1. Monogenic disorders risk calculations seminar No 425 Heredity

2. Key words: monogenic and polygenic heredity, autosomes, gonosomes (heterochromosomes), autosomal dominant (AD) a autosomal recessive (AR) disorders, phenocopy, genocopy, allelic heterogeneity, nonallelic (locus) heterogeneity, penetrance, expressivity, pleiotropy, symptom, syndrome, carrier, allele polymorphism, mitochondrial heredity, clinical genetics, genetic counselling

3. Binomial Distribution When there are two alternative events, one with probability p and the other with probability q (q = 1 - p), the frequencies of the possible combinations p and q in a series of n trials are given by the expansion of (p + q) n or by binomial expansion n! p m q n - m m! (n - m)! n = number in series p = probability of a specified event q =probability of the alternative event m = number of times p occurs n! = n(n-1)(n-2)…..1

4. 1. In village in Wales in 1984, 13 boys were born from 13 successive births. a) What is the probability of 13 successive male births? b) What is the probability of 13 successive births of a single sex? 2. What is the probability, that two children of healthy parents - carriers of cystic fibrosis (CF) mutation - will be: a) both healthy? b) both affected? c) one healthy and one affected?

5. 3. What is the probability that three children of healthy parents - carriers of cystic fibrosis (CF) mutation will be: a) all affected? b) all healthy? c) two affected and one healthy? d) two healthy and one affected? Use expansion of (p + q)3 or binomial expansion. 4. What is the probability that a couple of carriers of cystic fibrosis (CF) mutation will produce 5 children, three healthy and two affected?

6. 5. A man who has achondroplasia married a phenotypically normal woman. If they have four chidren, what is the probability that a) none of them will be affected with this disorder? b) all of them will be affected with this disorder ? 6. A woman has cystic fibrosis. What is the risk to be carrier for her mother, her father, her daughter, her daughter´s son, her brother, her brother´s child? 7. Healthy woman, whose father has albinism, is asking about the risk of having affected baby. Albinism is autosomal recessive disorder with frequency of heterozygous carriers in the population 1/150.

7. 8. Woman, whose brother has cystic fibrosis is asking about the risk of having affected baby. Cystic fibrosis is autosomal recessive disorder with frequency of heterozygous carriers in the population 1/25. 9.Neurofibromatosis is autosomal dominant disorder with penetrance 80%. a) What is the prognosis for patient´s child? b) What is the risk that their baby will be healthy, but carrier of this disorder? c) What is the chance, that baby of affected parent has only normal alleles?

8. 10.Penetrance of retinoblastoma (AD) is 90 %. A man who has retinoblastoma marries a healthy woman. What is the risk that their children will have retinoblastoma too? 11. A child has a paternal grandfather and maternal grandmother affected with sicle cell anemia (AR). What is the probability, that this child will be also affected? 12. A child has a paternal uncle and a maternal aunt affected with autosomal recessive disease. What is the probability that the chid will be also affected?

9. 13. A woman has sicle cell anemia (AR) and her husband´s father has this disease too. What is the risk of this disease for their child? 14. Both parents have autosomal dominant disease (their parents are healthy). What is the risk that their child will be affected? 15. Loss of hearing has autosomal dominant heredity (AD). A couple is healthy. Wife´s two brothers and her mother are affected. Husband´s sister and his father are affected too. a) What is the probability that their child has this disease? b) If affected sister marries a healthy man, what is the risk for their child?

10. Thompson and Thompson: Clinical genetics, chapter 7 : Single gene inheritance, pg. 115-134, 7th edition