Quantification of homozygosity in consanguineous individuals with autosomal recessive disease

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 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 homon zygous 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 similar to 5% over and above that predicted by simple models of consanguinity. This has important clinical and research implications.