Quantification of Homozygosity in Consanguineous Individuals with Autosomal Recessive Disease

• Published in: American journal of human genetics Vol. 78; no. 5; pp. 889 - 896
• Main Authors: Woods, C. Geoffrey, Cox, James, Springell, Kelly, Hampshire, Daniel J., Mohamed, Moin D., McKibbin, Martin, Stern, Rowena, Raymond, F. Lucy, Sandford, Richard, Malik Sharif, Saghira, Karbani, Gulshan, Ahmed, Mustaq, Bond, Jacquelyn, Clayton, David, Inglehearn, Chris F.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.05.2006; University of Chicago Press; Cell Press; The American Society of Human Genetics
• Subjects: Biological and medical sciences; Chromosome Disorders; Consanguinity; Families & family life; Foot Deformities, Congenital; General aspects. Genetic counseling; Genes, Recessive; Genetic Diseases, Inborn; Genetic Linkage; Genomics; Homozygote; Humans; Inbreeding; Lod Score; Male; Medical genetics; Medical research; Medical sciences; Microsatellite Repeats; Mutation; Pedigree; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Studies; Human; Autosomal character; Quantization; Recessive character; Genetics; Qualitative analysis; Consanguinity; Homozygosity; Quantitative analysis; Genetic disease
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/503875

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 ∼5% over and above that predicted by simple models of consanguinity. This has important clinical and research implications.