Mendelian disease

Pattern of autosomal dominant on a pedigree chart

Female and male both affected

through generations

high rate of mutations through out

Achondroplasia as autosomal dominant

1/10,000 live birth

Short limbs

Normal sized head, body and intelligence

Due to mutation in FGFR3 gene (inhibition of bone growth) - mutation in the transmembrane domain

Mutation causes the receptor to signal in the absence of ligand

What are complications to autosomal dominant pedigrees?

Variable expressivity

Penetrance

Variation in the age of onset

New mutations with advanced paternal age

What is variable expressivity?

Variation in the severity of the problems arising from a particular genetic defect

Always exhibit some symptoms

Manifestation of phenotype - development of symptoms differs in people with the same genotype

Within family, different members show different features of the syndrome

Variable expressivity - in Marfan syndrome

1/5000

Tall thin stature with long arms

Long double-jointed fingers

Short torso and very long legs

However, not all individuals exhibit these features

What is incomplete penetrance

The penetrance rate is the probability of a heterozygote presenting with the disease 

Penetrance = the proportion of individuals with a given genotype who actually express the associated phenotype

Reduced penetrance = skipping of generation 

Complete penetrance example - cystic fibrosis

Neurofibromatosis type 1

1/4000 individals

6 or more cafe au lait spots

Neurofibromas occur anywhere along the nerve

Most lead to normal life, but learning disability is frequent

Mutation in NF1 gene, and also exhibits variable expressivity

Incomplete penetrance example- breast cancer due to BRCA gene

Breast cancer penetrance to age 70 estimated at 68% and increase as gets older

Similar with ovarian cancer

Variation in the age of onset - penetrance referred to in terms of a time scale

Example : Huntington disease

Paternal age effect - new mutations with advanced paternal age

The mother transmit about 15 mutation to offspring regardless of age, but mutation transferred from dad increases with age

Could be associated with “selfish spermatogonia selection” : random mutation in a sperm cell gives it a growth advantage, leading to clonal expansion in the testis

As the individual age the proportion of sperm carrying this mutation gets higher

Majority are missense mutation that changes a single amino acid on fibroblast growth receptor

Random X activation in female

A mechanism of dosage compensation by epigenetic silencing

Females are therefore mosaics

Occurs within the first week of embryogenesis

The regressed chromosome forms a heterochomatic mass (Barr bodies)

However approx 15% of X-linked genes show biallelic expresson and are expressed from active and inactive X chromosome

X-linked disease: Duchenne muscular dystrophy

Affects 1/3500 males

Most severe and common MD

Progressive wasting of muscles, death by age 30

The DMD gene Dystrophin is on Xp21 hat is prone to internal deletion → No dystrophin at all

Mutations which affect the DMD gene are mostly frameshift but can be new mutations

DMD gene and dystrophin function 

the DMD gene codes fo dystrophin, which provides strength to muscle cells by linking the internal cytoskeleton to the surface membrane

Without the dystrophin, the cell membrane becomes permeable and the internal pressure inside the cell makes it burst and the damage is so extreme to the point where stem cells cannot repair

Becker muscular dystrophy 

Milder than DMD, age of onset is after 10y and may require wheelchair from 40-50 though normal life span 

Cardiomypathy - rare feature

Due to deletions and other mutations, the proteins are truncated leading to a partially functional protein 

Characteristics of X-linked mutations

Affects both sex, mor females affected

Females more mildly affected

No male-to-male transmission

Example : incontinentia pigmenti