Penetrance

BRCA1/2-Associated - Autosomal dominant

Hereditary Breast and Ovarian - Inherited cancer predisposition
Cancer - Penetrance = lifetime cancer risk
- Females have 87% risk/penetrance of developing associated cancer
- Males have 20% risk/penetrance —> reduced penetrance

Huntington disease (HD) - Autosomal dominant

- Caused by CAG repeat expansion in the HTT gene - trinucleotide
repeat expansion
- Shows age dependent penetrance (late 30s-40s)
- Disease causing alleles: 36 repeats or more (36-39 repeats: reduced
penetrance alleles, 40 or more repeats: full penetrance)
- Anticipation: CAG repeats can expand when pass to o spring
(occurs more with male transmission)
- Genotype-phenotype correlation: signi cant inverse correlation
between number of CAG repeats and the age of onset of HD

Clinical features:
- Chronic neurodegenerative disorder
- Adult-onset: late 30’s-40’s (juvenile HD: before 20)
- 15-20 year duration
- Triad of clinical ndings: motor, cognitive and psychiatric (chorea,
gait abnormalities, decreased awareness and memory)

Expressivity

Tuberous sclerosis (TSC1, - Autosomal dominant

TSC2) - Full penetrance in individuals at risk
- Variable expressivity

Clinical features:
- Hypomelanotic macules (patches of light-coloured skin)
- Shagreen patch (small areas of thickened skin), Angio bromas
(reddish bumps - also under or around nails)
- Retinal hamartoma, Mental disabilities,
- Renal angiomyolipomas
Neuro bromatosis type 1 (Nf1) - Autosomal dominant
- Fully penetrant after childhood
- Extreme clinical variability - variable expressivity

Clinical features:
- Co ee coloured spots (cafe au lait)
- Freckling on armpits/ groin
- Tiny bumps on iris (Lisch nodules)
- Soft pea-sized bumps on or under skin (neuro bromas)
- Optic nerve tumour (optic glioma)
Genomic imprinting

Angelman syndrome (AS) - Loss of expression of maternally inherited UBE3A gene

‘Happy puppet syndrome’
Clinical features:
- Severe developmental delay, minimal use of words
- Ataxia
- Microcephaly, seizures
- Excitability, laughter
- Prognathism, wide mouth
- Light colour skin, hair, eyes
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 Prader-Willi syndrome (PWS) - Loss of expression of paternally inherited genes SNRPN, NECDIN

Clinical features:
- Infancy: hypotonia, feeding di culties
- Later: excessive eating, obesity
- Developmental delay
- Hypogonadism
- Short stature
- Bitemporal narrowing
- Palpebral ssures (almond-shaped, slightly up-slanting)
Beckwith-Wiedemann - Pathogenic mutation in the maternal copy of CDKN1C gene
syndrome
Clinical features:
- Overgrowth syndrome (macrosomia)
- Macroglossia
- Neonatal hypoglycaemia
- Umbilical hernia
- Asymmetry/hemihyperplasia
- Embryonal tumours (Wilms, hepatoblastoma)
- Renal anomalies
- Ear creases/pits
Structural proteins

COL1A1/2-Related - Autosomal dominant

Osteogenesis Imperfecta (OI) - Caused by mutations in the genes COL1A1 and COL1A2 (encoding
pro⍺1 and pro⍺2 chains of type I collagen)
- Loss-of-function mutations: reduction of available pro⍺1 chains —
> mild, non-deforming OI (reduced but normal collagen)
- Missense mutations: dominant negative e ect, abnormal chains
are synthesised & incorporated into triple helix —> more severe
phenotype
- Type 1 procollagen formed by a triple helix made up of two pro⍺1
chains and one pro⍺2 chain)
- Severity ranges from lethality in perinatal period to very mildly
a ected individuals

Classic non-deforming (Type I)

