Mike Oldridge FRC path 17/9/2010

1. Describe the factors to be taken into account when constructing a pedigree, paying particular attention to ways in which family history may be misleading Mike Oldridge FRC path 17/9/2010

2. Pedigrees a diagram showing familial relationships in which genetic traits are recorded • Essential when documenting large complex family histories with inherited disease

3. Pedigree construction • Programs available to aid in construction • Comprehensive list of genetic analysis software http://linkage.rockefeller.edu/soft/list1.html#c • eg Cyrillic, Madeline 2.0 (web based) • Draws pedigrees and stores associated disease data / haplotypes. • Allows export to linkage analysis programs

4. Pedigree symbols

5. Uses of Pedigrees • Determining modes of inheritance • Linkage analysis – identify disease genes • Segregation studies – UV pathogenicity

6. Ways in which family history can be misleading • Misinformation • Common recessive disorders • Non-penetrance • Variable expression • Late onset penetrance • Locus heterogeneity • Imprinting • Male lethality • de novo mutations

7. Misinformation • Familial relationships are incorrect eg Non-paternity (UK 1-2%), adoption • Affected status is incorrect

8. Common recessive disorders • If mutations common in population, high probability that it may be brought into the pedigree independently by an unaffected carrier • Can give an apparent dominant inheritance pattern

9. Non-penetrance • Penetrance defined as the probability that a person who has a genotype will manifest the character • True dominant disorders will have 100% penetrance • In reality can be very variable, ranging from clinically normal (generation skipping) to fully affected dependent upon: • Genetic background • Environmental factors

10. Non-penetrance

11. Variable expression Waardenburg syndrome – 1st quadrant: hearing loss 2nd different coloured eyes 3rd white forelock 4th premature graying

12. Late onset disorders • Another example of reduced penetrance / variable expression • Genotype fixed at birth but phenotype does not manifest until later in life • Classic examples are HD and hereditary cancers • Penetrance may become 100% if the person lives long enough or some may not develop symptoms in their lifetime

13. Locus heterogeneity • Same clinical phenotype resulting from mutations at different loci • Classic example is recessive hearing loss - Many different genes involved in the hearing pathway, mutations in any one of these can lead to hearing loss • 2 affected parents often have normal children as mutations are at different loci - Complementation

14. Imprinting • Expression of trait depends upon parental origin eg. dominant glomus tumours only expressed when inherited from father

15. Male lethality • Absence of normal allele can lead to prenatal lethality in X-linked dominant conditions eg. incontinentia pigmenti • Only affects females who pass it on to ½ of their daughters and none of their sons

16. De novo mutations • An unaffected couple with no family history may have an affected child due to a new mutation • Cannot differentiate de novo from • Autosomal recessive • X-linked recessive if male child • Even when genetic cause is identified, if parents unaffected and do not carry mutation, could still be germline mosaicism and recurrent risk is hard to calculate

17. Key words Pedigree Inheritance Linkage Segregation Non- penetrance Non-Mendelian inheritance