Quantification of homozygosity in consanguineous individuals with autosomal recessive disease

Abstract

Individuals born of consanguineous union have segments of their genomes that are homozygous as a result of inheriting identical ancestral genomic segments through both parents. One consequence of this is an increased incidence of recessive disease within these sibships. Theoretical calculations predict that 6% (1/16) of the genome of a child of first cousins will be homozygous and that the average homozygous segment will be 20 cM in size. We assessed whether these predictions held true in populations that have preferred consanguineous marriage for many generations. We found that in individuals with a recessive disease whose parents were first cousins, on average, 11% of their genomes were homozygous (n = 38; range 5%-20%), with each individual bearing 20 homozygous segments exceeding 3 cM (n = 38; range of number of homozygous segments 7-32), and that the size of the homozygous segment associated with recessive disease was 26 cM (n = 100; range 5-70 cM). These data imply that prolonged parental inbreeding has led to a background level of homozygosity increased approximately 5% over and above that predicted by simple models of consanguinity. This has important clinical and research implications.

Figure 1

A, The size of the disease-associated homozygous segment in each of 100 individuals who have an autosomal recessive disease and whose parents are related. For these 100 individuals, the disease-associated homozygous segment was fully defined by flanking heterozygous markers. The degree of parental consanguinity is given for each individual on the X-axis. Offspring of double–first cousins would be expected to have 1/8 of the genome homozygous; first cousins, 1/16; first cousins once removed, 1/32; second cousins, 1/64; and third cousins, 1/256. B, The calculated total autosomal homozygosity for Pakistani and Arab individuals affected by autosomal recessive disease whose parents were related (n=48). C, The number of homozygous segments found in each of the Pakistani and Arab individuals shown in panel B.

Figure 2

A, The distribution of size of disease-associated homozygous regions for 100 individuals whose parents were first cousins and who have an autosomal recessive disease for which the locus was known. The size of the segment is given in 5-cM increments. B, The ranked ordered lengths of homozygous segments, shown in panel A, surrounding the causal disease locus plotted against the corresponding quantiles of a χ² distribution with 4 df. The line is calculated so that it passes through the median length. C, The distribution of size of all homozygous segments found in the 38 individuals from family set 1 whose parents were first cousins and who have an autosomal recessive disease. The size of the segment is given in 5-cM increments.

Figure 3

Ideogram of human chromosomes illustrating the position and size of the homozygous segments of one study individual. Homozygous segments are shown in red. The arrow indicates the recessive disease–associated homozygous segment. The individual was male, so the X and Y chromosomes would be expected to give homozygous results at all test SNP loci; this was the case for the X chromosome but was not assessed for the Y. Since this “homozygosity” between the X and Y chromosomes is the result of hemizygosity, it is not shown on the ideogram (University of Manitoba Department of Plant Science).