5.2. Complexity in single gene disorders

What is mosaicism?

A condition where not all cells in the body are genetically identical

What are examples of true mosaicism?

Mild Klinefelter's syndrome (XXY) and Turner's syndrome (XO)

What is a phenocopy?

An environmental effect that mimics a genetic disease — a trait caused by the environment that appears to be inherited

What is an example of a phenocopy?

Confusing genetic deafness with deafness caused by Rubella virus infection during pregnancy

What is anticipation in genetics?

A phenomenon where symptoms become more severe and appear earlier with each successive generation

What causes anticipation?

Unstable mutations that show directional variation, resulting in increased severity and decreased age of onset

What is the most common CFTR mutation type?

Missense mutations (810 cases)

What is the DF508 mutation?

A deletion mutation that removes the phenylalanine residue at position 508 of the CFTR protein, found in around 80% of CF patients in Western Europe

What type of mutation is DF508?

A deletion mutation

What disease is associated with the insertion mutation c.2416_2417InsG?

Familial hypercholesterolaemia (FH), identified in a consanguineous Pakistani family with elevated blood lipids

What type of mutation causes all cases of sickle cell anaemia?

A missense (substitution) mutation in β-globin — E6V — causing valine to be incorporated instead of glutamic acid at position 6

What is the E6V mutation?

A substitution mutation in β-globin where glutamic acid is replaced by valine at position 6, causing sickle cell anaemia

What mutation often causes Duchenne muscular dystrophy?

A nonsense mutation in the dystrophin gene (K1524X) — lysine to stop codon

What is genetic heterogeneity?

When mutations in different genes can lead to the same disease

What is Xeroderma pigmentosa (XP)?

A condition where mutations in any of eight genes involved in DNA damage repair cause hypersensitivity to sunlight and frequent development of carcinomas

What is the LMNA gene and why is it significant?

It encodes Lamin A, which supports the nuclear membrane; different mutations in this gene result in multiple distinct disorders

What is penetrance in the context of single gene disorders?

The frequency with which a person who carries a disease-causing mutation actually shows signs and symptoms of the disease

Do all dominant mutations display 100% penetrance?

No — penetrance can be less than 100% and is influenced by genetic and environmental factors

What factors influence penetrance of BRCA1 mutations?

Environmental factors including pregnancies, breastfeeding, smoking, and diet

What is the penetrance of Huntington's disease?

100% penetrant

What is variable expressivity in autosomal dominant disorders?

When modifier genes shift the range of disease phenotypes, causing individuals with the same disease-causing allele to express more or less severe phenotypes

What is tuberous sclerosis an example of?

A condition with complete penetrance but variable expressivity

What genes are mutated in tuberous sclerosis?

TSC1 or TSC2 genes, which encode subunits of a tumour suppressor

What are the types of CFTR mutations?

Missense, frameshift, splicing, nonsense, in-frame insertion/deletion, large insertion/deletion, promoter, sequence variation, and unknown