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VERSION 1.2

GENETICS
Autosomal Dominant Inheritance
Affected Father

Autosomal dominant conditions

● Polycystic kidney disease
● Huntington’s
● Neurofibromatosis

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Autosomal Recessive Inheritance

Autosomal recessive conditions

● Cystic fibrosis
● Thalassemia
● Sickle cell anaemia
● Wilson’s disease
● Congenital adrenal hyperplasia
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X-Linked Recessive Inheritance
(Affected Father)

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X-Linked Dominant Inheritance
(Affected Mother)

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X-Linked Recessive
(Carrier Mother)

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 Modes of Genetic Inheritance

Autosomal recessive:
If both parents are carrier:
● 25% chance of a child to be affected
● 50% chance of a child to be a carrier
e.g. cystic fibrosis, congenital adrenal
hyperplasia, sickle cell anaemia and thalassemia

Autosomal dominant:
If one of the parents is affected:
● 50% chance of a child to be affected
● 25% chance of a grandchild to be affected
e.g. Huntington’s diseases, neurofibromatosis,
autosomal dominant polycystic kidney disease

X-Linked recessive:
If one of the parents is carrier:
● 50% chance of a male child to be affected
e.g. Duchenne muscular dystrophy (DMD),
haemophilia

Careful: Is the question is asking

carrier or affected?
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 Cystic Fibrosis

It is caused by autosomal recessive mutation in

CFTR gene (cystic fibrosis transmembrane
conductance regulator gene)

↑ Viscosity
and High
thickness of chloride in
body’s the skin
secretion

It is an autosomal recessive disease

→ If both parents are carriers then the children:
● 25% = Unaffected (completely healthy and
does not carry mutated gene)
● 50% = Carrier (carry mutated gene but not
have the disease)
● 25% = Affected (have the disease)

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Symptoms of Cystic Fibrosis

● Salty skin - parents notice when kissing

child
● Finger clubbing
● Frequent cough, wheeze, SOB,
pneumonia and sinusitis - thick
secretion & mucus accumulates in the
‘alveoli’: Recurrent repetitive cough,
respiratory failure, bronchiectasis as long
term complications
● Congenital absence of vas deferens
→ Infertility in males
● Meconium ileus (first stool that is
passed by a newborn will not pass due to
thickness)
● Big appetite but poor weight gain,
failure to thrive, steatorrhoea
→Thick secretion blocking pancreatic
duct resulting in no pancreatic enzymes
released,↓ fat and protein absorption

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 Cystic Fibrosis Management

Airway clearance techniques

Immunomodulatory agent:
● For patients with deteriorating lung function
● Or repeated pulmonary exacerbation
→ Long term azithromycin
→ Or oral corticosteroid if no improvement with
azithromycin, stop azithromycin

Mucolytic agents:
● rhDNase + hypertonic sodium chloride or
hypertonic sodium chloride alone
● Mannitol dry powder
● Lumacaftor–ivacaftor

Treating pulmonary infections:

● Antibiotics or antifungals depends on types of
infection and sensitivity

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 Cystic fibrosis

Brain trainer:

A 3 year old boy presents with rectal prolapse,

failure to thrive, bulky stools and a repetitive
cough over the last few months. What is the most
appropriate initial test ?

➔ Sweat test

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 Polycystic Kidney Disease

It is an autosomal dominant disease

→ 50% affected in children if one parent has it

Features:
● Abdominal, flank, back pain
● Haematuria
● Hypertension (early manifestation)
→ ACE-inhibitors or ARB to control BP
● Cerebral aneurysms

Polycystic kidney disease is associated with

cerebral aneurysms
→ Once ruptured can cause subarachnoid
haemorrhage

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 Turner Syndrome

Facts:
● It affects female only
● Most have normal intelligence but some
have learning difficulties
● Advanced age mother is NOT a risk factor for
Turner’s syndrome
● Affected patients are infertile, however can
conceive by assisted reproductive techniques

Features:
Short stature Ovarian failure
(1yr amenorrhea)
Short webbed neck Impaired pubertal growth

Widely spaced nipples Bicuspid aortic valve

Management:
● Human growth hormone (GH) is used
during childhood to increase height
● Oestrogen replacement is used during
childhood:
→ Enhance breast and hip development
→ Prevent osteoporosis
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 Turner syndrome

Brain trainer:

What technique is available for women with

Turner’s syndrome to conceive ?