- Blue sclera
- Up to 100 fractures
- No short stature
- May have hearing loss
Perinatal lethal (Type II)
- Rib fractures, small thorax
- Deformed extremities
- Severe short stature
- Undermineralised skull
- Dark sclera
Progressively deforming (Type III)
- Fractures at birth, progressive deformity
- Marked short stature
- Blue sclera
- Frequent hearing loss
- Dentinogenesis imperfecta
Common variable (Type IV)
- Multiple fractures
- Mild to moderate deformity
- Variable short stature
- Normal to grey sclera
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 Ehlers-Danlos syndrome (EDS) - Connective tissue disorders
- A ect joints, skin, internal organs, blood vessels
- Range from mild to life-threatening

Classic Ehlers-Danlos
- Hyperextensible skin
- Fragile skin with abnormal wound healing
- Tendency to bruise
- Fleshy lesions over knees and elbows
- Joint hypermobility
- Variable expressivity within families
- No genotype/phenotype correlation
Hypermobility type
- Least severe type
- Joint hypermobility
- Subluxations/dislocations
- Chronic pain and degenerative joint disease
- Mild aortic root dilation
- Autonomic dysfunction
Vascular type
- Severe condition
- Gene for Type III collagen (COL3A1)
- Thin, translucent skin
- Typical facial features: thin narrow nose, prominent eyes
- Fragility of arteries, intestines, uterus
- Genotype/phenotype correlations: null mutations milder than
missense
Kyphoscoliotic EDS
- Autosomal recessive (PLOD1 gene)
- Rare condition
- Lysyl hydroxylase
- Early-onset and progressive kyphoscoliosis
- Hypotonia and signi cant delay in motor milestones
- Fragile sclera (risk of rupture)
- Fragile skin, joint laxity
Marfan syndrome - Autosomal dominant
- Loss of function mutation - haploinsu ciency
- Mutations in FBN1 gene (encodes brillin 1) —> degeneration of
micro bril architecture, loss of integrity of ECM
- Connective tissue disorder
- Ocular, cardiovascular, skeletal
- Variable expressivity
- No genotype/phenotype correlation

Clinical features:
- Ectopia lentis (lens displacement)
- Aortic root dilation
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 Trinuleotide repeat expansion

Huntington disease (HD)

Fragile X syndrome - X-linked inheritance

- FMR1-related disorder: CGG repeats in the untranslated region of
exon1 of the FMR1 gene
- Full mutation —> methylation of the FMR1 promoter and
inhibited transcription
- Loss of function mutation
- Normal alleles: 5-44 repeats, Intermediate alleles: 45-54 repeats (not
pathogenic but may expand into premutation if passed on by
females), Premutation alleles: 55-200 (risk of FXTAS and POI, may
expand into full mutation if passed on by females), Full mutation:
more than 200 repeats (causes Fragile X syndrome, males
a ected more severely than women)

Clinical features:
- Intellectual disability (moderate to severe in males, mild in females)
- Features in some a ected males: dysmorphic features (long,
prominent chin and ears), joint laxity, large testes after puberty
-
Fragile X tremor/ ataxia - X-linked inheritance
syndrome (FXTAS) - FMR1-related disorder
- Mutant transcript (permutation) —> neuronal inclusions and
neuronal damage
- Progressive ataxia and intention tremor
- Late onset
Fragile X-associated Primary - X-linked inheritance
Ovarian Insu ciency (POI) - FMR1-related disorder
- Menopause before the age of forty
Myotonic dystrophy type 1 - Autosomal dominant
(DM1) - CTG repeat expansion in the DMPK gene
- Normal alleles: 5-34 repeats, Premutation (intermediate) alleles:
35-49 repeats (asymptomatic but can expand in subsequent
generations), Full mutation: more than 50 repeats (fully penetrant,
larger repeats correlate with earlier onset and increased
severity)
- Anticipation is observed

Clinical features:
Multisystem disorder
- Muscle - weakness, myotonia, hypotonia, ptosis, facial muscle
weakness
- Eyes - cataract
- Endocrine system - multiple disorders
- Heart - cardiac conduction defects
- CNS - intellectual disability
Autosomal recessive inheritance

