Common Genetic Disorders

Question 1

Genetic aspects of Huntington Disease

Answer 1

• autosomal dominant inheritance
• genetic anticipation
• unstable chain length due to CAG expansion (polyglutamine tract resulting in aggregation of insoluble protein and neurotoxicity)
• <35 repeats: unaffected, 36-39: incomplete penetrance, >40: affected

Question 2

Clinical aspects of Huntington Disease

Answer 2

• onset between 30-50
• characterised by progressive chorea, dementia and psychiatric symptoms

Question 3

Genetic aspects of Myotonic Dystrophy

Answer 3

• autosomal dominant inheritance
• genetic anticipation
• unstable chain length due to CTG expansion which is transcribed but untranslated resulting in abnormal DMPK mRNA
• binds to splicing proteins making them unavailable to other genes that need them
• > 50 repeats: affected
• increased chance of expansion in female transmission

Question 4

Clinical aspects of Myotonic Dystrophy

Answer 4

Characterised by progressive muscle weakness in early adulthood, myotonia (inability of muscle of relax after contraction) and cataracts

Question 5

Genetic aspects of Cystic Fibrosis

Answer 5

• mutation in CFTR gene (chloride ion channel) resulting in increased thickness in secretions
• in-frame 3bp deletion resulting in loss of phenylalanine which prevents normal folding of the protein and insertion into the plasma membrane

Question 6

Clinical aspects of Cystic Fibrosis

Answer 6

• characterised by recurrent lung infections with bronchiectasis and obstructive lung disease
• pancreatic insufficiency
• infertility in males (due to bilateral absence of VD)
• screening of newborns can be done by checking immune reactive trypsin levels then confirmed with DNA/sweat testing

Question 7

Genetic aspects of Neurofibromatosis type 1

Answer 7

• autosomal dominant

Question 8

Clinical aspects of NF1

Answer 8

• characterised by cafe au lait maculopapules and neurofibromas
• short stature, macrocephaly, learning difficulties (30%)
• very variable expressivity
• Lisch nodules in eyes indicative of NF1 (not harmful)

Question 9

Genetic aspects of DMD and BMD

Answer 9

• X-linked recessive inheritance
• variant in DMD gene (responsible for coding for dystrophin which helps protect and stabilise muscle fibres)
• DMD: out of frame mutations (completely disrupts reading frame leading to no dystrophin formed)
• BMD: in frame mutations (some dystrophin formed)

Question 10

Clinical aspects of DMD and BMD

Answer 10

DMD: onset avg 3 years, wheelchair needed avg 12 years
BMD: milder form, onset avg 11 years, wheelchair needed later if not at all
High levels of serum creating kinase from birth

Question 11

Genetic aspects of fragile X syndrome

Answer 11

• X-linked recessive inheritance
• genetic anticipation
• expansion of FMR1 gene
• full mutation >200 repeats: males severely affected, females less

Question 12

Clinical aspects of Fragile X Syndrome

Answer 12

• elongated face, large ears, significant learning disability

Question 13

Aspects of Down Syndrome

Answer 13

• trisomy 21
• recurrence risk depends if trisomy or translocation (translocation means parent has abnormal arrangement of chromosomes)
• characterised by learning difficulties, heart malformations, hypothyroidism, single transverse palmar crease

Question 14

Aspects of Edwards Syndrome

Answer 14

• trisomy 18
• characterised by small chin, overlapping fingers, organ malformation, profound intellectual disability
• high risk of death before 1

Question 15

Aspects of Patau Syndrome

Answer 15

• trisomy 13
• characterised by congenital heart disease and profound intellectual disability
• cleft lip and palate, microphthalmia, abnormal ears, clenched fists, post-axial polydactyly
• high risk of death before 1

Question 16

How are trisomies formed?

Answer 16

By maternal non-disjunction: failure of normal separation of the chromosomes affected (21, 18, 13) in meiosis