Pedigrees

Why is it important to predict risk or affected/carriers

→ it is important to know how genetic diseases are inherited in humans

Predict risk of being affected:

• for family members of affect individuals

• Screening + treatment

Predict risk of being carriers:

• for family members of an affected

• Risk to unborn child

• Reproduction choices

Pedigrees

→ graphical representation of a family tree

• useful in calculating risk (affected or carrier) for well known disorders

• First step in establishing the mode of inheritance of a new disorder

Pedigree symbol meanings

Probands

• individuals affected by a genetic condition or who is concerned they are at risk

• Usually first person in a family to bring concern to healthcare professionals

• Denoted by an arrow with a P

Autosomal dominant inheritance

• 50% risk in offspring

• Transmission by females and males and both are equally affected

• Affected individuals have affected parent

• Teds to occur in every generation

Autosomal dominant pedigree

Autosomal recessive inheritance

• 25% risk in offspring with 2 carrier parents

• Males and females equally affected

• Usually no previous family history

• Increased risk if parents are related

X-linked recessive

• No male-to-male transmission

• Males affected almost exclusively

• Transmitted through unaffected female carriers

• All daughters of an affected male are carriers

E.g. Duchenne muscular dystrophy

X-linked pedigree

X-linked dominant

• males and females affected (often more females)

• Females usually less severely affected due to 2nd X

• Males transmit to ALL daughters and never sons

• Affected females transmit to 50% of her offspring

E.g. incontinnentia pigmenti

Incognentia pigmenti

• some alleles result in death before birth

• Females XX : skin abnormalities, hair loss, small/few teeth, eye problems, intellectual disability/neurological problems

• Males XY : lethal in utero in most males

X-linked dominant

Y linked inheritance

• affected males only

• Affected males transmit to all their sons

• Because there are so few genes on Y, only a few speculative cases have reported this

• Some mutations cause infertility = no inheritance

• Affected males ONLY have affected sons

Mitochondrial inheritance

• Conditions can appear in every generation of a family

• Can affect males and females

• Fathers don’t pass onto offspring - only females pass on as eggs but not sperm contain mitochondria

• Can pass on a mixed population→ different children inherit different no.s of mitochondria with the disease mutation:

Homoplasmy

Heteroplasmy = mix of mitochondrial types

Penetrance

→ % of people with the genotype that express the phenotype

• complete penetrance = all individuals have the phenotype

• Incomplete penetrance = individual genotype may not develop a phenotype

E.g BRCA1 = 80% lifetime risk

Anticipation in trinucleotide repeats

→ genetic disorder by a trinucleotide (codon) repeat

• signs and symptoms become more severe and appear at an earlier age as the disorder is passed from one generation to the next

• Typically occurs with disorders caused by an unusual mutation called trinucleotide repeat expansion

Anticipation - mechanism

• Expansion due to ‘slippage’ during DNA replication, above a threshold where the gene stops functioning normally

• People with the same disease genotype may have stronger or weaker forms of the disorder, or never develop it

E.g. Huntington’s, fragile X syndrome

Huntington disease

• more CAG repeats in the HTT gene, which makes aa glutamine

• 27-35 repeats = no disease but prone to repeat instability

• 36-55 =-19 common in patients with Huntington’s

• 60+ repeats = juvenile onset

Detecting anticipation

• Use PCR with one fluorescent primer and one standard primer

• Bind either side of the repeat region

• Capillary electrophoresis - exact size(s) of alleles and number or repeats detected using laser