Beta thalassaemia - Loss of function mutation in the HBB gene

- Impairment of β-globin chain synthesis —> imbalance between
alpha/non-alpha chains —> precipitation of unassembled alpha
chains
- Damage to erythroid precursors and anaemia
- Heterozygous carriers: clinically asymptomatic, slightly anaemic
with reduced MCV and MCH
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Sickle cell disease - Majority homozygous for p.Glu6Val mutation in HBB gene (HbS
allele) - AT LEAST one HbS allele
- Chronic haemolytic anaemia (RBC’s destroyed faster than they are
made)
- Vaso-occlusive events
- Dactylitis: swelling of ngers giving them ‘sausage appearance’
Tay-Sachs disease (TSD) - Loss of beta-hexosaminidase A (HEX A) enzyme activity
- Lysosomal storage disorder

Clinical features:
- Loss of motor skills and progressive weakness (onset at 3-6
months of age)
- Abnormal visual behaviour - ‘cherry red spot’ on retina
- Increased startle response
Autosomal dominant inheritance

Tuberous sclerosis (TSC1,

TSC2)

Charcot-Marie-Tooth (CMT 1A) - PMP22 duplication

- Gain of function mutation
- Peripheral nerve damage
- Smaller weaker muscles (legs and calfs)
- Foot deformities: hammertoes, high arches

Achondroplasia - FGFR3 mutation

- Gain of function mutation
- Short-limbed dwar sm
Familial - LDLR mutation
hypercholesterolaemia (FH) - Phenotype correlates with levels of LDLR receptor
- Heterozygous form is common
- Homozygous have severe phenotype (cholesterol deposition in
joints, eyelids and eyes)—> may develop coronary heart disease in
childhood

Sex-linked inheritance

Duchenne muscular dystrophy - X-linked recessive (XLR)

(DMD) - Loss of function mutation (deletions) in the Dystrophin gene
- Female carriers may show symptoms based on patterns of X
inactivation

Clinical features:
- Delayed motor milestones
- Progressive muscle weakness —> wheelchair dependency
- Cardiomyopathy
X-linked blindness - X-linked recessive (XLR)
X-linked hypophosphataemia - X-linked dominant (XLD)
- Heterozygous females are a ected and a ected males are viable
- Males and females a ected equally
- Increased renal phosphate loss
- Ranges from isolated hypophosphataemia to bowing of the lower
extremities —> variable expressivity
- Spontaneous dental abscess
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 Incontinentia pigmenti - X-linked dominant (XLD)
- Embryonic lethality for males

Clinical features:
- Retinal hypervascularisation
- Blistering
- Dental abnormalities
- Abnormal, pitted nails
- Swirling macular hyperpigmentation
Leri-Weill dyschondrosteosis - Pseudo-autosomal inheritance
(LWD) - SHOX gene happloinsu ciency

Clinical features:
- Disproportionate short stature
- Mesomelia
- Madelung deformity
Genetic disorders (channels, receptors, pathways)

Cystic brosis (CF) - Autosomal recessive

- Mutations in the CFTR gene (encoding a transmembrane ion
channel - on apical surface of epithelial cells: airways and
pancreatic ducts)
- Reduced chloride and bicarbonate transport
- CFTR dysfunction: viscous secretions (hard to clear by cilia —>
predisposes to infections), obstruction and organ damage

—> CF mutations:
- Class I: nonsense/frameshift mutations —> no CFTR (eg. G542X)
- Class II: abnormal CFTR processing - polypeptide missing 1
amino acid —> non/very little functioning (eg. F508del)
- Class III: abnormal channel activation (gating) —> a ect the
ability of channel to be regulated to open/close
- Class IV: abnormal chloride conductivity
- Class V: non-coding mutations —> reduced synthesis
- Class VI: reduced stability

—> Genotype/phenotype correlation:

- Best correlation relates to pancreatic function
- Pancreatic su cient Vs pancreatic insu cient
- Limited correlation in pulmonary disease
- CAVD: impound heterozygosity with a severe and a mild mutation

