CLINICAL GENETICS (MTD-356)

1. CLINICAL GENETICS (MTD-356) Lecture 3

2. Same Genetic Mutation, Different Genetic Disease Phenotype • Three individuals carry the same disease-causing mutation; two suffer from the disease but exhibit different symptoms, while the third is completely unaffected. Why?

3. For many inherited diseases, the same mutation is not always expressed in all individuals who carry it. • moreover, when the mutation is expressed, it is not always expressed in the same way. • These findings are the basis for the concepts of penetrance and expressivity. • Penetrancemeasures the proportion of a population of individuals who carry a disease-causing allele and express the related disease phenotype. • Expressivity measures the extent to which a genotype shows its phenotypic expression.

4. Example • Retinoblastoma is a cancer of the retina that primarily affects children and is caused by mutations in the Rb gene. • Interestingly, not all people who carry this mutation suffer from retinoblastoma. • For instance, two sisters could inherit the same mutation from their parents, and one might be affected by thedisease, while the other is not. • Perhaps even more interestingly, retinoblastoma is not alone in this regard; there are numerous other inherited diseases in which the same mutation is not expressed in all the individuals who carry it. These findings illustrate a concept that geneticists refer to as penetrance.

5. Penetrance is a measurement of the proportion of individuals in a population who carry a disease-causing allele and express the disease phenotype. • In the case of retinoblastoma, because not all individuals who carry the mutation are affected by the disease, this condition is said to display incomplete or reduced penetrance. • Other diseases with incomplete penetrance include Huntington's disease and breast cancer. • In contrast to these examples, a disease shows complete penetrance if all of the individuals who carry the related gene are affected by the disease. • For instance, the inheritance of a specific point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) always results in the disorder achondroplasia, which is characterized by abnormal bone growth and dwarfism.

6. Factors Affecting Gene Expression • Penetranceis how often a gene is expressed. • It is defined as the percentage of people who have the gene and who develop the corresponding phenotype. • A gene with incomplete or low penetrance may not be expressed even when the trait is dominant or when it is recessive and the gene responsible for that trait is present on both chromosomes. • Penetranceof the same gene may vary from person to person and may depend on a person's age. • Even when an abnormal allele is not expressed (nonpenetrance), the unaffected carrier of the abnormal allele can pass it to children, who may have the clinical abnormality. • In such cases, the pedigree appears to skip a generation. • However, some cases of apparent nonpenetrance are due to the examiner's unfamiliarity with or inability to recognize minor manifestations of the disorder.

7. complete penetrance. The allele is said to have complete penetrance if all individuals who have the disease-causing mutation have clinical symptoms of the disease. • highly penetrant. If an allele is highly penetrant, then the trait it produces will almost always be apparent in an individual carrying the allele. • incomplete penetrance or reduced penetrance. Penetrance is said to be reduced or incomplete when some individuals fail to express the trait, even though they carry the allele. • low penetrance. An allele with low penetrance will only sometimes produce the symptom or trait with which it has been associated at a detectable level. In cases of low penetrance, it is difficult to distinguish environmental from genetic factors.

8. Why Do Phenotypes Show Differences in Penetrance? • Penetrance can be difficult to determine reliably, even for genetic diseases that are caused by a single polymorphic allele. For many hereditary diseases, the onset of symptoms is age related, and is affected by environmental codeterminants such as nutrition and smoking, as well as genetic cofactors and epigenetic regulation of expression: • Age-related cumulative frequency.Penetrance is often expressed as a frequency, determined cumulatively, at different ages. For example, multiple endocrine neoplasia 1 (MEN 1), a hereditary disorder characterized by parathyroid hyperplasia and pancreaticislet-cell and pituitary adenomas, is caused by a mutation in the menin gene on human chromosome 11q13. In one study the age-related penetrance of MEN1 was 7% by age 10 but increased to nearly 100% by age 60. • Environmental modifiers. Penetrance may be expressed as a frequency at a given age, or determined cumulatively at different ages, depending on environmental modifiers. For example, several studies of BRCA1 and BRCA2 mutations, associated with an elevated risk of breast and ovarian cancer in women, have examined associations with environmental and behavioral modifiers such as pregnancies, history of breast feeding, smoking, diet, and so forth.

9. Genetic modifiers. Penetrance at a given allele may be polygenic, modified by the presence or absence of polymorphic alleles at other gene loci. Genome association studies may assess the influence of such variants on the penetrance of an allele. • Epigenetic regulation. Example ... genomic imprinting by the paternal or maternal allele.

10. Expressivity is the extent to which a gene is expressed in one person. • It can be graded as a percentage; e.g, when a gene has 50% expressivity, only half the features are present or the severity is only half of what can occur with full expression. • Expressivity may be influenced by the environment and by other genes, so people with the same gene may vary in phenotype. • It can vary even among members of the same family.

11. Neurofibromatosis • Neurofibromatosis is a disease caused by mutations in the neurofibromingene. • These mutations can cause the Schwann cells in an affected individual's nervous system to grow into tumors called neurofibromas, which appear as café-au-lait colored spots or bumps under the skin. • These tumors can result in skeletal abnormalities and neurological problems. • However, not all people who have the mutated neurofibromin gene are equally affected by this condition. • Research has shown that family members who carry the same mutated gene can exhibit a range of symptoms, with some individuals experiencing much more severe symptoms than others, although they all carry the same allele.

12. Holoprosencephaly • Holoprosencephaly is a condition in which the embryonic forebrain does not correctly divide into two lobes. • To date, scientists have described nine types of holoprosencephaly caused by deletions or duplications in various genes and chromosomal regions. • In 1993, researcher Amanda Collins and her colleagues studied a single large family with multiple children affected with holoprosencephaly, and they noted variable expressivity of the disease in the affected family members. • In the most severe cases, holoprosencephaly resulted in death. In contrast, in the mild cases, the family members had near-normal to normal brain development and only minor facial deformities, such as a single upper central incisor. • Other studies have shown that this disease also displays incomplete penetrance.

14. Van derWoude Syndrome • Van derWoude syndrome is a dominantly inherited developmental disorder that causes cleft lip and/or cleft palate. • This condition results from mutations in a single gene that encodes for a protein called interferon regulatory factor 6. • Studying a large family of seven generations affected with Van derWoude syndrome, Jankuet al. noted that the disorder displayed both incomplete penetrance and variable expressivity. Sometimes, individuals who did not realize they were affected were diagnosed with mild versions of the disorder upon careful examination. Most patients had characteristic lip pits, which were often observed alone and sometimes with other symptoms. Meanwhile, lip and palate clefts were observed in around one-fifth of individuals (Jankuet al., 1980).