➔ Assisted reproduction techniques

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 Prader Willis Syndrome

Facts:
● It is a genetic disease
→ Deletion of some genes of the paternal
chromosome #15

During neonatal period:

● Hypotonia (floppy baby)
● Difficult to feed due to thin upper lip and
downturned mouth
● Short extremities
● Almond-shaped eyes

During childhood period:

● Excessive eating (hyperphagia)
● Obese and short
● Learning difficulties
● Growth abnormalities
● Self-injurious behaviour

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 Angelman Syndrome

Facts:
● It is a genetic disease
→ Lack of expression of maternally inherited
UBE3A gene in the brain (CHR15)

During neonatal period:

● Normal head circumference at birth
● Developmental delay is apparent by 6
months

During childhood period:

● Functionally severe developmental
delay
● Delay disproportionate head
circumference growth
● Jitteriness from 6 months with irregulars,
coarse movement that prevent walking
and reach for objects
● Speech impairment with no or minimal use
of words
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Duchenne Muscular Dystrophy

Facts:
● It is an X-linked recessive diseases
● X-linked recessive only affects male
→ If one of the parents is carrier, then a
male child will have 50% to inherit the gene

Features:
● 4-8 yo boy started to walk late
i.e. >18 months rather than 12 months
● Gower’s sign → use his hands to push on
his legs to stand
● Proximal muscle weakness
● Waddling gait → Cannot run
● ↑ Creatine kinase, ALT, AST
● + Respiratory and/or cardiac manifestation

Diagnosis:
● Initial test → creatine kinase
● Muscle biopsy
● Genetic testing (obligatory after +ve muscle
biopsy)
DMD has a mutation defect in dystrophin
protein which lies in striated muscles
Other X-linked recessive: Haemophilia
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 Fragile X syndrome

Brain trainer:

What is the mode of inheritance for Fragile

X-syndrome ?

➔ X-linked dominant

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 Becker Muscular Dystrophy

Brain trainer:

What is the mode of inheritance for Becker

Muscular Dystrophy ?

➔ X-linked recessive

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 Trisomy Syndrome

Trisomy 13 Trisomy 18 Trisomy 21

Patau’s Edward’s Down
syndrome syndrome syndrome
Prominent Prominent Space between
calcaneus calcaneus 1st and 2nd toe
Cleft lips and Prominent Abnormally
palate occiput shaped ear
Microcephaly Microcephaly Small mouth
(small head) (Small head) with enlarged
tongue
Microphthalmia Micrognathia Upward slant to
(small eyes) (Small jaw) the eyes
Polydactyly Hands clenched Small nose with
(multiple fingers) into fists with depressed nasal
overriding bridge and joint
fingers laxity
● Single deep
crease across
palm
● Duodenal
atresia
● Double bubble
sign on chest
X-ray
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 DiGeorge Syndrome

Brain trainer:

A 3 month old baby with recurrent infections,

feeding difficulties, dysmorphic face and cleft
palate. X-ray shows absent thymic shadow. What
is the most likely diagnosis?

➔ DiGeorge syndrome

Remember CATCH-22
● Cardiac abnormality
● Abnormal facies
● Thymic aplasia
● Cleft palate
● Hypocalcemia/Hypoparathyroidism
● Chromosome 22 abnormality

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Congenital Adrenal Hyperplasia

Facts:
● It is an autosomal recessive disease
→ If both parents are carrier, then 25%
chance in child will be affected
● 21 hydroxylase deficiency is the most
common form

Features:
● + Cortisol deficiency
● + Aldosterone deficiency
● + Androgen excess

Male:
Female:
● Penile
● Ambiguous
enlargement
genitalia
● Hyperpigmentation
Infant male:
● Salt wasting due to aldosterone deficiency
● Vomiting
● Weight loss
● Lethargy
● Dehydration
● Hyponatraemia
● Hyperkalaemia
● 11-β-hydroxylase deficiency
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 Klinefelter Syndrome

Facts:
● It is also known as 47, XXY males
● It affects boys and males only

Features:
G-FELTER
● Gynecomastia
● Facial Hair - low
● Estrogen is high and testosterone is low
● Long limbs
● Tall and slim
● Elevated FSH and LH
● Rage - aggressive behaviour

Hypogonadism:
● Small Testes
● Azoospermia (no sperms in
seman)
● Male infertility

