Case 3 - SMA carrier risk calculation - Results

Mating type method

This method is illustrated as an alternative to the gamete square method. The gamete square method may be the method you would choose to use on a routine basis, but if you find the method difficult at first, you may find the logic in the mating type method easier to follow - even if somewhat longer.

The calculations are provided on the downloadable spreadsheets. As before, two calculations are provided - with either rounded genotype frequencies for an easier calculation, or unrounded frequencies. On this page, further information is provided to explain the steps in the calculations (using rounded allele frequencies).

Go to downloadable spreadsheets with rounded and unrounded allele frequency calculations.

Rounded allele frequencies - further information

The approach is to examine every possible mating type, determine the likely frequency of each mating type, and then examine the segregation products in each case. As in the gamete square method, the final carrier risk figure is determined by examining which segregation products have SMN1 copy number compatible with MLPA results, and the proportion of these with carrier status.

1. Initial assumptions. As before, the possibility of new mutations is not considered, and the possibility of alleles which are deleted for SMN1, but have multiple copies of SMN2 and mask clinical disease is not considered.

2. Prior knowledge of parental genotypes, and determining likely frequencies.
a) Parent 1: We know from the MLPA result in II2 (2x dosage) that one parent (nominated ‘parent 1’) must be a heterozygous carrier of an SMN1 deletion. Because this parent is also clinically unaffected, the opposite allele must be ‘normal’, although it may have either 1 or 2 copies of SMN1. Therefore, parent 1 must have one of 2 genotypes: del/n1 or del/n2 (see figure 1). The relative likelihood of these genotypes is equal to the relative frequencies of n1 and n2 in the population.
b) Parent 2: We also know from II2’s MLPA result that at least one of the alleles in parent 2 must be ‘normal’ and with a single copy of SMN1 (n1). We know nothing about the other allele in parent 2 (if for the moment we ignore knowledge of clinical status in II3). Therefore, the genotype of parent 2 could be any of the following: n1/del, n1/n1 or n1/n2. The relative likelihood of these genotypes is equal to the relative frequencies of the 3 alleles in the population (1:95:4).

Figure 1. Pedigree drawing, showing possible genotypes for parents of II2.

3. Examining segregation products – genotypes and frequencies. All possible zygote genotypes are determined by examining the four separate segregation products from each mating type. The zygote frequencies are determined by multiplying the likely frequencies of the parental genotypes together, and then again by 0.25 (as there are four segregation products). The clinical status and copy number of SMN1 is noted.

Figure 2. Illustration of segregation products from mating type del/n1 x n1/n2

4. Final calculation stage. The segregation products are examined, and those compatible with MLPA analysis in II3 (2x dosage) are highlighted. Those which are carriers are highlighted in yellow on the spreadsheets, while non-carriers are highlighted in green. Thus the carrier risk for II3 can be calculated from the sum of non-carriers, divided by all unaffecteds compatible with 2x dosage.

The final figures produced by the mating type method are identical to those produced by the gamete square method.

Spreadsheets for download with calculations

    Rounded allele frequencies - download spreadsheet

    Unrounded allele frequencies - download spreadsheet

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