Investigate the causes of genetic variation relating to the changes and conservation of the DNA sequence including: the use of pedigree analysis to identify patterns of inheritance and mutation

What this dot point is asking

NESA wants you to read a pedigree chart, identify the inheritance pattern (autosomal recessive, autosomal dominant, X-linked recessive, X-linked dominant) and link the pattern to where the mutation occurred. New mutations and de novo events are a common twist.

The answer

Pedigree symbols

Generations are labelled with Roman numerals (I, II, III), individuals within a generation with Arabic numerals (1, 2, 3).

Inheritance patterns

Autosomal dominant.

• Trait appears in every generation (no skipping).
• About 50 percent of offspring of an affected parent are affected.
• Both sexes affected equally.
• Affected father can pass to son (rules out X-linked).
• Example: Huntington disease, achondroplasia.

Autosomal recessive.

• Trait often skips generations (carriers are unaffected).
• Two unaffected carrier parents have 25 percent affected children.
• Both sexes affected equally.
• Often appears in offspring of consanguineous (related) parents.
• Example: cystic fibrosis, phenylketonuria, sickle cell anaemia.

X-linked recessive.

• Affects males more than females (males are hemizygous; one allele is enough).
• Affected father cannot pass the condition to sons (he passes Y), but all his daughters are carriers.
• Affected sons usually have a carrier mother.
• Can skip generations through unaffected carrier mothers.
• Example: haemophilia A and B, Duchenne muscular dystrophy, red-green colour blindness.

X-linked dominant.

• Affects both sexes but more females (they have two X chromosomes).
• Affected father transmits the trait to all daughters and no sons.
• No generational skipping.
• Example: fragile X syndrome (partly), incontinentia pigmenti.

Y-linked.

• Passed strictly father to son. Females never affected.
• Rare in syllabus questions but worth recognising.

Reading a pedigree: the decision tree

1. Is the trait in every generation?
   • Yes → likely dominant.
   • No → likely recessive.
2. Are males and females affected equally?
   • Yes → likely autosomal.
   • More males affected → likely X-linked recessive.
   • All daughters of affected father affected → X-linked dominant.
3. Does an affected father pass to a son?
   • Yes → autosomal (rules out X-linked).
   • No, with the rule "all daughters but no sons" → X-linked dominant.
4. Consanguinity present? Increases the chance of autosomal recessive.

Worked example: haemophilia in the British royal family

Queen Victoria was a carrier ($X^H X^h$). Her son Leopold was affected ($X^h Y$). Her daughters Alice and Beatrice were carriers and married into European royal houses, introducing haemophilia into the Spanish, Russian and Prussian royal families. The Russian Tsarevich Alexei was famously affected, contributing to the political instability that preceded the 1917 revolution.

The pedigree shows the classic X-linked recessive pattern: affected males, carrier females, no female-to-female transmission, and skipping through unaffected carriers.

Mutations on pedigrees

A trait may appear in a pedigree with no prior family history because of a de novo (new) mutation in a parental gamete or early in the embryo. Clues that suggest a de novo mutation:

• A single affected individual with no other family history and no consanguinity.
• A high-penetrance dominant condition that should be visible in the parents (e.g. achondroplasia, where roughly 80 percent of cases are de novo).
• An X-linked recessive condition (e.g. haemophilia) in a boy whose mother is not a known carrier.

Mosaicism is another explanation: a parent carries the mutation in only some of their gametes, so the mutation appears in only some of their children.

Examples in context

Example 1. Huntington's disease in a NSW family. Huntington's disease is an autosomal dominant disorder caused by an expansion of CAG repeats in the HTT gene on chromosome 4. A pedigree from a typical Hunter Valley family at the Royal North Shore neurogenetics clinic shows the disease appearing in every generation, affecting roughly half of offspring of each affected parent, and males and females equally. This pattern - vertical transmission, no skipping, no sex bias - is the classic signature of autosomal dominant inheritance. Genetic counsellors use the pedigree to estimate a 50 percent risk for each child of an affected parent and offer predictive genetic testing once the child is of legal age and capable of informed consent.

Example 2. Cystic fibrosis and the carrier-parent pedigree. Cystic fibrosis is autosomal recessive. In a typical pedigree presented at the Sydney Children's Hospital genetics clinic, two unaffected parents have an affected child, then have unaffected and affected siblings in roughly the 3:1 Mendelian ratio. The trait skips generations because carriers (heterozygotes) are phenotypically normal. Both parents must contribute the recessive allele, so both are obligate Aa carriers. The pedigree pattern - parents unaffected, child affected, no sex bias, often appearing in collateral relatives - confirms autosomal recessive inheritance, and counselling can offer prenatal testing for future pregnancies.

Try this

Q1. A pedigree shows a trait that affects only males, appears in every generation, and is passed from affected grandfathers to half of their grandsons through carrier daughters. Identify the inheritance pattern and justify your answer. [3 marks]

• Cue. X-linked recessive: only males affected, no male-to-male transmission, daughters are unaffected carriers.

Q2. In a pedigree of an autosomal recessive disorder, both parents are heterozygous carriers. They have four children. Calculate the probability that (a) exactly two children are affected, and (b) at least one child is affected. [2+2 marks]

• Cue. (a) Binomial: C(4,2) by (1/4) squared by (3/4) squared = 27/128. (b) 1 minus (3/4) to the fourth = 175/256.

Q3. A pedigree shows an unaffected mother and an unaffected father with an affected daughter. No relatives on either side have the disorder. (a) State why this is consistent with a new (de novo) autosomal dominant mutation. (b) Suggest two other inheritance patterns to consider before concluding it is de novo. (c) Describe a molecular test that could confirm a new mutation. [2+2+2 marks]

• Cue. (a) Trait appears with no carrier family history; both parents unaffected but child affected with dominant phenotype. (b) Autosomal recessive with both parents carriers; non-paternity. (c) Sequence the daughter and both parents - mutation present only in daughter confirms de novo.