Population Genetics (TRANSFERRED) Flashcards
Reference: Genetics residents in-training examination - March 2020 (Spring 2020)
A physician from your province’s Child Protection Services has referred a family to your clinic for your guidance. A 6-year-old boy has been recently placed in the care of his maternal aunt. His 44-year-old mother developed significant neurological and psychiatric symptoms over the past few years, and took her own life during an episode of severe depression. During this tumultuous time, she was diagnosed with CADASIL. The boy’s father is unknown, and his maternal grandparents died in a car accident in their 30s many years ago. This 31-year-old maternal aunt is the only surviving relative, and is trying to decide whether she should legally adopt the child or propose an outside adoption. She comes to you with two specific requests.
For this aunt, calculate her risk of developing CADASIL, provided that 25% of patients are asymptomatic by age 30.
See Genetics residents in-training examination
March 2020
Page 21
Using the most conservative interpretation of her limited family history, and - Using the information that she does not report having one specific clinical symptom(we can name migraine but this is a give-away for one of the clinical questions above) that is known to be present in 75% of individuals by the age of 30. Ref: From GeneReviews: « Migraine, when present, can be the first symptom of CADASIL. Migraine occurs in 30%-75% of individuals with CADASIL, with the first attack occurring at a mean age of 26-29 years [Adib-Samii et al 2010, Tan & Markus 2016, Guey et al 2016]. Eighty to ninety percent of those with migraine have migraine with aura [Guey et al 2016, Tan & Markus 2016]. Migraine auras are sometimes confused with transient ischemic symptoms, since aura may include focal neurologic deficits [Di Donato et al 2017]. Sixty percent of those with migraine with aura have experienced an atypical migraine attack: prolonged, basilar or hemiplegic aura, confusion, fever, or coma [Guey et al 2016]. »
Reference: Genetics residents in-training examination – Fall 2020
Sarah’s paternal grandfather died of Huntington disease (HD). Her father is 50 years old and is unaffected. Her brother was diagnosed at 34 years of age with HD. Sarah is now 30 and wants to know her chance to develop HD. Approximately 10% of HD gene carriers are clinically affected by 30 years of age, 50% by 50 years, and almost 100% by 70 years of age.
a. What is the chance that Sarah will carry the mutation, but will not be affected by 30 years of age?
b. What is Sarah’s chance to develop HD?
a. Answer: 9/10 who carry mutation will not be affected by 30 years of age (chance is 1/10 individuals carriers are clinically affected by 30 years of age)
b. Answer: see diagram below: 0.5 points for each correct calculation (therefore, 1 point in total for Prior risk (P) identified, Condition (C), Joint (Jx) and Post (total 4 points for entire table)
Diagram: see reference exam
Condition(C): Phenotype: 1/10 individuals affected by 30 years of age, so 9/10 who carry mutation will not be affected by 30 years of age
Spring 2021
The frequency of the allele GdB at the glucose- 6- phosphate dehydrogenase locus in samples from four different male populations are:
USA Blacks 0.770 USA Whites 0 West African Blacks 0.824 Afroamericans in Bluefields, Nicaragua 0.809
a) Calculate the proportion of West African black alleles in the USA Blacks and the Bluefields Afroamerican populations, assuming West African Blacks were the ancestral black population and whites the other ancestral population. (2)
b) Investigations of other alleles have suggested that approximately 90% of genes segregating in USA Blacks have come from West Africans vs 66% of those of Afroamericans in Bluefields. Are these data compatible with your earlier results? What explanation would you give for obvious discrepancies? (3)
a)
M (USA B) = p (USA B) – p (whites) / p (WAB) – p (whites)
M (WAB) = 0.770-0/0.824-0 = 93.4%
M (Bluefields) = p (Bluefields) – p (whites) / p (WAB) – p (whites)
M (Bluefields) = 0.809 – 0/0.824-0 = 98.2%
b)
They are compatible for the USA blacks [93.4% vs 90.0%], (1) but not got the Bluefields population [98.2% vs 66%] (1). The Bluefields population is an admixture of three or more populations: Whites including Hispanics, West African blacks, and Indigenous Nicaraguans so assuming there are just two ancestral populations gives erroneous results (1).
Spring 2021
A 25 year old woman had carrier testing through a commercial laboratory. She was found to be a carrier for congenital HAX1 related Neutropenia. She and her husband are of mixed European descent and are not consanguineous. According to the laboratory, the worldwide carrier frequency is 1/500 and their method detects 90% of carriers. Her husband had negative carrier testing through their laboratory. What is the couple’s chance of having a child with congenital HAX1- related Neutropenia? Show your work (4)
Husband carrier Husband not carrier Apriori 1/500 499/500 Condition (neg test) 1/10 1 Joint 1/5000 4990/5000 Posterior 1/5000 / 1/5000 +4990/5000 = 1/4991
Chance of affected child = 1X 1/4991 X ¼ = 1/19964
Spring 2021
In a study of aniridia, an autosomal dominant disorder due to heterozygous mutations in PAX6, a researcher found that 14 babies among a population of 750,000 live births had this condition (i.e. a congenital absence of all or part of the iris). On examining the parents, 6 were found to have similar findings, the other parents were completely normal.
a) If we assume these aniridia mutations to be completely penetrant, what did the researcher estimate the mutation rate of the wild type normal allele to an aniridia allele to be in this population? (2)
b) Further studies indicated that 1 child with aniridia and normal parents developed Wilms tumour and intellectual disability. Another child with aniridia and normal parents developed ataxia and intellectual disability, a pattern of findings indicative of an autosomal recessive disorder. Should these findings encourage the researcher to review her estimation of mutation rate? Why? What is the new mutation rate if an adjustment is required? (4)
a) Potentially 8 new dominant mutations in 750,000 x 2 alleles available to mutate. Mutation rate = 8/1,500,000 or 5.3/1,000,000.
b) Yes for the first case, it should be excluded from the calculation of the mutation rate (0.5). Wilms tumor and aniridia and ID is indicative of a deletion of 11p13 that includes both the WT and PAX6 genes (WAGR syndrome). This case is due to loss of heterozygosity not a new mutation of the PAX6 locus (which is what we are being asked to calculate) (1). Yes for the second case, it should be excluded as well (0.5). It is caused by autosomal recessive mutations at a different locus (ITPR1, Gillespie syndrome) (1). New mutation rate is 6 new mutations/1,500,000 alleles or 4/1,000,000 (1)
