Costain
Interpreting rare inherited CNVs
1
Table S1. Application of standard Bayesian analysis methodsa to determine the expected
probability of a transmitting parent with genetic variant g having disease X.b
Hypothesis
Has disease X
Does not have disease X
Prior probability
P
1 P
Conditional probability of having a child
f
1
P f
1 P
P f
P  f  (1  P)
1 P
P  f  (1  P)
Joint probability
Posterior probability
Symbol legend:
g = rare autosomal dominant-acting genetic variant
X = disease of interest
P = penetrance of the genetic variant g for disease X, where 0 < P < 1
f = relative reproductive fitness of individuals with the genetic variant g and with disease X
(compared to individuals with g and without X), where 0 < f < 1
a
See 1 for details regarding the general Bayesian approach used here. Other authors have also
considered risk estimation in the case of incompletely penetrant autosomal dominant disorders.2-8
b
In this simple model, the potential impact of (i) sex differences in reproductive fitness, (ii)
assortative mating, (iii) additional information bestowed by multiparity, (iv) imprinting and
parent-of-origin effects, (v) age, and (vi) other potential confounders are not considered.
Supplemental
Costain
Interpreting rare inherited CNVs
2
Table S2. Probability of disease X in transmitting parent with genetic variant g, for different values of penetrance P and relative
fitness f.a
Penetrance P of genetic
variant g for disease X
(%)
5
10
15
20
25
30
35
40
45
50
75
a
Relative fitnessb f associated with disease X in a population with genetic variant g (%)
1
2
0.1
0.1
0.2
0.2
0.3
0.4
0.5
0.7
0.8
1.0
2.9
5
0.1
0.2
0.4
0.5
0.7
0.8
1.1
1.3
1.6
2.0
5.7
10
0.3
0.6
0.9
1.2
1.6
2.1
2.6
3.2
3.9
4.8
13.0
25
0.5
1.1
1.7
2.4
c
3.2
4.1
5.1
6.3
7.6
9.1
23.1
50
1.3
2.7
4.2
5.9
7.7
9.7
11.9
14.3
17.0
20.0
42.9
75
2.6
5.3
8.1
11.1
14.3
17.6
21.2
25.0
29.0
33.3
60.0
3.8
7.7
11.7
15.8
20.0
24.3
28.8
33.3
38.0
42.9
69.2
See Table S1 and Equation 1 in the main text for details.
b
Fitness relative to those in the population with genetic variant g and without disease X.
c
Entry corresponds to the worked example regarding 22q11.2 deletions and schizophrenia in the main text, where only ~3% of
transmitting parents with 22q11.2DS would be expected to have schizophrenia.
Supplemental
Costain
Interpreting rare inherited CNVs
3
Supplemental references
1.
Young ID: Introduction to risk calculation in genetic counselling, 2nd edn. New York,
NY: Oxford University Press, 1999.
2.
Stevenson AC, Davison BCC, Oakes MW: Genetic counselling, 2nd edn. Philadelphia:
Lippincott, 1976.
3.
Aylsworth AS, Kirkman HN: Genetic counseling for autosomal dominant disorders with
incomplete penetrance. Birth Defects Orig Artic Ser 1979; 15: 25-38.
4.
Pauli RM, Motulsky AG: Risk counselling in autosomal dominant disorders with
undetermined penetrance. J Med Genet 1981; 18: 340-343.
5.
Friedman JM: Genetic counseling for autosomal dominant diseases with a negative
family history. Clin Genet 1985; 27: 68-71.
6.
Emery AE: Risk estimation in autosomal dominant disorders with reduced penetrance. J
Med Genet 1986; 23: 316-318.
7.
Otto PA, Maestrelli SR: Heterozygosity probabilities for normal relatives of isolated
cases affected by incompletely penetrant conditions and the calculation of recurrence
risks for their offspring. I. Autosomal dominant genes. Am J Med Genet 2000; 95: 43-48.
8.
Ogino S, Wilson RB, Gold B, Flodman P: Bayesian risk assessment in genetic testing for
autosomal dominant disorders with age-dependent penetrance. J Genet Couns 2007; 16:
29-39.
Supplemental