Diagnosis:
Karyotyping = chromosome analysis (47 XXY)

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 Huntington’s Disease

Facts:
● It is an autosomal dominant disease
→ If one parent is affected then 50% chance
of child will be affected

Features:
● Changes of personalities, self-neglect,
clumsiness - early sign
● Progressive cognitive impairment
e.g. memory loss, poor concentration
● Chorea - involuntary writhing jerky
movement of limbs
● Dystonia
● Rigidity
● Dementia

m b e r
Reme
Jerky involuntary movement

Cognitive impairment Family history

Anticipation = symptoms in next generation

appears earlier and earlier (at young age)

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 Investigating Potential
Genetic Diseases

Before pregnancy:
● Preimplantation genetic diagnosis (PGD)
1. Fertilization is done in vitro (laboratory)
2. Embryos are tested for genetic
abnormalities
3. 1-2 unaffected embryos are then implanted
to uterus
→ Suitable to check for possible serious
genetic diseases such as autosomal
recessive
→ To check for disease with strong family
history and if parent is carrier

Week 11-14 of pregnancy:

● Chorionic villus sampling (CVS)
→ a small sample of placenta is tested

Week 15-20 of pregnancy:

● Amniocentesis
→ A small sample of amniotic fluid is tested

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 Genetic screening

Brain trainer:

A woman with a family history of cystic fibrosis is

planning to have a baby and wants to receive the
earliest possible test for this disease. What test
would you recommend?

➔ Preimplantation genetic diagnosis

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 Genetic screening

Brain trainer:

A 41 year old pregnant woman is 17 weeks

pregnant and is worried about a chromosomal
abnormality. What is the most definitive
investigation at this stage?

➔ Amniocentesis

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 Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome is a collagen disorder

Features:

Hyperplasticity Hypermobility
of skin of joints

+
Blue sclera

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 Neurofibromatosis (NF)

Facts:
● It is an autosomal dominant disease
→ If 1 parent affected = 50% chance of child
affected

Diagnostic criteria or features:

● >6 cafe au lait macules
(>0.5cm in children or >1.5cm in adults)
● >2 cutaneous/subcutaneous
neurofibromatosis or one plexiform
neurofibromatosis
● Axillary or groin freakling
● Optic pathway glioma
● >2 Lisch nodules (iris hamartomas seen on
slit lamp examination)
● Bone dysplasia (sphenoid wing dysplasia,
bowing of long bone + pseudarthrosis)
● 1st degree relative with NF Type 1

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Neurofibromatosis (NF)

Type 1 NF

Present more with skin lesions

● Cafe-au-lait spots
● Axillary/groin freckles
● Iris hamartomas
● Scoliosis

Type 2 NF

Present more with CNS tumour

● BIlateral acoustic neuroma
● Multiple intracranial
schwannomas
● Meningiomas

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 Ovarian Cancer

Facts:
● Woman with strong 1st or 2nd degree family
history has higher risk
● Presence of BRCA1 and 2 genes increases
susceptibility

1. Do pelvic ultrasound

2. Genetic counselling if unremarkable for

full assessment of risk

3. Offer prophylactic
salpingo-oophorectomy if high risk

If there are manifestation:

Perform ultrasound
+
Check for Ca-125 Level
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 BRCA1

Brain trainer:

What is the mode of inheritance for BRCA1 gene

mutation?

➔ Autosomal dominant with incomplete

penetrance

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 Alport Syndrome

Facts:
● It is a X-linked disease
● Father passes on Y-chromosome,
mother passes on X-chromosome
● If father is affected but mother is not,
chance of male child affected is nearly
0%

Features:
● Kidney Disease:
→ Haematuria + proteinuria
→ End stage renal disease
● Hearing Loss
→ Sensorineural hearing loss (SHNL)
● Eyes abnormalities

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 Haemolytic disease of the
newborn

Brain trainer:

A pregnant woman who is blood type O negative

suffered with haemolytic disease of a newborn
when she was born. What is the likelihood of her
first born having haemolytic disease of a
newborn?

➔ 0%

Remember haemolytic disease of a newborn is NOT a

genetic condition!

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Genes & Associated Diseases

Gene Disease
BCL2 B cell lymphoma
Apolipoprotein E Alzheimer’s
(APOE)
FBN1 Marfan Syndrome
NOTCH1 T-cell leukaemia
HOXB13 Prostate cancer

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