Inherited disease

  • Created by: MazzaW
  • Created on: 29-11-19 13:05

Huntington's disease

Triple repeat of CAG (on HTT gene, chromosome 4):

  • <26: normal
  • 27-35: no HD but risk of passing it on
  • 35-40: incomplete penetrance, may develop some signs of HD
  • 26-40: may have disease but incomplete penetrance

Demonstrates anticipation with worsening Sx and earlier age of onset with subsequent generations

Sx: movement disorder (early = chorea, jerky movements, later = rigidity, Parkinsonism, dystonia), dementia, apathy, difficulty concentrating, depression.

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Myotonic dystrophy

CTG repeat:

  • <35: normal
  • 50-100: mildly affected, cataracts, mild muscle weakness later in adulthood
  • 200-500: classically affected, facial and distal muscle weakness, myotonia
  • >1000: congenital or childhood onset of disease

Demonstrates anticipation.

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Long QT syndrome

Usually autosomal dominant.

Blackouts during strenuous exercise (especially swimming) and when startled, predisposes to life-threatening arrhythmias (e.g. torsades de pointes)

Many genes implicated (genetic heterogeneity) so may not always be able to identify the causative gene.

Normal QTc on ECG does not rule out disease.

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Marfan's syndrome

Autosomal dominant, 95% cases have FBN1 mutation.

Skeletal, ocular and cardiac phenotypes:

  • tall, slim, long digits, short torso
  • dilated aortic root, aortic rupture/dissection, valve disease, arrhythmias
  • lens dislocation, glaucoma, myopia

High penetrance but variable expression.

Dx with Ghent criteria and genetic testing

De novo mutation in 25%

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Neurofibromatosis type 1

Mutation in NF1. 

Dx = 2+ of:

  • 6+ cafe-au-lait macules
  • 2+ neurofibromas (any type) or 1 plexiform neurofibroma
  • freckling in axillary/inguinal regions
  • optic glioma
  • 2+ Lisch nodules (iris hamartomas)
  • distinctive osseous lesion (sphenoid dysplasia, tibial pseudarthrosis)
  • 1st degree relative with NF1

100% penetrance but variable expression

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Tuberous sclerosis

TSC1 and TSC2 genes. Rare.


  • skin features
  • cerebral lesions (often causes epilepsy)
  • renal lesions
  • lung- mostly females >18, presents with SOB, can progress to emphysema-like disease

High penetrance, variable expressivity

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Down's syndrome

Trisomy 21: 47 ** +21 or 47 XY +21

Mostly via non-disjunction (failure of chromosomes to fully separate during meiosis leading to gain of chromosome)- 88% from mother, 8% from father. Risk increases with increasing maternal age.

Can also occur due to unbalanced Robertsonian translocation (e.g. of chromosomes 14 and 21). More common if the translocation comes from the mother. 

Screening helps to approximate risk: combined test (nuchal translucency, increased hCG, decreased PAPP-A), quadruple test (AFP, hCG, unconjugated oestriol, inhibin A). Dx can be confirmed by chorionic villus sampling (1st trimester) or amniocentesis (2nd trimester).

Sx: dysmorphic round face, learning difficulties, developmental delay, epicanthic folds, Brushfield spots on iris, small ears, flat occiput, protruding tongue, abundant neck skin, atlantoaxial instability, single palmar crease, cardiac defects, inwards-curving little finger, gap between 1st and 2nd toes, respiratory infections, duodenal atresia, increased risk of leukaemia and early onset Alzheimer's

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Edward's syndrome

Trisomy 18 (occurs by non-disjunction only).

Signs: prominent occiput, small jaw/mouth, short neck, dysplastic/malformed ears, clenched hands, overlapping fingers, shield chest, short prominent sternum, wide-set *******, flexed big toe, prominent heels

Other problems: kidney malformations, omphalocoele, structural heart defects (VSD), oesophageal atresia, microcephaly, median lifespan 5-15 days, cleft lip/palate

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Patau's syndrome

Trisomy 13, mostly by non-disjunction but can occur due to unbalanced translocation (e.g. chromosomes 13 and 14).