Clinical features:
Airways and sinuses:
- Recurrent bronchitis, sinusitis
- Progressive obstructive airway disease
- Recurrent infections
Gastrointestinal:
- Pancreatic insu ciency and malabsorption
- Meconium ileus
- Pancreatic/chronic hepatic disease
Sweat gland abnormalities (hyponatraemic dehydration)
Azoospermia (abnormal vas deferens): Congenital Absence of Vas
Deferens (CAVD) is a distinct phenotype/condition at the mild end of
CF spectrum
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 Multiple Endocrine Neoplasia - Autosomal dominant
Type 2 - Activating (gain-of-function) mutation of RET gene (in neural crest
and urogenital precursor cells)
- Aberrant signal transduction —> oncogenesis
- Medullary thyroid carcinoma (A, B), Phaeochromocytoma (A,B),
Parathyroid adenoma/hyperplasia (A), Mucosal neuromas (B),
Ganglioneuromatosis of GI tract (B)

Wilson disease - Autosomal recessive

- Mutations in the ATP7B gene
- De cient linking of copper to ceruloplasmin and exporting of copper
from cells into bile
- Disorder of copper metabolism —> excessive copper deposition

Clinical features:
- Hepatic disturbances: hepatitis, hepatic failure, chronic disease
- Movement disorders
- Depression
- Kayser-Fleischer rings (copper deposition in cornea)
HFE-Associated Hereditary - Autosomal recessive
Haemochromatosis - Reduced penetrance
- Abnormally high iron absorption from the GI tract (mucosal
absorption)
- Excessive storage in liver, pancreas, heart, joints, skin
- Elevated transferrin-iron saturation and ferritin concentration

Clinical features:
- Joint pain
- Skin pigmentation
- Cardiomyopathy
- Diabetes mellitus
- As disease progresses: liver cirrhosis
Mitochondrial inheritance

Kearns-Sayre syndrome - Mitochondrial DNA deletion syndrome

- Onset <20 years

Clinical features:
- Pigmentary retinopathy
- Progressive external ophthalmoplegia (PEO)
Plus, at least of one:
- Cardiac conduction defect/block
- CSF protein >100mg/dL
- Cerebellar ataxia
Non-syndromic mitochondrial - MT-RNR1-Related hearing loss - 1555A>G substitution
deafness - Homoplasmic
- Hearing loss with or without exposure to aminoglycoside
antibiotics (e.g. Gentamycin) - 100% penetrance with exposure,
reduced penetrance without exposure

Leigh syndrome - Most frequent mitochondrial disease in early childhood

- MRI: bilateral symmetrical basal ganglia and brain stem lesions

Clinical features:
Initial normal development followed by:
- Progressive stepwise deterioration: dystonia, ataxia, loss of
speech, loss of swallow, loss of bladder function
- Eventually central respiratory failure
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Multifactorial inheritance

Ischaemic heart disease - Only small minority of cases linked to Mendelian disorders (eg.
LDLR)
- Strong evidence for genetic factors: coagulation, in ammation,
lipid metabolism
- Stronger genetic liability and risks to relatives when a ected
individuals are female and younger
- Environmental factors and role of comorbidities
Diabetes mellitus type I - Autoimmunity against insulin-producing cells of the pancreas
- High monozygotic twin concordance
- High relative risk ratio
- Role of genetic factors at the Major Histocompatibility Complex
locus (genes involved in immune functions)
- Monogenic forms eg. MODY (1-2% of diabetes)

Cleft lip & palate Non-syndromic:

- Multifactorial - no single major locus, environmental factors (anti-
epileptic drugs, impaired folic acid metabolism, smoking)
Syndromic:
- Single gene defects
- Teratogenic
Epilepsy Structural/metabolic:
- Acquired brain lesions (HIE, head trauma, tumour, infection, stroke)
- Genetic (TSC, cortical malformations)
Multifactorial & polygenic:
- Common variants (GWAS) - ILAE consortium
- Rare variants (CNVs, ion channels, others…) - Epi4K/25K
RARE monogenic epilepsy syndromes:
- Genetic channelopathies (eg. SCN1A)
- Non-ion channel genes (eg. GLUT1)
- With developmental delay
- With neuronal migration disorders
- With neurodegeneration or IEM
- Progressive myoclonic epilepsies
- Chromosomal causes
- Mitochondrial disorders
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