestations of anaemia

  • Worst case scenario for baby is ¼ chance of moderately severe anaemia (--/⍺-)

  • ½ chance of appearing normal (-⍺/⍺⍺ & ⍺⍺/⍺⍺)

  • Remainder will have mild hypochromic anaemia like mother (--/⍺⍺)


  • Contact a Family


    • NHS National Genetics Education & Development Centre – education & training


    • Primary Care Genetics Society

  • NICE CG41

    • Guidelines on referral of certain conditions for genetic testing


    • Information on genetic testing

  • &

    • NHS antenatal screening programmes