Usually miscarries but can survive to birth- not compatible with life (80% die within 1st year).

Sx: small head, absent eyebrows, cleft lip/palate, dysplastic/malformed ears, clenched hands, polydactyly, undescended/abnormal testicles, holoprosencephaly (midline brain defects), rocker bottom feet, microcephaly, eye defects, omphalocoele

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Turner syndrome


Newborn: lymphoedema (puffy) of hands and feet, cystic hygroma

Older: short stature, premature ovarian failure (amenorrhoea, infertility, failure to develop secondary sex characteristics), facies (downslanting eyes, prominent earlobes, webbing of neck, crowding of teeth), genitourinary abnormalities (horseshoe kidney), cardiac abnormalities (VSD, aortic coarctation)

At increased risk of: diabetes, IBD, coeliac disease, hyperthyroidism

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Klinefelter's syndrome

XXY (due to non-disjunction). Male with additional X chromosome.

Male but may have small/undescended testes and more female characteristics: gynaecomastia, female-type pubic hair, absence of frontal baldness, tendency to grow fewer chest hairs, long legs, wide hips, poor beard growth, narrow shoulders.

May also have truncal obesity and minor learning disability. 

Tend to have fertility problems, may have lower libido/impotence (lack of response to FSH and LH- can give testosterone to alleviate problem)

Associated with diabetes, metabolic syndrome and hypothyroidism.

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Fragile X syndrome

Triplet repeat of CGG in FMR1 (X chromosome):

  • >200 repeats: silences gene, prevents production of FMR protein, disrupts nervous system
  • 55-200 repeats: premutation, can cause fragile X-associated primary ovarian insufficiency (oligomenorrhoea, early menopause, infertility, elevated FSH) or fragile X tremor-ataxia syndrome (late-onset neurodegenerative disorder mostly in males>50, intention tremor, cerebellar ataxia, Parkinsonism)

Characteristic physical features: long narrow face, large ears, prominent jaw/forehead, unusually flexible fingers, flat feet, enlarged testicles

Other features: developmental delay (speech and language), intellectual disability, autism spectrum disorder in 1/3, seizures

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Duchenne/Becker muscular dystrophy

X-linked recessive inheritance

Mutation of dystrophin gene: frameshift (Duchenne- no protein), or non-frameshift (Becker- abnormal protein)

Carrier women may hae some muscular weakness depending on pattern of X inactivation.

Muscle weakness that presents early in life (3-5 for DMD, 5-15 for BMD): abnormal gait (toe walking), Gower's sign (using hands on knees/thighs to push self up), fatigue. Later- respiratory/ cardiac involvement (dilated cardiomyopathy, respiratory failure) leading to death. 

Life expectancy: 30s (DMD), 40-50 (BMD)

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Mutation in FGFR3 gene (90% de novo). Protein contributes to collagen + other bone structures.

Sx: disproportionate dwarfism, shortening of proximal limbs, short fingers/toes, large head, prominent forehead, spinal kyphosis, varus/valgus knee deformity, small midface with flattened nasal bridge, dental crowding, recurrent otitis media (may cause hearing loss).

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Angelman syndrome

Imprinting disorder- methylated paternal gene so need functioning maternal copy. Disorder occurs when there is lack of functioning maternal copy of UBE3A gene (chromosome 15).

Facial features: epicanthal folds, sunken nasal bridge, small chin, unusually fair skin and hair, long upper lip, prominent lower lip, small and widely spaced teeth

Other features: developmental delay (severe speech impairment, problems with movement and balance- ataxia), intellectual disability, happy, laughing, hand flapping, seizures

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Prader-Willi syndrome

Imprinting disorder- lack of functioning paternal copy of part of chromosome 15 (several genes including SNRPN)

Facies: narrow temple distance and nasal bridge, almond shaped eyes, mild strabismus, thin upper lip, downturned mouth, overweight

Features: hypotonic (motor delay), extreme feeding problems (hyperphagia, can lead to obesity and T2DM), intellectual impairment, developmental delay.

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