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Cosegregation Analysis program help

Introduction.

We have developed an easy to use method which calculates the likelihood ratio (LR) of an unclassified variant in BRCA1 or BRCA2 to be deleterious. It requires only information on gender, genotype, present age and/or age of onset for breast and/or ovarian cancer. Although co-segregation analysis on itself is in most cases insufficient to prove pathogenicity of an UV, this method simplifies the use of co-segregation as one of the key features in a multifactorial approach considerably.

Input.

A table is made based on the pedigree of the family.
Create a table with 10 columns (see below for example).
These columns respectively contain:

  1. Person ID
  2. Father ID (0 if there is no father)
  3. Mother ID (0 if there is no mother)
  4. 1 for proband and 0 for others
  5. Current age (if ages are unknown, estimations can be made for each generation, based on the mean age of this generation)
  6. Gender (1=male, 2=female, 9=unknown)
  7. Age of onset of the first breast cancer (0 if there is no breast cancer)
  8. Age of onset of the second breast cancer (0 if there is no 2nd breast cancer)
  9. Age of onset of ovarian cancer (0 if there is no ovarian cancer)
  10. Genotype (0 non-carrier, 1 carrier and 2 for unknown genotypes)

For an example look at figure 2 from the manuscript:

Pedigree of 13 people with ages (of onset).

The corresponding matrix:

Person IDFather IDMother IDProbandAgeGender Age of onset BCAge of onset 2nd BCAge of onset OCGenotype
1560602354301
29100622515101
30008510002
40006020002
53409110002
60007020002
73408510002
80007520002
93307910002
100007920002
1178060253001
12910055250001
139101502313801

Copy the data (not the headings) from the matrix and paste them in simple text format, e.g. notepad.

Notepad screenshot.

Save the file as follows:

File name* FamilyID_BRCA1.ped or FamilyID_BRCA2.ped
Save as type All files
Encoding ANSI

*Use BRCA1 or BRCA2 depending on the gene in which the variant is located.

Gene selection.

Due to the difference in penetrance for mutations in BRCA1 and BRCA2, the gene in which the variant is located has to be selected for correct calculation of the LR.

Literature.

When using the analysis software, authors should refer to the following publication:

A simple method for co-segregation analysis to evaluate the pathogenicity of unclassified variants; BRCA1 and BRCA2 as an example. Leila Mohammadi, Maaike P. Vreeswijk, Rogier Oldenburg, Ans van den Ouweland, Jan C. Oosterwijk, Annemarie H. van der Hout, Nicoline Hoogerbrugge, Marjolijn Ligtenberg, Margreet G.Ausems, Rob B. van der Luijt, Charlotte J. Dommering, Jan J.Gille, Senno Verhoef, Frans B. Hogervorst, Theo A.van Os, Encarna Gómez García, Marinus J. Blok, Juul Th. Wijnen, Peter Devilee, Christi J. van Asperen and Hans C. van Houwelingen. Submitted for publication.

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